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Test #3 - This one Shawna!!!

Test #3 - This One Shawna!!!

by xxxj, Sep. 2009

Subjects: 5 6 7 8 biochemistry shawna week

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	First Law of Thermodynamics	"Energy can be transformed (changed from one form to another), but it can neither be created nor destroyed"
	Second Law of Thermodynamics	Entropy The energy available after a chemical reaction is less than that at the beginning of a reaction, energy conversions are not 100% efficient.
	Endergonic	Reactant has less energy than product, thus you use E to make product
	Exergoinc	Reactant has more energy than product, thus E is released during reaction Spontaneous; energy releasing
	What helps lower the E barrier of an exergonic reaction?	enzyme: it helps organize substrates to their max orientation.
	Example of an exergonic reaction in metabolism?	Glycolysis
	What is a calorie?	the quantity of heat needed to raise the temperature of 1 kg of water 1 degree C
	1g of fat has how many Cal?	9
	1 g of carbs has how many Cal?	4
	1 g of protein has how many Cal?	4
	What is an oxidation reaction?	Loss of electrons
	What is a reduction reaction?	Gain of electrons
	What is the equation for cellular respiration?	C6H12O6 + 6O2 --> 6CO2 + 6H2O + ATP
	What is being oxidized in cellular respiration?	glucose, since it will lose electrons
	What does glucose become once it is oxidized?	Carbon dioxide
	What is being reduced during respiration?	Oxygen because it will ultimately gain electrons
	What does reduced oxygen become in respiration?	Water
	What vitamin is NADH/NAD+ made from?	Niacin
	What is one of the key carriers in metabolism?	NADH/NAD+
	What does NADH do in metabolism?	It picks up an e- and takes it to the electron transport chain (NAD+ picks up e- and becomes NADH)
	What is the most common electron carrier in biological redox reactions?	NAD+
	resting lactate levels?	1 mm/L
	What are the carbon sources for gluconeogenesis?	Lactate and Alanine
	Catabolism is typically oxidative or reductive?	Oxidative and thus requires NAD+ as a coenzyme.
	Three stages of catabolism	1. Hydrolysis of complex molecules 2. Conversion of building blocks to acetyl CoA (some E is captured in the form of ATP but it is small in comparison to Stage 3) 3. Oxidation of acetyl CoA; oxidative phosphorylation. (TCA is the final common pathway in the oxidation of fiel molecules and large amounts of ATP are generated as electrons flow from NADH and FADH2 via oxidative phosphorylation.
	Catabolism is divergent or convergent? What about anabolism?	Catabolism is convergent because a variety of molecules get converted into a few common end products. Anabolism is divergent because a few precursors form a wide variety of products.
	What are the regulatory signals that inform an individual cell of the metabolic state of the body as a whole?	Hormones NTs availability of nutrients
	What does adenylyl cyclase do?	Converts ATP to cAMP.
	What are the receptors for adenylyl cyclase?	Beta and alpha2-adrenergic receptors
	What is the big picture of glycolysis? What does it do on the largest of scales?	It is a pathway that is employed by all tissues for the breakdown of glucose to provide energy in the form of ATP and intermediates for other pathways.
	What is the end product of aerobic glycolysis?	pyruvate
	What is the difference between the first 5 rxns of glycolysis and the subsequent rxns?	The first 5 (stage 1) correspond to an energy investment phase in which the phosphorylated forms of intermediates are synthesized at the expense of ATP. The subsequent reactions constitute an energy generation phase.
	Can phosphorylated sugar molecules penetrate the cell membrane?	No because there are no specific transmembrane carriers for these compounds and they are too polar to diffuse through the cell membrane.
	What happens to glucose 6-phosphate as a result of phosphorylization by hexokinase?	it becomes trapped in the cytosol and is thus committed to further metabolism.
	Three regulatory enzymes of glycolysis	Hexokinase Phosphofructokinase Pyruvate Kinase
	PFK1 inhibited by?	High ATP levels Citrate
	PFK1 activated by?	High levels of AMP Most potent: F2,6P
	What does PFK2 do?	forms fructose 2,6, bisphosphate, which activates PFK1
	What happens to F2,6P during the well-fed state?	The decreased levels of glucagon and elevated levels of insulin cause an INCREASE in F2,6P and thus in the rate of glycolysis. Thus, F2,6P acts as an intracellular signal, indicating that glucose is abundant.
	What happens to F2,6P during the starved state?	The elevated levels of glucagon and low levels of insulin decreased the intracellular [F2,6P] and thus decreases the overall rate of glycolysis and an increase in gluconeogenesis.
	Products of reaction catalyzed by aldolase?	dihydroxyacetone phosphate and glyceraldehyde 3-phosphate.
	Two major mechanisms of oxidizing NADH	1. NADH-linked conversion of pyruvate to lactate (anerobic) 2. oxidation of NADH via the respiratory chain
	What does pyruvate kinase do?	Converts PEP into pyruvate in an ATP favoring reaction
	What is an example of feed-forward regulation in glycolysis?	Activation of pyruvate kinase by 1,6BP.
	What does NADH production exceeding oxidative capacity of respiratory chain result in?	This occurs in exercising skeletal muscle and results in elevated NADH/NAD+ ration, favoring the reduction of pyruvate to lactate.
	What does the direction of the lactate dehydrogenase rxn depend on?	The relative intracellular concentrations of pyruvate and lactate as well as the NADH/NAD+ ratio.
	What is lactic acidosis? When does it occur?	elevated concentrations of lactate in the plasma. Occurs when there is a collapse of the circulatory system and there is a failure to rbing adequate amounts of O2 to the tissues - cells use anaerobic glycolysis to survive.
	Energy yield from anaerobic glycolysis	2 ATP for each molecule of glucose.
	Net consumption of NADH in anaerobic glycolysis	None.
	Energy yield of aerobic glycolysis.	2 ATP
	Net consumption of NADH in aerobic glycolysis	2 NADH produced
	How many ATP produced per molecule of NADH in ongoing glycolysis?	3 ATP per NADH
	What is oxidative carboxylation?	Performed by the pyruvate dehydrogenase complex, it irreversibly converts pyruvate to acetyl CoA.
	What does pyruvate carboxylase due?	converts pyruvate to OAA
	What does the pyruvate dehydrogenase complex do?	After pyruvate has been transported into the mito, it converts it to ACoA.
	What are the enzymes of the PDC?	Multimolecular aggregate of three enzymes: pyruvate dehydrogenase, dihydrolipoyl transacetylase, and dihydrolipoyl dehydrogenase. In addition to these enzymes participating in the actual conversion, there are two tightly bound regulatory enzymes: pyruvate dehydrogenase kinase and pyruvate dehydrogenase phosphotase.
	What are the co-enzymes of the pyruvate dehydrogenase complex?	Thiamine pyrophosphate Lipoic Acid CoA FAD NAD+
	What clinical problems can arise from a thiamin or niacin deficiency? Why?	serious central nervous system problems. This is because brain cells are unable to produce sufficient ATP (via the TCA) for proper function if the PDC is inactive.
	What inhibits the PDC?	A cAMP dependent kinase that is tightly bound to the complex.(Phosphorylation)
	What activates PDH kinase that inhibits the PDC?	ATP, acetyl CoA, NADH
	What is a potent inhibitor of the PDH kinase?	pyruvate
	What activates the PDC?	PDH phosphotase (dephosphorylation)
	What is the most common biochemical cause of congenital lactic acidosis?	a deficiency in E1 component of the PDC
	What is arsenic poisoning due primarily to?	Inhibition of enzymes that require lipoic acid as a cofactor.
	What is the mechanism of arsenic?	Arsenite forms a stable complex with the thiol of lipoic acid
	What does citrate synthase do?	Condenses OAA and ACoA to form citrate
	What inhibits citrate synthase?	Citrate, NADH, succinyl CoA
	What does aconitase do?	Isomerizes citrate to isocitrate
	What does isocitrate dehydrogenase do?	irreversible oxidative decarboxylation of isocitrate to alpha-ketoglutarate.
	What is the rate-limiting step of the TCA cycle?	Isocitrate dehydrogenase (conversion of isocitrate to alpha-KG)
	What inhibits isocitrate dehydrogenase?	ATP and NADH
	At what step is the first NADH of the TCA cycle produced?	Isocitrate dehydrogenase
	At what step is the first CO2 of the TCA cycle produced?	Isocitrate dehydrogenase.
	What does the alpha-ketoglutarate complex do?	Converts alpha-KG to succinyl CoA
	What is the alpha-ketoglutarate complex inhibited by?	ATP, NADH, GTP, succinyl CoA
	What is the alpha-ketoglutarate complex activated by?	Ca
	At what step is the second NADH released?	Alpha-ketoglutarate complex
	At what step is the second CO2 released?	Alpha-KG Complex
	What are the coenzymes of the alpha-KG complex?	Lipoic Acid NAD+ FAD+ CoA Thiamine
	What does succinate thiokinase do?	Converts succinyl CoA to succinate.
	At what step is the GTP produced in the TCA cycle?	Succinyl thiokinase
	What does succinate dehydrogenase do?	oxidizes succinate to fumarate
	Where is the FADH2 formed in the TCA cycle?	Succinate dehydrogenase
	What is the only TCA cycle enzyme that is embedded in the inner mito membrane?	Succinate dehydrogenase
	What does fumarase do?	Converts fumarate to malate.
	What does malate dehydrogenase do?	converts malate to OAA
	QWhere is the third NADH of the TCA cycle released?	Malate dehydrogenase
	Number of ATP molecules produced from the oxidation of one molecule of acetyl CoA	3 NADH --> 3 NAD = 9 ATP FADH2 --> FAD = 2 ATP GDP + P --> GTP = 1 ATP TOTAL: 12 ATP
	Net number of ATPs for cellular respiration	Glycolysis: 6 or 8 depending on the malate shuttle use. Krebs: 12 Oxidative carboxylation of pyruvate to ACoA: 6 Total: 36-38
	Three main precursors of gluconeogenesis?	glycerol, lactate, amino acids
	What is the Cori cycle?	Bloodborne glucose is converted by exercising muscle to lactate, which diffuses into the blood. This lactate is taken up by the liver and reconverted to glucose which is released back into the circulation.
	What does pyruvate carboxylase do in gluconeogenesis?	Carboxylates pyruvate to OAA
	Where does pyruvate carboxylase of gluconeogenesis work?	In the mito of liver and kidney cells
	What is pyruvate carboxylase of gluconeogenesis activated by?	Allosterically activated by ACoA
	What coenzyme is required by pyruvate carboxylase of gluconeogenesis?	Biotin
	What are the two main purposes of the reaction catalyzed by pyruvate carboxylase of gluconeogenesis?	1. provide important substrate for gluconeogensis 2. provide OAA that can replenish the TCA cycle
	What cycle does PEP-carboxykinase work in? What does it do?	It works in gluconeogenesis and converts OAA to PEP
	Where is PEP-carboxykinase of gluconeogenesis found? Explain this.	In both the cytosol and mito. The PEP that is formed in the mito is transported out. If it is formed in the cytosol it requires that OAA be moved out of the mito into the cytosol. OAA is unable to cross the mito by being converted to malate by dehydrogenase. Malate then crosses into the cytosol and is reconverted into the cytosol and is reconverted back in OAA by malate dehydrogenase.
	What does PEP-carboxykinase of gluconeogenesis do?	Decarboxylates and phosphorylates OAA to PEP
	Where does PEP-carboxykinase work in the cell? Does it have an energy requirement?	Cytosol. Yes it uses a GTP.
	What does Fructose1,6-bisphosphotase of gluconeogenesis do?	Turns F1,6BP into fructose 6-phosphate
	What inhibits Fructose-1,6-bisphosphotase gluconeogenesis?	Elevated levels of AMP (which signal an "energy-poor" state in the cell) and F2,6BP
	What activates Fructose 1,6-bisphosphotase of gluconeogenesis?	High levels of ATP and low [AMP]
	What does Glucose 6-phosphotase of gluconeogenesis do?	hydrolyzes glucose 6-phosphate into free glucose.
	Where in the body does Glucose 6-phosphate work?	Liver and Kidney are the only organs to release free glucose from G6P
	What is Type 1a glycogen storage disease caused by?	It is in an inherited deficiency of glucose-6-phosphotase.
	What is Type 1a glycogen storage deficiency characterized by? Why?	Severe fasting hypoglycemia because free glucose is unable to be produced from gluconeogenesis or glycogenolysis.
	What are the three gluconeogenesis enzymes that circumvent the irreversible reactions of glycolysis?	Glucose 6-phosphotase (circumvents hexokinase activity), Fructose 1,6-bisphosphotase (circumvents PFK1) and pyruvate carboxylase/PEP-carboxykinase (circumvents pyruvate kinase)
	What is the momentary regulation of gluconeogenesis determined by?	The circulating levels of glucagon and the availability of gluconeogenic substrates.
	What are the ways that glucagon stimulates gluconeogenesis?	1. Lowers levels of F1,6BP, resulting in activation of F1,6BPhosphotase and inhibits of PFK 2. Stimulates phosphorylation of pyruvate kinase (which makes it inactive) 3. Increases transcription of PEP-carbxoykinase
	What three primary sources can blood glucose come from?	the diet, degradation of glycogen, and gluconeogenesis.
	Where are the main stores of glycogen found in the body?	Skeletal muscle and liver, although most other cells store small amounts of glycogen for their own use.
	What is the purpose of stored muscle glycogen?	serve as fuel reserve for the synthesis of ATP during muscle contraction
	What is the purpose of stored liver glycogen?	maintain the blood glucose concentration, particularly during the early stages of a fast.
	Describe the structure of glycogen?	branched-chain homopolysaccaride made exclusive from alpha-D-glucose. The primary glycosidic bond is an alpha(1-->4) linkage. After an average of 8-10 glycosyl residues, there is a branch containing a alpha(1-->6) linkage.
	What is depleted faster: muscle or liver glycogen?	Liver glycogen fluctuates much more easily with dietary changes. Muscle glycogen is not affected by short periods of fasting (a few days)
	Where in the cell does glycogen synthesis occur?	cytosol
	What is the source of all the glucosyl residues that are added to the growing glycogen molecule? (specifically)	alpha-D-glucose attached to UDP (UDP-glucose)
	What does the elongation of a glycogen chain involve?	Transfer of glucose from UDP-glucose to the nonreducing end of a growing chain.
	What end of the growing glycogen chain is glucose from UDP-glucose added?	The nonreducing end
	Where is the glycosidic bond of glycogen formed during elongation?	The anomeric hydroxyl of C1 of the activated glucose and C4 of the accepting glucosyl residue.
	If the glycogen branching enzyme didn't work on animal glycogen, what compound would result?	Amylose (found in plants)
	Main regulatory enzyme is glycogen synthesis?	Glycogen synthase
	What are the benefits of branching glycogen?	makes it much more soluble than amylose, and increases the number of non-reducing ends to which new glucosyl residues can be added (which increases the rate of glycogen synthesis and degradation)
	What does phosphoglucomutase do?	Converts glucose 6-phosphate to glucose 1-phosphate
	What does UDP-glucose pyrophosphorylase do?	Synthesizes UDP-glucose for glycogen syntehsis
	What does glycogen synthase do?	It is responsible for making the alpha(1-4) linkages.
	What is glycogenin? What does it do? Why do we have glycogenin?	It is a protein that can serve as an acceptor of glucose residues from UDP-glucose. We need glycogenin because glycogen synthase can only elongate existing chains of glucose.
	What does nucleotide diphosphate kinase do?	Converts UDP back to UTP after the addition of glucose to glycogen from UDP-glucose
	What is the branching enzyme called? What does it do?	amylo-alpha(1-4) --> alpha(1-6) transglucosidase. It transfers a chain of 6-8 glucosyl residues from the nonreducing end of the glycogen chain, breaking an alpha(1-4) bond to another residue on the chain and attaches it to an alpha(1-6) linkage.
	What is the primary product of glycogenolysis?	glucose-1-phosphate
	What results from breaking the alpha(1-4) glycosidic bonds of glycogen?	glucose-1-phosphate
	What results from breaking the alpha(1-6) glycosidic bonds of glycogen?	free glucose
	What does glycogen phosphorylase of glycogenolysis do? What are the products?	Sequentially cleaves the alpha(1-4) glycosidic bonds between glucosyl residues. Produces glucose 1-phosphate and dextrin.
	Required coenzyme of glycogen phosphorylase?	pyridoxal phosphate - it is covalently bonded to the enzyme
	What is dextrin?	the four glucosyl unit structure that remain on glycogen - phosphorylase cannot continue to cleave the bonds past this point.
	What is the debranching enzyme? What does it do?	A bifunctional protein with two enzymatic functions. Oligo removes the outer three of the four glucosyl residues attached at a branch. It then transfers it to another chain and lengthens it. A alpha(1-4) is broken and then remade, so it is a 4:4 transferase. The remaining single glucose residue attached in an alpha(1-6) linkage is removed by amylo, which releases a free glucose.
	What does phosphoglucomutase of glycogenolysis do?	Converts G1P to G6P
	Where in the body does the glycogenolysis enzyme glucose-6-phosphotase work? What does it do?	Works in the Liver ER. It converts G6P to free glucose. This is the same enzyme that is used in the last stage of gluconeogenesis
	What happens to the glucose formed from G6P in the liver ER by glucose-6-phosphotase?	It is transported out of the ER into the cytosol. Hepatocytes release glycogen-derived glucose into the blood to help maintain blood glucose levels until the gluconeogenic pathway is actively producing glucose.
	What happens to G6P from glycogenolysis in muscle?	Because muscle doesn't contain glucose-6-phosphotase, G6P goes straight into glycolysis to provide E for muscle contraction.
	What is acid maltase (alpha(1-4)glucosidase)	It is a lysosomal enzyme that degrades 1-3% of glycogen.
	What does deficiency of acid maltase cause?	Accumulation of glycogen in the lysosomes, resulting in Type 2 glycogen storage.
	What causes Type 2 glycogen storage disease?	a deficiency in acid maltase
	In the liver, when does glycogen synthesis accelerate?	During periods when the body has been well fed.
	In the liver, when does glycogen degradation accelerate?	During periods of fasting.
	In skeletal muscle, when does glycogen degradation occur?	During active exercise
	When does glycogen synthesis occur in skeletal muscle?	As soon as the muscle is again at rest.
	What are the two levels that glycogen metabolism is accomplished?	1. Glycogen synthase and glycogen phosphorylase are allosterically controlled? 2. The pathways of glycogen metabolism are hormonally regulated.
	How does the well fed state affect glycogen synthase?	It is allosterically activated by G6P when it is present in high []
	What inhibits glycogen phosphorylase? In liver?	G6P, ATP Liver - glucose
	What protein related to glycogen metabolism is affected by the Ca-Calmodulin complex?	phosphorylase kinase. It is activated by the complex.
	What is the effect of Ca in muscles on glycogen metabolism?	Activates glycogen degradation. Ca binds to calmodulin and forms a Ca-Calmodulin complex which activates phosphorylase kinase, which then phosphorylates glycogen phosphorylase, thus activating it.
	What happens to glycogen phosphorylase when phosphorylated?	It is activated.
	During extreme conditions of anoxia and ATP depletion, how is glycogen phosphorylase activated?	high [AMP] - does not need to be phosphorylated
	What effect does the binding of hormones like glucagon and ephinephrine to membrane receptor signal the need for? (glycogen synthesis or degradation?)	Degradation - either to elevate blood glucose levels or to provide energy to exercising muscle
	Is phosphorylated glycogen synthase active or deactivated?	It is inactive. The conversion from one form to another is catalyzed by several different protein kinases that are regulated by cAMP or other signaling mechanisms.
	What is the structure of a bile salt?	Sterol ring with a side chain to which a molecule of glycine or taurine is covalently attached by an aminde linkage.
	The TAG, cholesteryl esters, and phospholipids are enzyimatcially degraded by the enzymes of what organ?	Pancreatic
	What does pancreatic lipase do?	Preferentially removes the fatty acids of a TAG at C1 and C3
	What is CCK?	Cholecystokinin - it is a peptide hormone secreted by the cells in the mucosa of the jejunum and lower duodenum in response to the presence of lipids and partially digested proteins entering these regions of the upper intestine.
	What does CCK do?	It acts on the gallbladder, causing it to contract and secrete bile and on the exocrine cells of the pancreas, causing them to release digestive enzymes.
	What are the primary products of lipid digestion in the jejunum?	Free fatty acids, free cholesterol, 2-monoacylglycerol
	What forms micelles?	The primary products of lipid digestion (fatty acids, cholesterol, 2-monoacylglycerol), bile salts, and fat-soluble vitamins
	What are micelles?	disk-shaped clusters of amphipathic lipids that coalesce with the hydrophobic groups on the inside and their hydrophillic groups on the outside.
	How are plasma free fatty acids trasported?	Serum albumin
	At physiological pH, what does the carboxyl group on the end of a fatty acid do?	It ionizes (COO-)
	Humans and primates are among the few mammals that can't synthesize which vitamin?*	Vitamin C
	Sailors carried limes on board to avoid which vitamin deficiency?*	Scurvy
	Vit C is the key reducing agent in which carrier?*	Carnitine
	Why do burn patients require Vit C?*	Because Vit C is required post translationally for collagen synthesis.
	Relationship between Vit C and iron?*	Vit C enhances non-heme iron absorption
	Which Vitamin status can be assessed by measuring transketolase activity in the erthrocyte?*	Thiamin
	To assess Riboflavin status the activity of erythrocyte glutathione reductase is measured because it requires which of the following co enzymes?*	FAD
	Aside from obtaining Niacin from dietary sources it can be made in the liver from which amino acid?*	Alanine
	Which vitamin has been used to treat hypercholesterolemia?*	Niacin
	Pantothenic acid is part of which compound that is common in the metabolism of all three energy producing macronutrients?*	Acetyl CoA
	The presence of avidin in raw eggs binds which of the following vitamins?*	Biotin
	Which of vitamin/s helps to heep homocysteine levels down?*	Folate and B12
	A vegan who consumes no fortified food products is at greatest risk for which vitamin deficiency?*	B12
	Intrinsic factor is needed for absorption of which vitamin/minerals?*	B12
	Unlike most water soluble vitamins, which vitamins can be stored in the body for long periods of time?*	B12
	Which vitamin is derived from a steroid?*	Vitamin D
	Which vitamin prevents free radical damage by donating its H ion to the free radical?*	Vitamin E
	Which mineral plays an important yet indirect role in antioxidant functions?*	Selenium
	Newborns are given a shot of what vitamin at birth?*	Vit K
	It is not a great idea to give kids milk with dinner because calcium interferes with the absorption of which mineral?*	Iron
	What are the two dietary essential fatty acids?	Linoleic acid and alpha-linoleic acid
	What can essential fatty acid deficiency result in?	scaly dermatitis as well as visual and neurologic abnormalities
	Where does fatty acid synthesis occur in the body of adult humans?	primarily in the liver and lactating mammary glands. To a lesser extent in adipose tissue.
	What is the first step in de novo fatty acid synthesis?	transfer of acetate units from mito ACoA to the cytosol
	How is mitochondrial ACoA produced?	oxidation of pyruvate and the catabolism of fatty acids, ketone bodies, and certain amino acids
	What happens to the glycerol released from TAG degradation in adipocytes?	Adipocytes lack glycerol kinase, so the glycerol is transported through the blood to the liver, where it can be phosphorylated. The resulting glycerol-P can be used to form TAG in the liver, or it can be converted to DHAP.
	What is the fate of the fatty acids that result from TAG breakdown in adipose tissue (in general)?	Thye move through the cell membrane of the adipocyte, and immediately bind to albumin. They are transported to the tissues, where the fatty acids enter cells, get activated to their CoA derivatives, and are oxidized for energy.
	Which two types of cells cannot use free fatty acids for E? Why?	RBCs because they have no mito Brain cells because of the BBB
	What does hormone sensitive lipase do?	hydrolytic release of fatty acids and glycerol from their TAG form. Removes a fatty acid from C1 and/or C3 of the TAG.
	How is hormone sensitive lipase activated?	PHOSPHORYLATION by 3,5-cAMP-protein dependent kinase
	What is hormone sensitive lipase inhibited by?	In the presence of high plasma levels of insulin and glucose, HSL is dephosphorylated and becomes inactive.
	General mechanism of B-oxidation of fatty acids? (What does it do?)	Catabolizes FAs by removing two-carbon fragments from the carboxy end of the fatty-acyl CoA, producing ACoA, NADH, and FADH2
	What does ACoA synthetase do? (Fatty acids)	Attachment of CoA which occurs on the on the cytoplastic face of the outer mitochondrial membrane
	How many ATP are used to convert free fatty acids to their activated CoA form?	2 ATP (ATP is hydrolsed to AMP and pyrophosphayte (PPi). Rapid hydrolysis of PPi to inorganic phosphate (Pi) by pyrophosphatase consumes a second "high energy" phosphate bond. Hydrolysis of these two high energy bonds drives the reaction. The energy change is so large that the reaction is irreversible.)
	Why is carnitine necessary to beta-oxidation of fatty acids?	The activated fatty acid must be transported across the mitochondrial membrane (which is impermeable to CoA). Carnitine is the carrier.
	What are the steps in activated fatty acid translocation into the mitochondria?	1. the acyl group (LCFA) is transferred from CoA to carnitine by carnitine acyl transferase I (CAT1). This regenerates free CoA. 2. The newly formed acylcarnitine is transported into the mito matrix in exchange for free carnitine by carinitine-acylcarnitine translocase. 3. Acyl-CoA is then reformed in the inner mito membrane by CAT2, thus regenerating free carnitine.
	What is carnitine acyltransferase1? Where is it located?	It is the enzyme of the outer mito membrane that transfers the acyl group from CoA to carnitine.
	What does carinitine-acylcarnitine translocase do?	It exchanges acylcarnitine for free carnitine in the mito matrix. Part of beta-oxidation of fatty acids
	Where is carnitine acyltransferase 2 located?	Inner mito membrane
	What two things inhibit the carnitine shuttle of beta-oxidation of FA?	1. Malonyl CoA inhibits CAT1. This is because when fatty acid synthesis is occurring in the cytosol (and thus malonyl CoA is present) the fatty acids cannot be transported into the mitochondria for degradation. 2. The acetyl-CoA/CoA ratio: as the ratio increases, the thiolast rxn decreases.
	What amino acids can carnitine be synthesized from?	Lysine and methionine
	What are the basic steps of the beta-oxidation reactions?	1. oxidation that produces FADH2 2. Hydration 3. Oxidation that produces NADH2 4. Thiolytic clevage that releases a molecule of ACoA
	What are the results of beta-oxidation of palmityol CoA?	7 NADH 7 FADH2 8 Acetyl CoA
	Describe the difference between beta-oxidation for even number chain and odd number chain fatty acids.	Beta oxidation is the same for odd # chains as for even # fatty acids, until we reach the final 3 carbons. Even number chains repeat the four steps of beta-oxidation (n/2)-1 times (where n is the number of carbons). The final thiolytic cleavage produces an extra ACoA. The final products of ODD NUMBER CHAIN are proinoyl-CoA and acetyl CoA
	According to lecture, what is the net ATP yield from beta-oxidation of palmitoyl CoA?	108
	What process are the diseases methylmalonic acidemia and aciduria associated with?	beta-oxidation of odd-number chain fatty acids. They both result in metabolic acidosis and developmental retardation.
	What are the steps to metabolized the final product of odd-chain fatty acid beta oxidation?	1. Synthesis of D-methylmalonyl CoA (requires biotin) 2. Formation of L-methylmalonyl CoA 3. Synthesis of succinyl CoA which can then enter the TCA cycle.
	What is alpha-oxidation for?	Branched fatty acids because the beta site is branched and thus acetyl-CoA dehydrogenase cant get to it
	According to lecture, what occurs during starvation or Type 1 diabetes in relation to fatty acid oxidation?	"Burn the fat instead of the carbs!"
	According to lecture, what is the only site for regulation of 'fat burn'?	Hormone sensitive lipase in adipose tissue.
	What activates Hormone Sensitive Lipase?	Epinephrine (low carb diet=low insulin=fat burn)
	What inhibits Hormone Sensitive Lipase?	Insulin (high carb diet =high insulin=block fat burn)
	According to lecture, how can training affect fat metabolism?	1. Aerobic training increases ability to oxidize fat 2. Trained muscles have higher uptake or improved transport across membrane of plasma FFA 3. higher carnitine levels 4. spares glycogen 5. Rely on fat as fuel to higher intensity
	Where can ketone bodies be synthesized? Why would they be synthesized?	Liver mitochondria have the capacity to convert ACoA derived from FA oxidation to ketone bodies. This usually occurs during starvation (times of high ACoA levels) Ketones are transported in the blood to peripheral tissues where they can be reconverted to ACoA for the TCA cycle.
	Why are ketones an important source of fuel for the peripheral tissues?	1. they are soluble in aqueous solution and therefore, do not need to be incorporated into lipoproteins or carried by albumin 2. they are produced in the liver during periods when the amt of ACoA present exceeds the oxidative capacity of the liver 3. they are used in proportion to their concentration in the blood by extrahepatic tissues (ie Brain)
	What are the three compounds that are classified as ketone bodies?	1. acetoacetate 2. beta-hydroxybutyrate 3. acetone
	What is ketosis?	A metabolic condition in which ketone bodies are produced faster than they are consumed by tissues and the smell of acetone (fruity) can be detected on the person's breath.
	What is ketoacidosis?	Occurs when there are too many circulating KB in the blood which leads to acidified blood. Blood pH <7.2 Typically associated with diabetes Ketonuria: g of KB/24 hr in urine >>> normal, Acidemia: KB levels rise in the blood : 90 mg/dL, normal is 3 mg/dL!)
	What is Jamaican Vomiting Sickness and what process is it associated with?	It is a disease associated with fatty acid metabolism. unripe fruit of the Jamaican ackee tree contains a toxin, hypoglycin, which inhibits the medium and short chain acyl-CoA dehydrogenases, which inhibits b-oxidation
	What is Carnitine deficiency and what process is it associated with?	Associated with fatty acid metabolism. produces muscle aches and weakness following exercise, elevated blood free fatty acids. Nonketotic hypoglycemia results because gluconeogenesis cannot be supported by fat oxidation!
	What is Zellweger Syndrome and what process is it associated with?	Associated with fatty acid metabolism. very long (20-26 carbon) fatty acids are normally degraded in peroxisomes. In ZS, the absence of peroxisomes in the liver and kidneys, lead to accumulation of very long chain fatty acids in the brain.
	How is cholesterol degraded?	The intact sterol nucleus is eliminated from the body by conversion to bile acids and salts, which are excreted in the feces and by secreted of cholesterol into the bile, which transports it to the intestine for elimination.
	Describe the structure of bile acids.	24 carbons with two or three hydroxyl groups and a side chain that terminates in a carboxyl group. Hydroxyl group in alpha orientation Methyl groups in beta oritenation
	Are bile salts ionized or protonated and neutral at physiological pH?	They are not fully ionized because their pKa is about 6.
	Where are bile acids synthesized?	Liver parenchymal cells
	What is the rate limiting step in bile acid synthesis?	The addition of a hydroxyl group at C7 by cholesterol-7-alpha-hydroxylase (CYP7A1)
	According to lecture, how are secondary bile salts created?	Created by the action of bacterial enzymes in the intestines on the primary bile salts.
	According to lecture, how is bile secretion controlled?	Hormones ie: cholecystokinin and the arrival of recycled bile acids.
	What are gallstones?	they are formed in the gallbladder when bile becomes supersaturated with cholesterol.
	What is enterohepatic circulation? Describe the pathway.	Enterohepatic circulation is the continuous precess of secretion of bile salts into the bile, their passage through the duodenum where some are converted to bile acids and their subsequent return to the liver as a mixture of bile acids and salts. Pathway:Mixture of primary and secondary bile acids and bile salts is absorbed in the ileum --> transported from intestine into the portal blood --> removed by liver parenchymal cells --> liver converts them into bile salts and secretes them into the bile.
	What are the three classes of steroid hormones?	C21 Corticosteroids (adrenal cortex) C19 Androgens (testis) C18 Estrogens (ovary)
	According to lecture, how are steroid hormones secreted?	most are excreted via the kidney in the urine after some pre-processing in the liver to make them more water soluble (via glucuronide or sulfate linked to 3-OH)
	According to lecture, what is the electron transport chain?	Generates bulk of ATP for maintaining homeostasis through oxidative phosphorylation Has several large protein complexes and two independent components
	Where does the electron transport chain occur?	In the inner mitochondrial membrane
	What is complex I of the ETC?	Lecture: NADH-Q Reductase NADH Dehydrogenase: An enzyme complex that has a tightly bound molecule of flavin mononucleotide (FMN) Transfers two electrons from NADH and proteins to CoQ
	What is complex II of the ETC?	Lecture: Succinate-Q Reductase Succinate dehydrogenase: multi-subunit complex of 3 enzymes 2 electrons from FADH2 pass to CoQ along with 2 protons
	According to lecture what is CoQ?	Coenzyme Q small & lipid soluble, diffuses & shuttles electrons to complex III from I and II. Lippincotts: links the flavoproteins to the cytochromes
	What is Complex III of the ETC?	Lecture: Cytochrome C reductase Cytochrome bc1 complex:transfers electrons along with protons to cytochrome C
	What is a cytochrome?	Each contains a heme group made of a prophyrin ring containing an atom of iron.
	What is Complex IV of the ETC?	Lecture: cytochrome oxidase Contains cytochrome a and a3 Uses Cu and Fe Transfers electrons to O2 It is here that the transported electrons, molecular oxygen and free protons are brought together to produce water.
	According to lecture, what is cytochrome c?	A water soluble protein that accepts electrons from Complex III and shuttles them to Complex IV
	How many molecules of water are formed for every NADH or FADH2 oxidized?	1 molecule 4 electrons transferred to complex IV, eventually transferred with 4 H+ to O2 to form 2 H2O molecules
	What is Complex V of the ETC?	ATP synthase Synthesizes ATP, using the energy of the proton gradient generated by the ETC
	What part of the ETC does cyanide affect?	It blocks complex IV
	What part of the ETC does carbon monoxide affect?	it blocks complex IV
	What part of the ETC does rotenone affect?	it blocks complex I
	What part of the ETC does amytal affect?	It blocks complex I
	What part of the ETC does Antimycin A affect?	It blocks complex III
	What part of the ETC does ogliomycin affect?	It blocks the proton channel in ATP synthase
	What are uncoupling proteins/agents?	Occur in the inner mitochondrial membrane. They create a proton leak, that is they allow protons to re-enter the mito matrix without energy being captured. (Bypasses ATP synthase - Electron transfer has been UNCOUPLED from ATP synthase)
	What is thermogenin?	Uncoupling protein 1 - responsible for the acativation of fatty acid oxidation and heat production in brown adipocytes. Provides a channel through the IMM - the heat energy released as the protons rush down their concentration gradient through this channel keeps the mammal warm.
	What is Leigh Syndrome?	Most frequent of the mito diseases EXTENSIVE GENETIC HETEROGENEITY Mutations in both nuclear and mito-encoded genes involved in E metabolism (all complexes of ETC and deficiency of CoQ) It presents as a progressive, subcortical encephalopathy with optic atrophy, opthalmoparesis, hypotonia, ataxia, and dystonia.
	What is MELAS?	Mitochondrial encephalopathy, lactic acidosis and stroke like episodes.
	What is MERRF?	Myoclonus epilepsy with ragged red fibres
	What is DDP?	Deafness-dystonia syndrome -- nuclear DNA mutation phenotype
	Does the TCA use or include oxygen?	No.
	According to lecture, what are the two primary regulators of the TCA cycle?	ATP levels Oxygen levels
	According to lecture, what are the four points of regulation of the TCA cycle?	Pyruvate Deyhdrogenase Complex Citrate Synthase Isocitrate Dehydrogenase Alpha-KG Dehydrogenase Complex
	What is Fumarase Deficiency?	mitochondrial encephalomyopathy signs of hypotonia, lactic and pyruvic acidemia, cerebral atrophy, developmental delay, and failure to thrive.
	What is Beri Beri disease?	The body has requirements for non-protein cofactors, thiamine (vitamin B1) An insufficient dietary thiamine leads to - decreased PDH and alphaKGDH activities - decreased ability of the Krebs cycle to meet metabolic demands
	Vitamin B1 is also known as?	Thiamine
	Where does the Pentose Phosphate Pathway occur in the cell?	in the cytosol
	How much ATP is consumed/used in the Pentose Phosphate Pathway?	None
	What is the purpose of the Pentose Phosphate pathway?	Generase pentose phosphates for the synthesis of RNA and DNA. It is important for Red Blood cells (who dont need to make DNA) Generates NADPH
	Biosynthesis of what molecules requires NADPH?	fatty acids, cholesterol, steroid hormones, bile salts
	What are the sites that NADPH is active/used?	Lactating mammary glands liver adrenal cortex RBCs adipose tissue
	The ratios of reduced/oxidized forms of NADPH in the cytosol of hepatocytes favor a reductive or oxidative role for NADPH?	Reductive NADPH/NADP+ = 10/1
	The ratios of reduced/oxidized forms of NADH in the cytosol of hepatocytes favor a reductive or oxidative role for NADH?	Oxidative NADH/NAD+ = 1/1000
	NADPH is used to reduce what?	Glucathione
	What is Glucathione?	a key antioxidant
	According to lecture, how does an RBC derive its energy?	Converting lgucose into two molecules of lactate, gaining two ATP
	What percentage of the glucose entering the RBC flows into the PPP to generate NADPH?	10%
	What are the predominant carbohydrate metabolism in RBCs?	Glycolysis - provides ATP for membrane ion pumps and NADH for reoxidation of methemoglobin PPP - supplies NADPH to maintain reduced state of glucathione 2,3BPG metabolism
	Overall yield of PPP?	A sequence of three enzymes forms 2 moles of NADPH per mole of Glc-6-P, which is converted into ribulose-5-phosphate, with evolution of CO2.
	What is the first step in PPP?	Irreversible Oxidative reaction in which glucose-6-P is converted to 6-phosphoglucono-lactone Reaction is catalyzed by glucose 6-phosphate dehydrogenase
	What is the primary regulation step of PPP?	Glucose 6-phosphate dehydrogenase
	What does Glucose 6-phosphate dehydrogenase (g6PD) of the PPP do?	G6p --> 6-phosphoglucono-lactone Generates an NADPH
	What inhibits glucose-6-phosphate dehydrogenase of PPP?	NADPH (competitively)
	What is Glucose-6-P Dehydrogenase Deficiency?	Hereditary deficiency in this enzyme causes hemolytic anemia due to inability to detoxify oxidizing agents (owing to insufficient reduced glutathione)
	What is the second step in PPP?	Irreversible reaction in which 6-phosphogluconolactone is converted to 6-phosphogluconate Enzyme:6-phsophogluconolactone hydrolase
	What is the third step in PPP?	6-phosphogluconate is oxidatively decarboxylated to ribulose 5-phosphate Enzyme: 6-phosphogluconate dehydrogenase Produces a second molecule of NADPH
	What are the three irreversible steps in PPP?	1. Dehydrogenation of Glucose-6-phosphate (glucose 6-phosphate dehydrogenase) 2. 6-phosphogluconolactone hydrolase. 3. Formation of ribulose 5-phosphate (6-phosphogluconate dehydrogenase)
	What is the interconversion stage of PPP?	The carbon skeletons of three molecules of ribulose-5-phosphate are shuffled to form two molecules of Fructose 6-phosphate and one molecule of glyceraldehyde 3-phosphate Enzymes: transketolase and transaldolase. To form ribose, the nonoxidative reactions can synthesize ribose 5-P from glyceraldehyde 3-P and fructose 6-P (bypasses oxidative reactions)
	What is the cofactor for transketolase of the PPP?	Thiamine Diphosphate (TPP)
	What are the enzymes that TPP is a cofactor for?	transketolase pyruvate carboxylase alpha-ketoglutarate dehydrogenase (TCA cycle) branched-chain alpha-keto acid dehydrogenase (of branched chain amino acid metabolism)
	Does the nucleotide include the phosphate group?	Yes
	What are the purines?	G and A
	What are the Pyrimidines?	C and T
	What is the conversion of PRPP to purine nucleotides catalyzed by in the de novo pathway?	amido-PRT
	What is the conversion of PRPP to purine nucleotides catalyzed by in the salvage pathway?	APRT and HGPRT
	What is PRPP?	phosphoribosyl pyrophosphate
	What is APRT?	the enzyme that catalyzes the salvage pathway conversion of PRPP to purines. It stands for adenosine phosphoribosyltransferase
	What is HGPRT?	the enzyme that catalyzes the salvage pathway conversion of PRPP to purines. It stands for hypoxanthine-guanine phosphoribosyltransferase
	What is amido-PRT?	The enzyme that catalyzes the de novo pathway conversion of PRPP to purines. It stands for amido-phosphoribosyltransferase.
	What are the two categories of amino acids?	Glucogenic Ketogenic
	What are glucogenic amino acids?	AA whose catabolism yields pyruvate or one of the of the intermediates of the citric acid cycle.
	What are ketogenic amino acids?	AA whose catabolism yields either acetoacetate or one of its precursors (ACoA or acetoacetyl CoA)
	What are the ketogenic amino acids?	Leucine Lysine
	What are the essential amino acids?	Histidine Methionine Threonine Valine Isoleucine Pheynlalanine Tryptophan Leucine Lysine
	What are the seven products that amino acids can be used to make?	pyruvate ACoA acetoacetate alpha-ketoglutarate succinyl CoA oxaloacetate fumarate
	What are the amino acids that are both keto and glucogenic?	Tyrosine Isoleucine Phenylalanine Tryptophan
	According to lecture, what are the processes involved in amino acid catabolism?	1. Degradation of dietary protein to form AA 2. Transfer of amino group from AA to alpha-ketoglutarate (transamination reaction. Enzyme = TRANSAMINASE or AMINOTRANSFERASE) 3. Glutamine transports ammonia from bloodstream 4. Alanine transports ammonia from muscle 5. Glutamate releases amino group as ammonia.
	What does aminotransferase do in AA catabolism?	It transfers the amino group from the AA to alpha-KG
	Describe the glucose-alanine cycle.	Alanine plays a special role in transporting amino groups to liver. Alanine is the carrier of ammonia and of the carbon skeleton of pyruvate from muscle to liver. The ammonia is excreted and the pyruvate is used to produce glucose, which is returned to the muscle.
	How does glutamate release its amino group?	As ammonia in the liver The amino groups from many of the alpha-amino acids are colleccted in the liver in the form of the amino group of L-glutamate molecules. Glutamate undergoes oxidative deamination catalyzed by L-glutamate dehydrogenase.
	What is the enzyme that catalyzes the oxidative deamination of glutamate? What is the product? Where	L-glutamate dehydrogenase Product: alpha-ketoglutarate
	Where is L-glutamate dehydrogenase (the enzyme that oxidatively deaminates glutatmate) located?	Mitochondrial matrix
	What is the only enzyme that can use either NAD or NADP as the acceptor of reducing equivalents?	L-glutamate dehydrogenase
	What is transdeamination?	The combined action of an aminotransferase and glutamate dehydrogenase
	What is formed when excess ammonia is added to glutamate? What enzyme does this?	glutamine Enzyme: Glutamine synthetase Glutamine enters the liver and NH4 is liberated in the mitochondria by the enzyme glutaminase. Ammonia is removed by urea synthesis.
	What does the enzyme glutaminase do?	liberates NH4 from glutamine in the mitochondria
	According to lecture, what is the fate of ammonia in the liver of mitochondria?	- recycle for use in biosynthesis - excrete
	What is phenylalanine hydroxylase?	a mixed-function oxygenase: one atom of oxygen is incorporated into water and the other into the hydroxyl of tyrosine. The reductant is the tetrahydrofolate-related cofactor TETRAHYDROBIOPTERIN, which is maintain in the reduced state by NADH-dependent enzyme dihydropteridine reductase.
	What is phnylketonuria?	Missing or deficient phenylalanine hydroxylase results in hyperpheylalaninemia. Phenylketonuria is the most widely recognized hyperphenylalaninemia (and most sever). It is a genetic disease. Mental retardation caused by the accumulation of phenylalanine, which becomes a major donor of amino groups in aminotransferase activity and depletes neural tissue of alpha-ketoglutarate. Absence of alpha-KG in the brain shuts down the TCA cycle and the associated production of aerobic energy, which is essential to normal brain development.
	What does glutaminase do?	cleaves glutamine to glutamate and free ammonia
	What does glutamate dehydrogenase do?	Converts glutamate to ammonia and alpha-KG
	What does carbomoyl phosphate synthetase I do?	It is the rate determining step in the Urea cycle. It makes citrulline.
	How is alanine formed?	transfer of an amine group by aminotransferase from pyuruvate.
	How is aspartate formed?	transfer of an amine group by aminotransferase from oxaloacetate
	How is glutamate formed?	transfer of amine group by aminotransferase from alpha-KG or reverse oxidative deamination catalyzed by glutamate dehydrogenase
	What are some transaminases that are important in the diagnosis of heart and liver damage caused by heart attack, drug toxicity or infection?	Alanine-alpha-KG transferase Aspartate-alpha-KG transferase
	What is the coenzyme required in the formation of tyrosine?	tetrahydrobiopterin (BH4) which can be synthesized from GTP in the body
	How are purine nucleotides synthesized in general?	The atoms of the puring ring are contributed by amino acids, CO2, and N10-formyltetrahydrofolate. The purine ring is constructed by a series of readctions that add the donated carbons and nitrogens to a preformed ribose 5-phosphate.
	How is PRPP made?	It is synthesized from ATP and ribose-5-phosphate via PRPP synthetase.
	What is required for the de novo synthesis of IMP?	4 ATP Glutamine N10-tetrahydrofolate glycine
	What is the first step in the formation of IMP?	RSP is converted to PRPP by PRPP synthetase
	Describe in general the conversion of IMP to AMP or GMP.	The conversion of IMP to either AMP or GMP uses a two step, energy-requiring pathway. The synthesis of AMP requires GTP and the formation of GMP requires ATP. The first reaction in each pathway is inhibited by the end product which provides a mechanism for diverting IMP to the synthesis of the species of purine present in lesser amounts.
	What is the purine salvage pathway?	The pathway in which purines are derived from the normal turnover of cellular nucleic acids or that are obtained from the diet and not degraded.
	Describe the purine salvage pathway in general.	Adenine, hypoxanthine and guanine can all react with PRPP to form AMP, IMP, and GMP respectively. The enzymes involved are APRT or HGPRT
	What is Lesch-Nyhan Syndrome?	X-linked, recessive disorder associated with a virtually complete deficiency of HGPRT. This results in an inability to salvage hypoxanthine or guanine from which excessive amounts of uric acid are produced. This also leads to an over-accumulation of PRPP and decreased IMP and GMP levels. This leads to increase in purine synthesis and degradation leading to excess uric acid (the degradation product of amino acids) CLINICAL SIGNS: gouty arthritis, mental retardation, spasticity, aggression, and self-mutilation by biting and scratching.
	Describe in general the degradation of purines pathway.	IMP, AMP, XMP, and GMP all can be converted to their respective free bases by phosphorylases. These are then all catabolized to one common base: xanthine. In the last step, xanthine is oxidized by xanthine oxidase to form uric acid, the final metabolic product of purine metabolism.
	What is the final metabolic product of purine metabolism?	uric acid
	What causes gout?	Excess uric acid in body fluids.. UA has low solubility and precipitates as needle-shaped urate crystals. This leads to decreased renal clearance, HGRPT deficiency, and glucose-6-phosphate deficiency. Glu-6-phosphate deficiency stimulates the pentose phosphate pathway which increases the synthesis of ribose-5-phosphate, which then is converted to PRPP, resulting in an overproduction of purines = higher UA levels. Allopurinol is converted to its bioactive form, alloxanthine, which blocks xanthine oxidase and gives reduced levels of UA.
	How does Glucose-6-phosphate deficiency lead to gout?	Glu-6-phosphate deficiency stimulates the pentose phosphate pathway which increases the synthesis of ribose-5-phosphate, which then is converted to PRPP, resulting in an overproduction of purines = higher UA levels.
	Describe the cause of Severe Combined Immunodeficiency Syndrome.	It is a fatal disorder that results from defects in immune function. 50% of patients: genetic defect in the purine salvage enzyme: adenosine deaminase. Pathophysiology involves both thymic and bone-marrow lymphocytes and self destruction of differentiated cells following antigen stimulation Unknown cause of cell death but may be due to accumulation in lymphoid tissues of adenosine, deoxyadenosine, and dATP accompanied by ATP depletion.
	How does pyrimidine synthesis differ from purine synthesis?	The purine ring is synthesized from a pre-existing ribose-5-phosphate. The pyrimidine ring is synthesized before being attached to ribose-5-phosphate, which is donated by PRPP.
	What are the sources of atoms for the pyrimidine ring?	Glutamine, CO2, aspartic acid
	What is the regulated step of de novo pyrimidine synthesis?	Formation of carbamoyl phosphate from glutamine and CO2, catalyzed by carbamoyl phosphate synthetase II.
	Describe the differences between CPS I and II in the following categories: Location? Pathway involved? Source of nitrogen? Regulators?	Location: CPS ! - cytosol; CPS II - mitochondria Pathway involved: CPS I - urea cycle; CPS II - pyrimidine synthesis Source of nitrogen: CPS I - ammonia; CPS II - gamma-amide group of glutamine Regulators: CPS I activator: N-acetyl gluamate; CPS II activator: ATP; CPS II inhibitor: UTP
	What is the CAD multifunctional protein?	The protein that catalyzes the first 3 steps of de novo pyrimidine synthesis.
	What is orotic aciduria?	Very rare disorder characterized by anemia. Orotic acid crystals precipitate in vivo and cause obstruction of the urinary tract DEFICIENCY OF UMP SYNTHASE causes accumulation of ortic acid which is excreted in the urine
	What is the difference between Type 1 and Type 2 Orotic Aciduria?	Type 1 is complete loss of UMP synthase Type 2 is deficient in OMP decarboxylase (treated with chronic uridine therapy)
	What are the triphosphate analogues of the pyrimidines?	UTP and CTP
	Describe the pyrimidine salvage pathway.	Free pyrimidines fromdiet or breakdown of nucleic acids can be recycled via: uracil + PRPP --> UMP + PPi UPRTase is also required to activate chemotherapeutics like 5-flourouracil or 5-flourocytosine Lippincotts: Few pyrimidine bases are salvaged in human cells. However, the pyrimidine nucleosides can be salvaged by nucleoside kinases that utilize ATP in the phosphorylation of the nucleosides to nucleotides
	Describe the degradation of pyrimidines.	The monophosphate analogues (CMP, UMP, TMP) can be dephosphorylated to their respective nucleosides. Unlike the purine ring, which is not cleaved in human cells, the pyrimidine ring is opened and degraded to highly soluble products.
	What hormone/s takes action during the hypoglycemic state?	Insulin (increase plasma glucose)
	What hormone/s take action during the hyperglycemic state?	Glucagon, epinephrine, cortisol, growth hormone (decrease plasma glucose)
	What are the sources of glucose?	Dietary intake: absorption from the gut Endogenous production: via glycogenolysis and gluconeogenesis Tissue utilization: glycolysis, pentose phosphate pathway, tricarboxylic acid cycle and glycogen synthesis
	What is the major determinant of fuel metabolism?	Molar ratio of insulin/glucagon
	Is insulin anabolic or catabolic?	Anabolic
	How is insulin secreted?	By the pancreatic islets of Lagerhans Beta-cells (70% of islet cells)
	Is glucagon anabolic or catabolic?	Catabolic
	How is glucagon secreted?	pancreatic islets of Langerhans Alpha cells
	How is insulin translated?	It is synthesized in the RER of the pancreatic beta-cells packaged into secretory vesicles in the Golgi C-peptide is equimolar to insulin concentration, so its a good marker for beta cell function
	Why is C protein a good marker for beta cell function?	It is equimolar to insulin concentration because it is produced when proinsulin is cleaved to form insulin
	According to lecture, what are the 5 steps of the first phase of insulin release?	1. when you eat, glucose enters B-cells through Glut 2 and triggers insulin secretion and suprresses glucagon. 2. Glucose is then phosphorylated by glucokinase 3. As glucose metabolism is stimulated ATP/ADP ratio in the cell increases 4. This event closes the ATP sensitive K+ channel and depolarizes the cell and opens the Ca2+ channel. 5. As the Ca ions enter the cell they stimulate the release of the secretory granules containing preformed insulin.
	What is the second phase of insulin release?	Involves synthesis of new insulin Responds to an increase in concentration of cytosolic long chain acyl-CoA (a sign of well fed state and high glucose intake)
	Insulin secretion is stimulated by which amino acids?	leucine arginine lysine
	What are the gastrointestinal hormones that potentiate insulin secretion?	Following food intake: glucose-dependent insulinotropic peptide (GIP) cholecystokinin, glucagon-like peptide-1 (GLP1) vasoactive intestinal peptide (VIP)
	Why is insulin response to oral glucose higher than IV infusion?	because gut hormones like GIP, GLP 1, cholecystokinin and VIP potentiate insulin secretion
	What leads to a higher insulin response? Oral intake of glucose or IV infusion?	Oral
	What are the three main targets of insulin and its role therein?	Liver, adipose tissue, skeletal muscle. It promotes the anabolic state and channels metabolism towards protein synthesis and the storage of carbs and lipids Also promotes cellular potassium uptake
	What is different in muscle tissue in terms of energy absorption?	Muscle does not have glucose-6-phosphotase and cannot release glucose into the bloodstream. Therefore it relies on glycogen Does not have a glucagon receptor
	Muscle contraction (working out) increases the expression of which glucose transporter?	GLUT-4 (independently of insulin)
	What do fatty acids to do the expression of GLUT4 in muscle?	Decrease the expression
	Describe Type 2 Diabetes.	plasma [glucose] increases due to defective insulin signaling patients FIRST present with impaired glucose tolerance cause of insulin resistance is typically due to post receptor signal transduction defects
	What do patients first present with in Type II diabetes?	impaired glucose tolerance
	What is the cause of insulin resistance in Type II diabetes?	post-receptor signal transduction defects. IRS-phosphoinositol kinase pathway may no operate normally Impairs translocation of the GLUT4 transporter in adipocytes (but not in muscle) observed in both diabetes and obesity
	Where is glucagon activity observed?	Glucose activity is confined to the liver but mobilizes glucose from every available source. Also, increases lipolysis and ketogenesis from acetyl-coA
	What does epinephrine do?	Because there are no glucagon receptors in muscle tissue, you need epi to stimulate glycogenolysis in muscle. Inhibits glycolysis and lipogeneiss and stimulates gluconeogenesis
	What is the mechanism (receptor, cascade?) that epinephrine works via?	Uses alpha and beta adrenergic receptors. Mainly the beta2 receptor and link to the cAMP cascade. key enzyme responsible for hyperglycemia with stress
	What is the key enzyme responsible for hyperglycemia with stress?	Epinephrine
	What are fork-head transcription factors?	The way insulin regulates synthesis of key enzymes - it down regulates the follow TFs. Foxo1 and Foxa2 - essential for switching metabolism from anabolism to catabolism.
	What do Foxo1 and Foxa2 do?	The are transcription factors associated with insulin that are essential for switching metabolism from anabolism to catabolism. Foxo1 - promotes gluconeogenesis in the liver in the fasted state by inducing genes which code for PEPCK and 6-6-Pase Foxa2 - regulates fatty acid oxidation in the fasted state by inducing genes encoding enzymes of glycolysis, Fatty acid oxidation and ketogenesis.
	How does phosphorylation usually affect enzymes of catabolism? Anabolism?	Stimulates enzymes of catabolism Inhibits enzymes of anabolism.
	Define pharmacology.	The broad study of drugs including mechanisms, effects, interactions, and kinetics within the body.
	Define pharmacy.	The science concerned with the manufacture, preparation and dispensing of drugs.
	Define pharmacodynamics.	The study of the mechanism of action, effects and interactions. "What the drug does to the body."
	Define Pharmacokinetics.	AKA ADME The study of the absorption, distribution, metabolism, and elimination of drugs. "What the body is doing to the drug"
	Define Pharmacogenomics/pharmacogenetics.	Often used interchangeably. Generally regarded as the study or clinical testing of genetic variation that gives rise to differing response to drugs.
	Define pharmacotherapeutics.	Deals with drugs in the prevention and treatment of disease. Based on a solid understanding of pharmacodynamics, pharmacokinetics, and now, pharmacogenomics.
	Define pharmacognosy.	The study of chemistry, activity, and use of natural compounds.
	Define toxicology.	The study of poisons.
	Define pharmacovigilance.	The study and surveillance of adverse effects and drug interactions.
	What is the working definition of drug?	Any chemical agent that in SMALL QUANTITIES, affects the processes of living beings.
	Define receptor.	The specific component of a cell that binds to a drug or natural agent and initiates the biochemical events leading to the physiological response. Demonstrates: specificity or selectivity.
	Drug receptors can be membrane bound. They can appear as 5 other motifs. Name them.	1. Enzymes (HMG-CoA reductase, Acetylcholinesterase) 2. Na+, K+-ATPase pump 3. structural proteins (tubulin) 4. Nucelic acids (for cancer chemotheraputic drugs) 5. DNA (steroid drugs/hormones)
	Name the 4 receptor super families.	Ligand Gated Ion Channels G-Protein coupled receptors Receptor Tyrosine Kinases Nuclear Hormone Receptors
	What is a ligand gated ion channel?	A receptor super family category that is important in central and peripheral nervous systems, excitable tissues (heart and neuromuscular junction).
	What is a G-protein coupled receptor?	The most important receptor super family category. Most targeted by current drugs. Activated signals by conformational change.
	What is a receptor tyrosin kinase?	A receptor super family category. Best examples are growth factor receptors, cytokine receptors. Increasingly important for treatment of neoplastic disease.
	What is a nuclear hormone receptor?	A receptor super family category that is located in the cytosol and translocates to nucelase. These receptors are typically ligand activated transcription factors. Steroid hormones and retinoic acid are endogenous ligands.
	What is an agonist? Subtypes?	Drug that binds to receptor and activates it like a ket that will fit into a lock and turn it. Subtypes: Partial, inverse
	What is an antagonist? Subtypes?	Drug that binds to the receptor but does not activate it. Blocks activity of endogenous ligand. Subtypes: competitive, non-competitive.
	How is the quantitative relationship between drug concentration and response determined?	The AFFINITY of a drug for the receptor.
	The AFFINITY of a drug for a receptor determines what?	The quantitative relationship between drug concentration and response.
	What is responsible for the specificity of drug action?	Receptors and their distribution in tissues.
	Receptors and their distribution in tissues are responsible for what aspect of drug action?	Specificity
	What is the Law of Mass Action? What does it govern?	D+R<-->DR<-->DR-->-->Response Governs interaction of drug and receptor. since receptor concentration is small and fairly constant compared to amount of drug, there is a direct proportionality between [D] and response. MORE DRUG = MORE REACTION = GREATER RESPONSE
	What is the Arithmetic Method of visualizing dose response?	Plot [D] vs %Emax Difficult to determine Kd (which occurs at 50% Emax) Limited dosage range cant compare drugs
	What is the Logarithmic Method of visualizing dose response?	Plot LOG [D] vs %Emax More sensitive Broader range of doses Allows comparison of drugs At lower doses and Emax doses are approximate
	Qhat is a quantal LDR curve?	All or none Example: asleep or not asleep
	What is a graded LDR curve?	More common for comparing pharmacokinetic and parmacodynamic parameters.
	What is ED50?	The dose that would produce the effect in 50% of patients OR 50% of Emax
	What is LD50?	The dose that is lethal to 50% of individuals
	What is the therapeutic index?	Relates dose of drug required to produce and effect to that which is lethal = LD50/ED50
	What is TD50?	Median toxic dose. Dose required to produce a particular side effect in 50% of individuals.
	What is the protective index?	Similar to therapeutic index. Estimates usefuless of drug without undesirable side effects. TD50/ED50
	What does potency mean?	Concentration of drug required to produce a given effect (or degree of effect). Drug that produces the given effect at lowest dose is most potent.
	What is efficacy?	Intrinsic activity. What maximal effect can be acheived with a drug. Determined by proportion of receptors that are forced into active conformation when bound.
	What is a full agonist?	Capable of inducing same Emax as endogenous compound.
	What is a partial agonist?	Lower efficacy; acnnot induce same Emax as endogenous compound.
	What is a competitive antagonist?	Block can be overcome by increasing dose of agonist.
	What is a non-competitive (irreversible) antagonist?	Block can not be overcome by increasing dose of agonist.
	What is an inverse agonist?	Reduces constitutive activity of receptor.
	define absorption.	The process by which drugs enter circulation.
	Define distribution.	The process by which drugs partition throughout the body and reach their site of action
	What is metabolism?	The process by which drugs are broken down by the body. This may increase or decrease activity and/or toxicity
	What is elimination?	The process by which drugs are removed from the body.
	What are some of the characteristics affecting transfer of drugs across barriers?	Molecular size Solubility Ionization (most drugs are weak acids or bases)
	Describe first order kinetics.	Rate of a first order process is proportional to the amount present. A rate constant describes the fractional change in concentration over time. Example: .3/hr = 30% of drug is eliminated/hr
	Describe Zero order Kinetics	Rate of a zero order process is constant, and independent of the dose or amount of drug present.
	What are the four factors influencing drug absorption?	Solubility Concentration Circulation Surface Area
	What are the four factors that influence drug distribution?	Blood Flow Lipid Solubility Molecular Size Protein Binding
	How does blood flow influence drug distribution?	The most highly perfused organs receive most of the drug during the first few minutes after absorption. Delivery of drug to muscle, viscera, skin and fat is slower (slower blood flow)
	How does lipid solubility influence drug distribution?	Lipid soluble drugs that cross the membrane poorly are restricted in their distribution and hence in their site of action.
	How does molecular size influence drug distribution?	extremely large drugs are mainly confined to the plasma compartment. Ex: heparin
	How does protein binding influence drug distribution?	Distribution may be limited by drug binding to plasma proteins. Only the unbound drugs cross the cell membrane. Acidic drugs bind to SERUM ALBUMIN Basic drugs bind to ALPHA-ONE GLYCOPROTEIN
	What do acidic drugs bind to? Basic drugs?	Acidic drugs bind to SERUM ALBUMIN Basic drugs bind to ALPHA-ONE GLYCOPROTEIN
	Name some drug reservoirs.	Plasma proteins - drugs bound to plasma proteins are in equilibrium with free drug. Fat - highly lipophilic drugs are stored in fat (alcohol, thiopental) Bone - drugs may accumulate in bone by adsorption onto the bone-crystal surgace and eventual incorporation into the crystal lattice (tetracycline) Cellular reservoirs - Some drugs accumulate in the muscle and other cells at higher [] than in extracellular fluids (ex antimalarial agent, quinacrine, azithromycin)
	Name some of the cellular barriers to drugs.	BBB - exclusion of foreign agents such as penicillin protects the CNS against severely toxic effects. Placenta (not a barrier) - the fetus is exposed to some extent to essentially all drugs taken by the mother.
	What is the volume of distribution (Vd)?	Hypothetical volume of fluid into which drug has distributed. Calculation : Vd = Dose or total amount of drug in the body/plasma concentration of drug Vd = D/Cp The only compartment that can be readily examined is plasma (Vd can not be estimated from extravascular doses). Important in determining dosage regimen, since it influences clearance.
	What is the 20/40/60 rule?	20% of body weight = ECF 40% of body weight = ICF 60% of body weight = total body water 4% of body weight = plasma volume
	What is apparent volume of distribution?	Vd which is greater than the plasma compartment indicate that the drug is also present in tissue or fluids outside of this compartment. The larger the Vd, the less drug present in plasma after a dose (concentrated or tissue binding outside plasma) Smallest Vd=3.5L (volume of plasma)
	What is a Phase I reactions?	Mainly degradative resulting in inactivation, change in activity, or activation (prodrug) or drugs. The main Phase I reactions are: Oxidation Reduction Hydrolysis
	What are the main Phase I reactions?	Oxidation Reduction Hydrolysis
	What are Phase II reactions?	mainly involved in coupling of the drug or its polar metabolite from a Phase I reaction to an endogenous substrate (e.g. glucuronate). The phase II reactions are known as: Conjugation
	What are the Phase II reactions called?	Conjugation
	True or False: the more polar the drug the more easily and rapidly it is eliminated?	True
	According to lecture, what is the most important Phase I reaction?	Mixed-function oxidases/monooxygenase Catalyzed by cytochrome P450 system; a family of isoenzymes with overlapping specificities. This enzyme system is found in microsomal fraction (smooth endoplasmic reticulum) of cells, mainly in liver but also in lung and kidney.
	What are the most important enzymes of the non-microsomal oxidation system?	alcohol dehydrogenase aldehyde dehydrogenase
	What are some enzymes that carry out hydrolysis reactions?	Esterases (acetylcholine, procaine) Amidases (lidocaine, procainamide) Peptidases
	What enzymes do conjugation (Phase II reactions) use?	transferases
	What is the most common conjugation reaction?	The coupling of the drug from the phase I reaction to an endogenous substrate such as Glucuronic acid.
	True or false: Most conjugates are highly polar (water soluble) in Phase II reactions?	True. This means they are unable to cross the plasma membrane, making them almost always pharmacologically inactive and of little or no toxicity.
	What are six factors influencing drug metabolism?	Physiologic or disease state Genetic Variation Drug Dosage Age Route of Drug Administration Enzyme Induction or Inhibition
	How do physiological factors or disease state affect drug metabolism?	Pathological factors that alter liver function can influence a drug's hepatic clearance. Congestive Heart Failure can decrease hepatic blood flow and distribution of drugs. Alteration in albumin production can alter the ratio of bound to unbound drug.
	What is an example of how genetic variation influences drug metabolism?	there is a great variation in the activity of N-acetyl transferase enzyme among different populations
	How does drug dosage influence drug metabolism?	As the drug dosage increases, drug concentration may saturate the metabolic enzyme
	What is an example of how age influences drug metabolism?	Infants and young children have immature livers so their hepatic enzymes are not fully functional Older children have livers that develop faster than the general increase in body weight so calculations must take this into account. Geriactric patients experience a decline in metabolizing enzymes
	What is one example of how route of drug administration can affect drug metabolism?	first pass effect: combined action of bacterial enzyme within intestine and liver on the drug taken orally. (portal vein)
	How can enzyme induction or inhibition influence drug metabolism? Example?	Drugs can increase the synthesis or decrease the degradation of enzymes responsible for metabolizing other drugs. Example: cigarette smokers have lower plasma levels of drugs such as theophylline, than non smokers because the polycyclic aromatic hydrocarbon component of cigarette smoke appears to induce the N-demthylation pathway Enzyme induction can produce a condition known as pharmacokinetic tolerance.
	What are the kinetic models of elimination?	First Order - rate of elimination is proportional to the amount present. Zero Order - rate is constant and fixed, and independent of the dose or amount of drug present. Few drugs are eliminated via zero order kinetics
	What does the rate constant describe?	describes the fractional change in concentration over time
	What are the three processes involved in renal excretion?	glomerular filtration active tubular secretion passive tubular reabsorption
	Describe biliary excretion.	Enterohepatic recirculation (biliary cycling). Transport systems analogous to those found in kidney actively secrete drugs and drug metabolites into bile. Lipid soluble drugs and conjugatd drug metabolites, including the glucuronate and some sulfate derivative are excreted in the bile and reabsorbed from the GI tract. Biliary excretion favors compounds with molecular weight which is great than 300. Conjugated drugs can be hydrolyzed to the free drug by intestinal bacteria and reabsorbed into circulation. This process reduces the elimination of drugs and prolongs their duration of action in the body.
	How are anesthetic gases and alcohol excreted?	Via the pulmonary system
	What is bioavailability (F)?	The fraction of administered dose that reaches systemic circulation after a particular route of administration. F = AUC oral/ AUC injected AUC = area under curve
	What is terminal differentiation?	When the cells express their final subset of genes that will mark their final phenotype. Often (not always) associated with the exit of cells from the cell cycle.
	What are the four types of tissues?	Connective Epithethial Muscle Nervous
	What is one way that asymmetry across the lipid bilayer is achieved?	The larger head groups cluster togther and so do the smaller head groups on the other side - looks like a fan.
	What are the types of membrane proteins?	Integral Membrane Proteins Peripheral membrane proteins (eg: spectrin)
	Which membrane proteins are detergent soluble? Insoluble?	Integral membrane proteins are detergent soluble. Peripheral membrane proteins are insoluble.
	Describe the NA+/K+ ATPase.	Cells contain relatively high [K ions] but relatively low [Na]. this is important for the Resting Potential for driving facilitated membrane transport (glucose and amino acids) the establishment of NA gradient (Na/glucose symporter) cell volume
	What are the stages of exocytosis?	1. translation coupled-insertion of proteins across or into the bilayer in the RER 2. Trafficking of proteins from the RER to SER. Initial modifications of proteins 3. Trafficking of proteins through Golgi Complex and final modifications 4. Trafficking of proteins to the plasma membrane and fusion with the lipid bilayer. This is not random. Vesicles can be directed to specific sites (snare complex for vesicle docking)
	Name the order of compartments (started with ER ending at plasma membrane) that a trafficked protein would encounter.	1. ER 2. ERGIC: ER-golgi intermediate compartment 3. CG: Cis golgi 4. MG: medial golgi 5. TG: Trans-golgi 6. TGN: trans-golgi network 7. RE: recycling endosome 8. SE: sorting endosome 9. ISG: immature secretory granule 10. MRG: mature regulated granule
	What are the three types of coated vesicles?	Clathrin coated Coatomer coated Caveolin Coated
	What is clathrin? What is it function?	Clathrin triskelion to form a cage like lattice around the vesicle. Function: 1. receptor mediated uptake (endocytosis) 2. signal directed exocytosis (TGN secretory granules or late endosome-lysosome pathway)
	What is coatomer? Function?	Coating of "coat" proteins (COPS) Function: bulk flow of membrane through the cell (constitutive protein transport). RER --> ERGIC --> CG --> TGN --> PM
	What is caveolin vesicle? Function?	vesicles are coated with the protein caveolin. Function: rarer. cell signaling, transcytosis, and endocytosis,
	What are the main types of endocytosis based on vesicle size?	1. Phagocytosis (bacteria, viruses) 2. Pinocytosis (extracellular fluid, proteins) 3. Receptor-mediated endocytosis (specific uptake)
	What are the components of the three filament system of the cytoskeleton?	Microfilaments (7 nm - actin) Microtubules (25 nm - tubulin subunit) Intermediate filaments (8-10 nm)
	How does actin polymerize?	It has a binding pocket for ATP which is essential for the polymerization into microfilaments. It is [] dependent The growing actin filament is polarized, which a + end (barbed) and a - end (pointed). Monomers are preferentially added at the + end (can also "treadmill" where monomers are added at the + end and are dissociated at the - end) 50% of action is found close to the membrane (cortical actin)
	What are some examples of proteins that regulate filament assembly to stabilize or disassemble the filament?	Capping proteins for + or - ends Monomer sequestration agents Nucleating agents Filament severing molecules
	What is myosin?	a large family of ATP-dependent molecular motors that can move along actin filaments (or if anchored can move actin filaments). Almost always toward the + end of the filament.
	Where are myosin motors almost always found?	At the + end of the actin filament.
	What are the roles for myosin?	Cargo delivery - short range Contraction
	What are microtubles? Structure?	Structural filaments that are composed of heterodimers of alpha and beta tubulin. Main functions are in flagella and cillia as well as composing the spindle apparatus during mitosis. Alpha tubulin GTP does not hydrolyse to GDP. Beta does. Microtubules are 25nm cylinders composed of 13 profilaments. Doublet and triplet microtubules can also be formed.
	How do microtubules polymerize?	Both subunits of the heterodimer need to be in the GTP state for polymerization to occur Polymerization of the heterodimer to protofilament results in hydrolysis of the internal GTP. Lateral assembly of 13 protofilaments result in a hollow tube. Heterodimers can be added preferentially at the + end to increase growth. Normally the - end is protected from losing heterodimers
	What is the microtubule organizing center?	(-) ends of the microtubule are embedded in the MTOC (centrioles composed of gamma tubulin) Centrosome is the MTOC associated with cell division Basal bodies are the MTOCs associated with cillia and certain intracellular junctions in epithethial cells.
	What do spindle poisons do? Name 3 of them.	De or unregulated cell division is a characteristic of cancer. Many cancer therapeutics target cell division (mitotic inhibitors) by perturbing the mitotic spindle. Taxol Vinca alkaloids Colchicine
	What is Taxol?	Used in the treatment of lung, ovarian, breast, head, and neck cancer. Hyper-stabilizes MTs by binding to beta-tubulin and preventing dynamic instability.
	what is Vinca alkaloids?	Used in the treatment of leukemia and lymphoma. Binds to tubulin dimmers to inhibit their assembly.
	What is Colchicine?	Used largely in the treatment of gout. High affinity for tubulin and prevents polymerization.
	What is the basal body?	The place where cilia extend from the cell body. A type of MTOC.
	What are kinesin and dyenin?	Microtubule motors used for long distance intracellular particle movement. Kinesin: + end movement (anterograde) Dyenin: - end moment (retrograde) Example: in axonal transport, dynein brings stuff to the cell body whereas kinesin brings stuff to the synapse.
	What are intermediate filaments?	Filaments that have a size in between microfilaments and microtubules.- PROVIDE MECHANICAL STRENGTH TO THE CELL less dynamic and non-polarized compared with MFs and MTs components are far more diverse than MTs and MFs
	Describe the structure of intermediate fiilaments.	Unique NH2 domain on one end Alpha-helical domains along the length of the filament separated by spacers. At opposite end of NH2 is a unique COOH-domain
	What are some types of intermediate filaments?	Type I and II - acidic and basic keratins Type III - desmin, GFAP, Peripherin, Vimentin Type IV - nestin, neurofilaments Type V - nuclear lamins
	How do you build an intermediate filament?	You begin with a monomer. These monomers form a coiled-coiled dimer which self associate at the alpha-helical region. Then a staggered tetramer formation occurs where two coiled-coiled regions stack together unevenly (thus staggered). Two of these tetramers then stack together in a staggered formation (there are now 8 monomers together) Finally, 8 of these tetramers that are bound together form a ropelike filament.
	What are nuclear lamins?	A type of intermediate filament Responsible for adding strength and support to the nuclear membrane. Phosphorylated at the end of prophase as nuclear envelope breaks down. Dephosphorylated during reformation.
	What is epidermolysis bullosa?	A rare genetic disease caused by mutations in keratin 5 or 14 (intermediate filaments) basal layer of epithelium. Keratins linked to cell junctions (desmosomes) provide mechanical strength to basal layer. When keratin absent cells are damaged by mechanical stress, blisters form.
	What are the three types of cell motility?	Isolated appendages of cells (eg: cilia and the movement of fluids by cells) Whole cell movement (movement through fluid or movement through tissue) Intracellular movement (organelles and single celled organisms)
	How do cilia move?	Dynein (microtubule motor) causes adjacent filaments to slide over each other to produce movement of the cilia.
	Sinus inversus can be associated with that -pathy?	Ciliapathy. the early embryo is symmetric. Left-Right asymmetry is established by a ciliated structure known as the node.
	What is Primary Ciliary Dyskinesia (PCD)?	Rare autosomal dominant ciliopathy encompassing 250 proteins affecting dynein inner and outer arms. When combined with situs inversus, chronic sinusitis and brochiectasis it is known as Kartagener syndrome.
	What syndrome results when Primary Cilliary Dyskinesia is combined with situs inversis, chronic sinusitis, and bronchiectasis?	Kartagener syndrome.
	How do cells crawl?	Most cells exhibit the ability to crawl over surfaces rather than swim through liquids. Crawling relies on the intrinsic properties of the actin/microtubule cytoskeleton Crawling cells often rely on cues (chemotaxis) Crawling cells can move over other cells or on the ECM In maturing neurons, only one part of the cell is motile, the axon growth cone allowing neurons to "wire up" over long distances.
	Describe "pushing and grunting" cell motility.	1. Cell extends a leading edge (and area of the cell that protrudes). This can either be an extensive flat edge (lamellipodia) or a single process (filopodia). 2. Adhesions are established between the protrusive edge and the substrate (another cell or ECM). Actin filaments become associated with these adhesions. 3. The cell is able to retract its trailing edge and pull itself forward.
	What is lissencephaly?	Smooth brain. A neuronal migration defect caused by mutations in the gene Lis1. Lis1 is believed to play a role in the modulation of the cytoplasmic dynein protien.
	What are the six principles of cell adhesion?	1. Cells express a mixture of plasma membrane adhesion proteins as part of their differentiation program. 2. Many adhesion proteins bind only one main ligand and many ligands bind a single type of receptor. 3. cells modulate adhesion by regulation the surface density, state of aggregation, and state of activation of their adhesion proteins. 4. The rates of ligand binding and dissociation are important determinants of cellular adhesion. 5. Many adhesion proteins interact with the cytoskeleton inside the cell. 6. Association of ligands with adhesion proteins can activate intracellular signaling pathways that lead to changes in gene expression, cellular differentiation, secretion, motility, receptor activation, and cell division.
	What are the 5 basic families of adhesion proteins?	1. Immunoglobiun - heter or homo interactions 2. E-cadherins - homo interactions 3. Integrins - matrix interactions 4. P-selectin - transient hetero interactions 5. Mucin - transient hetero interactions
	What are integrins?	cell adhesion molecules that are concentrated in focal adhesions (the adhesion sites for cells moving on a matrix) Cellular contact with ECM (fibronectin/Laminin) causes clustering of integrins.
	What does clustering of integrins activate?	1. Actin filaments are recruited to the intracellular part of the molecules through a series of adaptors (stress fibers). Therefore any stress between cell and ECM is transmitted through stress fibers (also used in motility) 2. Signaling cascades are initiated that lead to changes in gene expression. Therefore the extrernal attachments that a cell makes helps to regulate whether it grows, dies, divides, survives, or differentiates.
	What are selectins?	They are a family of cell adhesion molecule. Found only in vertebrates circulatory system. Bind to oligosaccharides There are three types: L - leukocytes E - endothelial P - platelets From Wiki: As the leukocyte rolls along the blood vessel wall, the distal lectin-like domain of the selectin binds to certain carbohydrate groups presented on proteins (such as PSGL-1) on the leukocyte, which slows the cell and allows it to leave the blood vessel and enter the site of infection. The low-affinity nature of selectins is what allows the characteristic "rolling" action attributed to leukocytes during the leukocyte adhesion cascade.
	According to lecture, what are the three requirements of the epithelial barrier?	1. the cells must be connected together such that nothing passes between them. 2. the cells must be polarized so that materials pass between the inside and outside of the barrier in the right direction 3. the cells must be mechanically connected such that stress is dissipated.
	What are tight junctions?	the closely associated areas of two cells whose membranes join together forming a virtually impermeable barrier to fluid. Tight junctions join together the cytoskeletons of adjacent cells. Main proteins are CLAUDINS - form semi-permeable pores
	What is an adherens junction?	a cell junction whose cytoplasmic face is linked to the actin cytoskeleton. Composed of Cadherins that span the membrane through Ca2+ mediated homophilic interactions. Link to actin filaments to form the adhesion belt. Myosin contraction of the adhesion belt can cause the pursestring phenomenon that might aid the formation of epithelial tubes from sheets.
	What are desmosomes?	Desmosomes help to resist shearing forces and are found in simple and stratified squamous epithelium. Utilize desmoglein.desmocollein which are cadherin like molecules. these are connected to intermediate filaments to handle tensile stress.
	What is a gap junction?	Allow for direct communication between cells. They are open/closed aqueous channels. Consist of hexamers of connexin proteins called CONNEXONS. Connexons from adjacent cells form a continuous channel between cells.
	What is a hemi-desmosome?	Hemidesmosomes (HD) are very small stud- or rivet-like structures on the inner basal surface of keratinocytes in the epidermis of skin. While desmosomes link two cells together, hemidesmosomes attach one cell to the extracellular matrix. Rather than using cadherins, hemidesmosomes use integrin cell adhesion proteins.LINK TO INTERMEDIATE FILAMENTS INSTEAD OF ACTIN.
	What are the molecular causes of Epidermolysis Bullosa?	Defects in Keratin Defects in collagen Defects in laminin Defects in integrins
	Tight Junctions: Target Molecule? Adhesive Protein? Cytoplasmic Proteins? Cytoskeletal Filaments?	SEALING OF EXTRACELLULAR SPACE Target Molecule - OCCLUDIN and CLAUDIN Adhesive Protein - OCCLUDIN and CLAUDIN Cytoplasmic Proteins - ZO-1, ZO-2, cingluin, spectrin Cytoskeletal Filaments - actin
	Gap junction: Target Molecule? Adhesive Protein? Cytoplasmic Proteins? Cytoskeletal Filaments?	COMMUNICATION BETWEEN CELLS Target Molecule - CONNEXIN Adhesive Protein - CONNEXIN Cytoplasmic Proteins - ZO-1, drebrin Cytoskeletal Filaments - actin
	Adherens Junctions: Target Molecule? Adhesive Protein? Cytoplasmic Proteins? Cytoskeletal Filaments?	ADHESION TO OTHER CELLS Target Molecule - CADHERIN Adhesive Protein - CADHERIN Cytoplasmic Proteins - Catenins, plakoglobin Cytoskeletal Filaments - actin
	Desmosome: Target Molecule? Adhesive Protein? Cytoplasmic Proteins? Cytoskeletal Filaments?	ADHESION TO OTHER CELLS Target Molecule - DESMOGLEIN, DESMOCOLLIN Adhesive Protein - DESMOGLEIN, DESMOCOLLIN Cytoplasmic Proteins - plakoglobin, desmoplkin Cytoskeletal Filaments - INTERMEDIATE
	Hemidesmosome: Target Molecule? Adhesive Protein? Cytoplasmic Proteins? Cytoskeletal Filaments?	ADHESION TO EXTRACELLULAR MATRIX Target Molecule - laminin Adhesive Protein - integrin Cytoplasmic Proteins - plectin, BP 180 Cytoskeletal Filaments - Intermediate
	Focal Contact: Target Molecule? Adhesive Protein? Cytoplasmic Proteins? Cytoskeletal Filaments?	ADHESION TO EXTRACELLULAR MATRIX Target Molecule - Fibronectin Adhesive Protein - integrin Cytoplasmic Proteins - talin, vinculin, alpha-actinin Cytoskeletal Filaments - actin
	What junction/s is/are involved in sealing of extracellular space?	Tight junction
	What junction/s is/are involved in communication between cells?	Gap junctions
	What junction/s is/are involved in adhesion to other cells?	Adherens junctions Desmosomes
	What junction/s is/are involved in adhesion to ECM?	Hemidesmosomes Focal Contact
	How is tensile strength achieved?	2 ways: 1. cell-cell interactions and the cytoskeleton (intermediate filaments) 2. ECM - substance secreted and modeled by cells of varying consistency and amount.
	What are the functions of the ECM?	1. strength and support for the cell and tissue 2. feedback signals from the tissue to the cell (stretching) 3. regulation of proliferation, differentiation, migration, and cell-cell interactions 4. reservoir and co-receptor for growth factors
	What are the relative levels of ECM in each of the 4 tissue types?	Epi - very minimal Neural - minimal Muscle - minimal The majority of ECM (most abundant) is found in connective tissue
	According to lecture, what are the four components of ECM?	Collagens: tensile strength Proteoglycans: compression resistant space fillers Elastin: flexibility Fibronectin/Laminins: cell signaling
	What is collagen characterized by? How is it synthesized?	Characterized by triple helical nature. Gly-X-Y characteristic repeating structure. It is synthesized when the coil-coil domains of collagen wrap around each other to form the procollagen molecule. Then they go to the Golgi to be secreted. Once they are outside they cell they are subject to proteolytic cleavage and N glycosylation.
	What is osteogenesis imperfecta?	It is a disease in which mutations in the gly-X-Y repeat cause defects in type 1 collagen. Type 1 cominates in bone so brittle bones are the main symptom. Other symptoms include thin skin, short stature, abnormal teeth, and weak tendons.
	What is the main function of proteoglycans in the ECM?	They soak up water via the GAGs and become compression resistant. (the GAGs extend by electrostatic repulsion and are highly charged polyanions.) The proteoglycans are the concrete, the collagen is the rebar. PGs are also found on the surface of cells where they can bind growth factors as co-receptors, they also act as reservoirs for local GF activity.
	What are elastic fibers? What is their function in the ECM?	they are similar to rubber and are prominent in the connective tissue of skin, the walls of arteries, and lung. They are a misture of three components: a network of fibrillin microfibrils embedded in a core of cross-linked ELASTIN. Both the fibrillin and elastin are produced by fibroblasts.
	What is Marfan Syndrome?	Dominant trait affection the firbrillin-1 gene. Severity can run from mild to severe. Symptoms: very tall, long limbs, heart problems, early death.
	What is fibronectin?	an adhesive glycoprotein that binds collagen, proteoglycan and integrins. Has a role in x-linking the matrix and linking cells to the matrix found in connecting tissues throughout the body but particularly in embryos and would healing.
	What is laminin?	An adhesive glycoprotein that is associated with basement membranes (basal lamina). Also binds integrins, dystroglycans, heparin, heparin sulphate, and indirectly to collagen.
	What is tenascin?	an adhesive glycoprotein associated with the ECM of embryonic tissues/wounds. Binds to integrins/proteoglycans and Ig superfamily members.
	What is the basal lamina?	a planar ECM that provides a foundation for muscle, nerves, and epithelial tissue. Epithelia sit on the BL which provides cues for polarization. BL also acts as a semi-permeable filter for certain macromolecules.
	What are matrix metalloproteinases?	specific enzymes that help remodel the ECM Two types: Secreted Membrane Anchored
	What is tissue engineering?	uses a combo of cells, engineering and materials to imporve or replace the biological functions of tissues or organs. Engineering and materials science can be used in the manufacture of a scaffold which can be populated by cells either in vivo or in vitro. Some scaffolds can be modified or even degraded by the cell populations.
	Name some of the processes that ion channels are basic and essential for.	- cardiac pacemaking - nerve conduction - muscle contraction - electrolyte balance - hormone secretion - vascular tone
	What are some common ion channel structural motifs?	Pore-forming subunit = alpha subunit Alpha subunit forms selectivity filter Selectivity filer gives ion channel its specificity Accessory sub-units often exists
	What is ion gating?	Channels can change between conducting and non-conducting Ion channels can change their conformation frequently Some conformations are "open" and some "non-conducting"
	Why do channels gate between different states?	Various effectors make channels gate: -Voltage gated - changes in transmembrane voltage exert forces on the charged amino acids which pull the channel into different conformations. - Ligand Gated -metabolically linked (ATP-gated) - mechanical (stretch activated) - Drugs
	1. When the membrane potential is negative, what is the conformation of the Na+ channel? 2. What happens when the membrane depolarizes? 3. What happens if the membrane stays positive?	1. Closed 2. Opens 3. channel becomes inactivated
	What is laminin?	An adhesive glycoprotein that is associated with basement membranes (basal lamina). Also binds integrins, dystroglycans, heparin, heparin sulphate, and indirectly to collagen.
	What is tenascin?	an adhesive glycoprotein associated with the ECM of embryonic tissues/wounds. Binds to integrins/proteoglycans and Ig superfamily members.
	What is the basal lamina?	a planar ECM that provides a foundation for muscle, nerves, and epithelial tissue. Epithelia sit on the BL which provides cues for polarization. BL also acts as a semi-permeable filter for certain macromolecules.
	What are matrix metalloproteinases?	specific enzymes that help remodel the ECM Two types: Secreted Membrane Anchored
	What is tissue engineering?	uses a combo of cells, engineering and materials to imporve or replace the biological functions of tissues or organs. Engineering and materials science can be used in the manufacture of a scaffold which can be populated by cells either in vivo or in vitro. Some scaffolds can be modified or even degraded by the cell populations.
	Name some of the processes that ion channels are basic and essential for.	- cardiac pacemaking - nerve conduction - muscle contraction - electrolyte balance - hormone secretion - vascular tone
	What are some common ion channel structural motifs?	Pore-forming subunit = alpha subunit Alpha subunit forms selectivity filter Selectivity filer gives ion channel its specificity Accessory sub-units often exists
	What is ion gating?	Channels can change between conducting and non-conducting Ion channels can change their conformation frequently Some conformations are "open" and some "non-conducting"
	Why do channels gate between different states?	Various effectors make channels gate: -Voltage gated - changes in transmembrane voltage exert forces on the charged amino acids which pull the channel into different conformations. - Ligand Gated -metabolically linked (ATP-gated) - mechanical (stretch activated) - Drugs
	1. When the membrane potential is negative, what is the conformation of the Na+ channel? 2. What happens when the membrane depolarizes? 3. What happens if the membrane stays positive?	1. Closed 2. Opens 3. channel becomes inactivated
	Where are embryonic stem cells derived from?	the inner cell mass of the pre-implantation blastocyst and are capable of differentiating into all cell types in the body.
	What is self renewal in reference to stem cells?	the process by which a stem cell divides to a daughter stem cell with developmental potentials that are indistinguishable from those of the mother cell.
	According to lecture, what are the applications of ES cells?	- rebuilding the NS - repair injured myocardium - diabetes - traumatic spinal cord injury - Purkinje Cell degeneration - liver failure - muscular dystrophy - osteogenesis imperfecta - toxicology
	What is apoptosis?	Programmed cell death. It can be caspase independent or dependent.
	What occurs during caspase dependent apoptosis?	Cell shrinking and blebbing Cell fragmentation Apoptotic bodies Requires ATP Ladder-like DNA fragmentation individual cells can be affected NO INFLAMMATION THESE do not occur during caspase independent - we are not sure exactly how caspase independent apoptosis works.
	What occurs during necrosis?	Cell swelling Membrane breakdown Cellular rupturing Whole tissue areas are affected ALWAYS GET INFLAMMATION
	What is necrosis?	Passive, unprogrammed cell death that usually occurs via injury Less precise than apoptosis
	How is apoptosis induced?	Two pathways: 1. cell surface death receptor mediated - extrinsic 2. mitochondrial-initiated pathway (intrinsic)
	Describe the extrinsic apoptosis pathway.	Death ligands bind with death receptors which initiate CASPASE 8 which activates Caspase 3 and this leads to apoptosis.
	Describe the intrinsic pathway of apoptosis.	DNA damage and p53 activate mitochondria which releases cytochrome C --> initiator Caspase 9 --> Caspase 3 --> apoptosis
	What is the caspase that is common to both the extrinsic and intrinsic apoptosis pathways?	Caspase 3
	What are the major ligands in apoptosis?	FasL - Receptor = FAS (CD95) TNF - Receptor = TNF-R TRAIL - Receptor = DR4 (Trail-R)
	What are some factors that can induce the intrinsic pathway of apoptosis?	Stress UV Chemo Hypoxia GF withdrawl
	What are caspases?	Cysteine proteases that cleave over 100 substrates to induce cell death Synthesized as inactive zymogens
	How are caspases inactivated? Activated?	Inactivated: Nuclear lamins DNA repair enzymes Activated: Cytoskeleton Other caspases (cascade) Caspase-activated DNAase (CAD)
	What are the two classes of caspases?	Intiator Caspases: activated by upstream signaling events that cause pro-caspase to aggregate and undergo autocleavage. These can cleave and activate the effector caspases Effector caspases: are responsible for cleaving most apoptotic substrates
	What are the substrates of caspases?	Apoptotic and inflammatory regulators Protein kinases and other signal transduction regulators Cytosolic and nuclear structural proteins Repair and housekeeping enzymes Cell Cycle Regulators Disease related factors
	What is a diseases associated with insufficient apoptosis?	Cancer - cell accumulation Autoimmunity - failure to eliminate autoreactive lymphocytes Restenosis - accumulation of vascular smooth muscle cells in the walls of arteries Persistent infections - failure to eradicate bacteria- or virus-infected cells
	What are some conditions/diseases associated with excessive apoptosis?	Ischemia Heart failure - loss of myocardiocytes Neurodegeneration Osteoarthritis HIV - depletion of T lymphocytes Bacteria infection - apoptosis inducing virulence proteins are secreted into the cytosol of host cells Type I diabetes - immune mediated destruction of the islets of Langerhands
	According to lecture, what is included in the "chromosome cycle" of the cell cycle?	DNA replication (synthesis in S) Physical separation of two complete genomes to daughter nuclei
	According to lecture, what is included in to the "growth cycle" of the cell cycle?	Replication of all other cell components Physical Separation to daughter cells
	What are the stages of the cell cycle?	M (G0) G1 S G2
	What are the major regulators of the cell cycle? What do they work on?	Cyclins they work on cyclin-dependent kinases Multiple cdks and cyclins regulate passage of mammalian cells through the cell cycle Every cyclin has a unique pattern of expression
	What cyclins are expressed during G1?	Cdk4 - cyclin D Cdk6-cyclin D Different cyclins and cdks can interact together*
	What is a CDK?	cyclin dependent kinase
	What is the cell cycle checkpoint in between G1 and S?	DNA Damage - G2 arrest
	What is the cell cycle checkpoints in between S and M?	Unreplicated DNA - S arrest DNA damage - G2 Arrest
	What is the cell cycle checkpoint at M?	Improper spindle formation - M arrest
	G1 and G2 arrest in cells with damaged DNA depends on what?	p53 tumor suppressor p53 mutiations drive cells into S phase - found in > 50% of cancers
	According to lecture, what are three cancers that arrive from epithelial, mesenchymal, and hematopoietic cells?	Epi - carcinomas mesenchymal - sarcomas Hemopoeitic - leukemias and lymphomas (liquid cancers)
	In terms of differentiation, what is benign? What is malignant?	Benign - structure often typical of tissue or origin Malignant - structure often atypical (poor differentiation)
	In terms of mode of growth, what is benign? What is malignant?	Benign - purely expansive, within capsule Malignant - infiltrative and expansive with no capsule
	In terms of rate of growth, what is benign? What is malignant?	Benign - slowly progressive or may stop figures scantly and normal Malignant - rapid with many abnormal mitotic figures
	In terms of metastasis, what is benign? What is malignant?	Benign - absent Malignant - frequently present
	How are benign tumors characterized?	localized usually grow slowly compress, rather than infiltrate, adjacent tissue, often forming a capsule do not spread generally do not recur after removal may be self limiting or regress have cellular structure resembling that of the tissue of origin
	How are malignant tumors characterized?	infiltration of malignant cells into surrounding tissues invasion of neoplastic cells into blood and lymph vessels spread of tumor cells to other parts of the body to establish secondary growths (metastasis)
	What is the definition of malignant cells? What are their characteristics?	Definition - anaplstic, invasive and metastatic Characteristics: Unregulated cell growth loss of contact inhibition of growth undifferentiated - loss of gorwth regulation and therefore grow uncontrollably dedifferentiated - loss of function invasive in nature unlimited mitosis DNA changes multinucleated phenotype
	what is hyperplasia?	increase in size of organ or tissue due to increase in cell number REVERSIBLE
	What is dysplasia?	abnormal cell proliferation REVERSIBLE loss of normal architecture chronic irritation/inflamation
	What is metaplasia?	Transformation of tissue from one type to another. REVERSIBLE From wiki: The change from one type of cell to another is generally caused by some sort of abnormal stimulus. In simplistic terms, it is as if the original cells are not robust enough to withstand the new environment, and so they change into another type more suited to the new environment.
	what is anaplasia?	Loss of structural differentiation Reversion to a more primitive state REVERSIBLE
	What is neoplasia?	Disease of cells Alteration in normal growth IRREVERSIBLE
	What is an acquired mutation?	not inherited but "added" in the sense that it was no present at birth - result of carcinogenesis
	What are some types of agents that cause mutations related to cancer?	Viral Chemical Physical Microbial Genetic
	What is the Ames test for carcinogenicity? What is the procedure?	A test to see how carcinogenic a substance is. Prodcedure: Homogenize rat liver Insert test compound Metabolic activation of test compound by rat liver enzymes Add to Salmonella bacteria unable to grow without histidine in culture medium Count number of bacterial colonies that have undergone mutation enabling them to grow without added histidine - THIS SHOWS THE ABERRANT GROWTH WITHOUT THE NECESSARY MEDIUM. CAN GROW IN PRESENCE OF ANTIBIOTICS ETC.
	What is a proto-oncogene?	A normal growth controlling gene that when mutated or abnormally expressed can contribute to tumorigenesis as an oncogene. All of these can become an oncogene: GFs GFs receptors non-receptor kinases signal transducers transcription factors nuclear proteins
	What is a tumor suppressor gene? Examples?	anti-oncogene is a gene that protects a cell from one step on the path to cancer. When this gene is mutated to cause a loss or reduction in its function, the cell can progress to cancer, usually in combo with other genetic changes. Ex: p53 - transcription factor Retinoblastoma protein (pRb)
	What are some of the mechanisms of proto-oncogene activation to oncogenes?	point mutations, deletions, insertions gene amplification translocation loss of promotoer control enhancers
	What is genomic imprinting?	Selective repression of expression of genetic allele from iether the maternal or paternal gene set
	What is trinucleotide expansion?	Interspersed repeated DNA sequences can undergo a variation in copy number (dynamic mutation) results from an increase in tinucleotide sequences.
	What is a monoclonal tumor?	A tumor that is made up of a clone of the same cell
	What is a polyclonal tumor?	A tumor that is made up of variants of a single cloned cell.
	What is a tumor angiogenic factor?	Substance released by solid tumors that induces formation of new blood vessels to supply the tumor.
	What is vascular endothelial growth factor?	A peptide released from vascular endothelial cells and other cells in response to hypoxia, ischemia, or hypoglycemia. VEGF promotes angiogenesis.
	How do TAF and VEGF aid in tumor growth?	tumor cells can secrete these and sustain their own growth and help ensure their own survival
	What is meant by "the non-random pattern of metastasis"?	certain tumor types tend to metastasize to specific organs metastasis depends on cross-talk between sleected cancer cells (the 'seeds') and specific organ microenvironments (the 'soil')
	What is metastasis?	the process by which cancer spreads from the place at which it first arose to distant locations in the body, by way of the circulatory system.
	According to lecture, what are some of the treatment options for tumors?	Tumor immunology Surgery Chemo Radiation biotherapy chemoprevention
	What percentage of patients treated with a certain medication may no get any benefit?	25-75%
	What does CYP2D6 *4 mutation do?	create a non-functional protein
	What is a type 1 error?	Reject null when null is valid (false positive)
	What is a type II error?	accept null when alternative is valid (false negative)
	What is clinical sensitivity?	proportion of all people with disease who test positive Value approaching 1 is desirable for ruling OUT disease and indicates a low false negative rate If 100% sensitivity, False negatives = 0
	What is clinical specificity?	proportion of all people without disease who test negative. Value approaching 1 is desirable for ruling IN people with the disease and indicates a low false positive rate.
	What happens if you set the cut off low? High?	Low - maximize sensitivity High - maximize specificity
	What is positive predictive value?	Proportion of positive test results that are true positive. *if the prevalence of a disease in a population is low, even tests with high specificity or high sensitivity will have low PPV As prevalence increases, PVP always increases for any test with set sensitivity and specificity. PVN will decrease.
	What is Negative predictive value?	Proportion of negative test results that are true negative.

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