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298 Cards in this Set
- Front
- Back
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In broad terms, what are the two stages of glycolysis?
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GLUCOSE makes 2 TRIOSE-PHOSPHATES in stage 1.
TRIOSE PHOSPHATE is made into 2 PYRUVATES in stage 2. |
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What is the first commited metabolite of glycolysis?
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Fructose 1,6 bisphosphate
Made by the PFK-1 mediated ATP phosphorylation of Fructose-6-phosphate |
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What is the rate limting reaction in glycolysis?
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The PFK-1 mediated ATP phosphorylation of Fructose-6-phosphate to make Fructose 1,6 bisphosphate.
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At what two points in Stage 1 glycolysis is ATP spent?
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Conversion of Glucose to Glucose-6-phospate (trapping it in the cell)
The PFK-1 mediated ATP phosphorylation of Fructose-6-phosphate to make Fructose 1,6 bisphosphate. |
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What are the two triose phosphate products of Stage 1 glycolysis?
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Dihydroxyacetone phosphate
Glyceraldehyde-3-phosphate. Both are made from fructose 1-6-bisphosphate by aldolase. Triose phosphate isomerase can turn either one into the other but usually favors G3P since it is the substrate for stage 2 of glycolysis. |
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When G3P enter stage 2 of glycolysis, what is the first thing that happens to it?
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It is phosphorylated by G3P dehydrogenase to make the higher energy 1,3-Bisphophoglycerate (BPG)
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In which two glycolysis reactions is ATP actually made?
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BPG converted to 3-phosphoglycerate by phosphoglycerate kinase.
Phosphoenolpyruvate turned into pyruvate by pyruvate kinase. Both are in stage 2 of glycolysis. |
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BPG is typically converted to 3-phosphoglycerate by phosphoglycerate kinase. What other fate can this molecule have though?
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In RBC's about 25% of the total glucose can be converted to 2,3-Bisphosphoglycerate by Bisphosphoglycerate mutase. 2,3 BPG lowers the oxygen affinity of hemoglobin.
Fetal hemoglobin has a lower affinity for this compound than adult hemoglobin which is important for placental oxygen exchange. |
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What happens to the 3-phosphoglycerate made from BPG by phosphoglycerate kinase in stage 2 of glycolysis?
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It is manipulated first by phosphoglyceromutase which transfers phosphate from C3 to C2 and then by enolase to result phosphoenolpyruvate (PEP).
PEP is the second to last molecule in glycolysis and is acted upon by pyruvate kinase to make pyruvate and ATP. |
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What characteristic of pyruvate kinase helps with the regulation of glycolysis?
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More active in the fed state than the fasting state.
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Under anaerobic conditions, Pyruvate is converted into...
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Lactic acid by lactate dehydrogenase.
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Under aerobic conditions, pyruvate is converted into...
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Acetyl Co-A by the pyruvate dehydrogenase complex.
The PDH complex is what connects anaerobic metabolism to aerobic metabolism. |
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What are the three main parts of the PDH complex?
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E1 subunit-The pyruvate dehydrogenase enzyme which carries out decarboxylation of pyruvate (Pulls off a CO2).
E2 subunit- The dihydrolipoyl transacetylase portion that actually makes acetyl CO-A E3 subunit- The dihydrolipyl dehydrogenase portion that regulates the REDOX state of the complex and allows it to do what it does over and over again. |
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The E1 subunit of the PDH complex which removes a CO2 from pyruvate works by binding and unbinding...
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Thiamine pyrophosphate (TPP)
The result is a 2 carbon fragment that enters E2. |
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The 2 carbon fragment is transfered from the E1 to E2 subunit of the PDH complex by...
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The cofactor lipoic acid.
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The E2 subunit of the PDH complex is responsible for...
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Adding CO-A to the 2 carbon fragment it gets from E1.
In the process, the lipoic acid gets reduced. |
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The E3 subunit reoxidzes the lipoic acid of E2 but in the process....
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It reduces FAD to FADH.
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The FADH made by the E3 subunit of the PDH complex is unusable and must be reoxidized for the PDH complex to keep working. This is done by converting...
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NAD to NADH.
The NADH is fed into complex 1 in the mitochondrial matrix to make ATP. |
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When a person comes in with a lactic acid/pyruvate acidosis, we give them..
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Thiamine
This is to try and jump start the PDH complex. |
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Arsenic works by...
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Inhibiting one of the subunits of the PDH complex.
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The 2C Acetyl Co-A made by the PDH complex will be bound to...
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4C oxaloacetate which comes FROM the TCA cycle.
Together these two molecules make citrate that can enter the TCA cycle. The enzyme responsible is citric synthase and is said to be "the pacemaker" because it controls the rate of the TCA cycle. |
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Citric synthase is regulated prinicipally by...
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The binding of oxaloacetate.
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What is the first thing that happens to citrate when it enters the TCA cycle?
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Water is removed and then added to it in a different position by the Fe/S containing enzyme aconitase to make isocitrate.
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What happens if there is a disease of the enzyme aconitase?
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TCA cycle cannot proceed.
Eg. If Fe/S is not added to aconitase by fraytaxin, the outcome is friedrich's ataxia which hits neural tissues hardest because they are the most aerobic. |
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What is the fate of the isocitrate made by aconitase?
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It is acted upon first by isocitrate dehydrogenase and then by the alpha-ketogluterate dehydrogenase complex to make succinyl CO-A.
Both reactions produce NADH by removing a CO2 (decarboxylation) |
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What is the fate of the succinly Co-A made by the alpha-ketoglutarate complex?
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The energy in the thioester bond of the Succinly Co-A is used to drive the synthesis of a high energy phosphate (GTP) when it is is dismantled by Succinyl Co-A synthetase to make succinate.
Succinate dehydrogenase then acts on the remaining succinate and converts it to fumarate while producing an FADH2 in the process. |
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What happens to fumarate made by succinate dehydrogenase in the TCA cycle?
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It is made into malate and then oxaloacetate by fumarase and then malate dehydrogenase.
Malate dehydrogenase makes NADH in the process. |
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What are the intemediaries in order of the TCA cycle?
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Oxaloacetate
Citrate Isocitrate alpha-Ketoglutarate Succinyl-CoA Succinate Fumarate Malate Mnemonic: Our City Is Kept Safe And Sound From Malice All enzymes of the TCA cycle are in the mitochondrial matrix except succinate dehydrogenase which is in the inner mitochondrial membrane. |
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How does cytosolic oxaloacetate get into the mitochondrion?
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The malate aspartate shuttle.
Oxaloacetate is an intemediary compound between malate and aspartate. Energy (one NADH)is invested in the cytosol to turn it into malate which can enter the mitochondria and is then recouped by turning it back to oxaloacetate and generating an NADH for electron transport and ATP synthesis. The reverse happens if aspartate is needed in the cytosol with different energy molecules (glutamate/alpha-ketoglutarate). |
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Why is the malate aspartate shuttle important?
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It regenerates the NAD in the cytosol required to maintain glycolysis.
The NADH made in the cytoplasm can be used to generate ATP. |
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What intemediaries of the TCA cycle can be shunted off to other pathways?
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Oxaloacetate-amino acids
Citrate-fatty acids, cholestrol α-Ketoglutarate- Amino acids Succinyl CoA-Porphyrins |
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The unifying theme of TCS cycle regulation is that...
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The allosteric effectors that influence the rate limiting enzymes reflect the energy status of the cell.
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What are the three key reactions that regulate glycolysis?
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Hexokinase/glucokinase phosphorylation of glucose.
(mostly dependant of amount of enzyme in the cel-lots of both in the liver) Conversion of fructose-6-phosphate to fructose-1,6-bisphosphate by PFK-1. (binding affinity for substrate is decreased by ATP and citrate but increased by AMP and ADP) Manufacture of Pyruvate from phosphoenolpyruvate by pyruvate kinase. (Inhibited by the fasting signal glucagon which ultimately leads to phophorylation of PFK-1 by PKA and inactivates it. It can also be upregulated by its own product fructose-1,6-bisphosphate or downregulated by molecules that signal the very well fed state such as Alanine, Acetyl – CoA and fatty acids) |
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How is the pyruvate dehydrogenase complex that makes acetyl-CoA regulated?
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A kinase and a phosphatase are attached to the complex.
The kinase can phosphorylate the pyruvate binding E1 part of the complex and inactivate it in response to elevated levels of ATP,NADH and Acetyl-CoA. The phosphatase can dephosphorylate E1 and activate it in response to calcium. |
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What are the major sites of regulation in the TCA cycle?
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Isocitrate dehydrogenase
(inhibited by high ATP, upregulated by high ADP and/or calcium) Alpha-ketoglutarate dehydrogenase. (Inhibited by high levels of its products succinyl-CoA and NADH, upregulated by calcium) |
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How does chronic fructose intolerance present?
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Poor feeding
Failure to thrive Incessant crying Irritability Apathy Jaundice Hepatomegaly Tremor Edema Poor growth |
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What is typically the pathology of fructose intolerance?
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Fructose-1-P (made by the highly active fructokinase) becomes elevated in liver,kidney and small intestine because of a deficiencey in the fructose-1-phosphate-aldolase enzyme that is supposed to turn it into G3P.
ATP is depleted. F-1-P also acts as an inhibitor of key enzymes. Amongst other things, this deficiency affects liver protein synthesis and clotting factors. Patients suffer from a renal fanconi like syndrome as well as decreased gluconeogeneis and glycogenolysis. Tx: Eliminate fructose and sucrose from the diet. |
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The most common glycolysis deficiency is...
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Pyruvate kinase deficiency.
It is common in pennsylvania and hits blood cells very hard because they are highly glycolytic and because glycolysis plays a role in RBC osmoregulation. The disorder generates echinocytes (damaged or shrunkne red blood cells) which lead to phagocytosis and anemia. Splenectomies and bone marrow transplants can help. |
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What are the three mechanisms for the maintenance of euglycemia?
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Diet
Glycogenolysis Gluconeogenesis |
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Which organs are inflexible about their need for glucose?
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Brain
Red blood cells Kidneys |
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Which molecules can be the substrates for gluconeogenesis?
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Amino acids
Lactate Glycerol |
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What are the steps of glycogen synthesis?
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Initiation
Elongation Branching Elongation |
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Every glycogen contains an initiation protein called...
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glycogenin
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Glycogen is bound together by..
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alpha 1,4 glycosidic bonds
alpha 1,6 glycosidic bonds at the branch points. |
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Glycogen synthesis begins on the 194 tyrosine residue of the glycogenin molecule which has an intrinsic glycosyl transferase activity. Glucose monomers are added by glycogen synthase but come from...
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UDP glucose
(uridine diphosphate glucose) Phosphoglucomutase converts glucose-6-phosphate to glucose-1-phosphate. Glucose 1-phosphate reacts with UTP in a reaction mediated by UDP-glucose pyrophosphorylase to make UDP glucose. |
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The rate limitng enzyme in glycogen synthesis is...
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Glycogen synthase.
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What enzyme creates the branching in glycogen?
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Branching enzyme
aka Amylo-1,4 -1,6 transglycosylase |
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In the fasting state, how does glycogenolysis occur?
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Phosphorolysis
Debranching Dephophorylation |
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What is phosphorolysis?
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The enzyme glycogen phosphorylase breaks the alpha 1,4 bonds using inorganic phosphate.
The result is glucose-1-phosphate which in muscle cells can be reconverted to glucose-6-phosphate by phosphoglucomutase. Not so in the liver though.Here the glucose-6-phosphate is taken up into the ER where it is coverted to free glucose by glucose-6-phosphatase. It is then transported to the cell membrane by T2 and T3 and thrown into the blood stream by the facilitated glucose transporter GLUT-2. |
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How is debranching of glycogen handled?
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Debranching enzyme
aka (1,4) TO (1,4) Glucantransferase- Amylo (1,6) Glucosidase. It modifies branch point stubs so that glycogen phosphorylase can break them. |
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The rate limiting enzyme for the breakdown of glycogen (glycogenolysis) is....
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Glycogen phosphorylase.
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Regulation of glycogen storage or breakdown is based on signals from...
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Insulin
(Causes glycogen synthase to make glycogen) Glucagon (Causes glycogen phosphorylase to break glycogen) |
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Where are the enzymes associated with glycogen metabolism?
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Bound to the glycogen particle.
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When insulin binds an insulin receptor on a liver cell and thus signals the well fed state, what happens?
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It activates a kinase which puts phosphate on protein-phosphatase-1 .
PP-1 in turn, pulls phosphates off of phosphorylase kinase and glycogen phosphorylase and causes them to turn off and stop glycogen breakdown. This makes sense because we dont want to use glycogen in the well fed state. PP-1 also takes a phosphate off of glycogen synthase which causes it to become more active and store more glycogen. |
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When glucagon binds a glucagon receptor on a liver cell and thus signals the fasting state, what happens?
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It activates adenyl cyclase to make cyclic AMP.
Cyclic AMP activates protein kinase A which adds phosphates to phosphorylase kinase and glycogen phosphorylase (activates them)as well as to glycogen synthase (inactivates it). Phosphorylase kinase also activates (phosphorylates) an inhibitor protein of protein phosphatase 1 to prevent that enzyme from undoing the work of phosphorylation. The net result is promotion of gluconeogenesis and inhibition of glycogen synthesis. |
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How long is glycogen good for as an energy source?
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12 hours tops.
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Other than glycogen, what other molecules can be sources of glucose through gluconeogenesis?
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Amino acids
Lactate Glycerol They can be turned into pyruvate and then converted to glucose. |
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What is the main gluconeogenic amino acid?
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Alanine
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How do people typically die of starvation?
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Pneumonia.
Protein resources in the diaphragm and intercostal muscles are exhausted by gluconeogenesis and poor ventilation leads to infection. |
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Gluceoneogenesis is similar to which other pathway?
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It is essentially glycolysis in reverse.
From pyruvate to glucose. |
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In gluconeogenesis, the enzymes that convert pyruvate to phosphoenolpyruvate are...
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PEP-Carboxykinase
Pyruvate Carboxylase The glycolysis (forward reaction) equivalent of this is pyruvate kinase. |
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In gluconeogenesis, the enzyme that turns fructose 1,6-bisphosphate into fructose-6-phosphate is....
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Fructose-1,6-bisphosphatase
The glycolysis (forward rection) equivalent of this is PFK-1. |
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In gluconeogenesis, the enzyme that turns glucose -6-phosphate into glucose is....
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Glucose-6-phosphatase
The glycolysis (forward rection) equivalents of this are Hexokinase and glucokinase. |
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In gluconeogenesis, how is pyruvate brought out of the mitochondria and into the cytosol to make phosphoenolpyruvate?
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The biotin containing enzyme pyruvate carboxylase (which is allosterically regulated by acetyl CoA) adds a CO2 using ATP and turns it into oxaloacetate which becomes malate.
Malate passes out of the mitochondrion and is turned back into oxaloacetate in the cytosol. PEP carboxykinase then removes the CO2 from oxaloacetate in the cytosol to make phosphoenolpyruvate but this too requires a high energy phosphate that comes from GTP. |
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Pyruvate carboxylase is allosterically regulated by...
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Acetyl Co-A
If Acetyl Co-A is high,it activates pyruvate carboxylase to promote gluconeogenesis and inhibits the PDH complex that feeds the TCA cycle. In along term fast, making circulating glucose is more important than TCA cycle for an individual cell. |
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Gluconeogenesis is regulated by rates of gene transcription. How does this work?
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Glucagon (fasting state signal) activates a nuclear signal through a protein kinase cascade that upregulates the transcription of gluconeogenic enzyme genes.
Specifically: PEP carboxykinase Glucose-6-phosphatase Fructose-1,6-bisphosphatase |
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Where do lactate and alanine for gluconeogenesis come from?
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Muscle
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What is the relationship between fructose bisphosphatase and PFK-1 in the reciprocal regulation of glycolysis and gluconeogenesis?
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Fructose 2,6 bisphosphate is an activator of PFK-1 and a competitive inhibitor of FBPase.
This means that when Fructose-2,6-bisphosphate is elevated, glycolysis is upregulated and gluconeogenesis is downregulated. Conversely, low levels of Fructose-2,6-bisphosphate favor gluconeogenesis and supress glycolysis. |
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How is the level of fructose-1,6-bisphosphate regulated?
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In the fed state, insulin causes PFK-2 (which has both a kinse and a phosphorylase side) to be dephosporylated which means it is active as a kinase and inactive as a phosphorylase.
This causes stimulation of glycolysis and inhibition of gluconeogenesis. In the fasting state, glucagon elevates cyclic AMP which activates PKA. PKA phosphorylates PFK-2 which leads to a decline in FRU-2,6-BP levels. This favors gluconeogenesis. |
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What is a simpler way of stating the action of PFK-2?
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PFK-2 is a kinase in the fed state which favors glycolysis by elevating fructose-2,6-bisphosphate.
During fasting it is a phosphatase which favors gluconeogenesis by lowering fructose-2,6-bisphosphate levels. |
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What does glucose-6-phosphatase, the gluconeogenic equivalent of hexokinase and glucokinase do?
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It turns glucose-6-phosphate into glucose and this allows it to be transported out of the cell and into the circulation.
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How does the adipocyte contribute to gluconeogenesis ?
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Glycerol can be turned into glycerol-3-phosphate which can make dihydroxyacetone phosphate. This can make glyceraldehyde-3-phosphate which undergoes a reverse aldolase reaction to bring us right back to fructose-1,6-bisphosphate.
PEP carboxykinase is not a factor because this process skips the pyruvate stage. |
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What are the sites of glycogen metabolism disorders?
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In the cytosol:
Debranching enzyme Branching enzyme Glycogen phosphorylase GLC-6-P Phosphatase In the lysosome: α -1,4-Glucosidase |
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Type 1 glycogenosis or von gierkes disease is a defect in...
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Glucose 6-p phosphatase
These cupee doll babies have a problem converting Glucose-6-phosphate to free glucose which results in a fasting hypoglycemia, hyperlipdemia and hyperurecmia (gout) Type 1a (most common): Catalytic activity of G-6-Pase activity is damaged. Type 1b: GLC-6-P transporter is damaged. Type 1c: Phosphate transporter is damaged. Tx: Nasogastric nocturnal feeding. Uncooked corn starch. |
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Pompe's disease is a defect in...
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Alpha-1,4-glucosidase in the lysosome.
Glycogen acumulates in the lysosomes and eventually ruptures them and releases dangerous lysosomal enzymes. Patients typically have muscle issues including cardiac hypertrophy and weakening of respiratory muscles. They seldom live to 1 year. |
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Andersens's disease is a defect in...
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Glycogen branching enzyme.
There is a normal amount of glycogen but with very long outer branches. Affects the liver and spleen. Usually fatal by age 2. |
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Cori's disease is a defect in...
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Glycogen debranching enzyme
There is a large amount of glycogen but with short outer branches. Affects liver and muscle. Net result is like a mild pompe's disease. |
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What is I-cell disease?
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Degraded cellular constituents accumulate in the lysosome because lysosomal enzymes are not properly glycosylated in the golgi by N-acetylglucosamine-phosphotransferase and thus dont make it into the lysosome to do their work.
The buildup of cellular debris in the lysosomes becomes toxic. In addition, lysosomal enzymes are free floating in the cell and do significant damage. |
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What happens when the pyruvate dehydrogenase complex is defective?
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Lactic acidemia.
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How does glucagon promote gluconeogenesis?
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Regulation of PFK-2 and consequently Fructose-2,6-bisphosphate.
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Xanthomas (keloid like lesions on the skin) represent....
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Deposition of cholesterol ester in the fibroblasts of the tissues because of familial hypercholestrolemia.
(LDL receptor defect) |
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Lipids in the body are used for...
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Storage
Energy Biosynthesis |
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Lipids can be divided ito
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Complex lipids:
Glycerophospholipids Sphingolipids Triclyceride Simple lipids: Derived from cholestrol (steroid nucleus). Fancy name is cyclopentano-phenanthro ring system. |
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The difference between saturated and unsaturated fatty acids is that....
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Unsaturated fatty acids do not have hydrogens at every position of the chain.
They have some Cis double bonds that restrict their geometry and cause them to occupy more space. |
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The supramolecular form of lipids that carries lipid molecules through the blood is called a...
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Chylomicron
It is a lipoprotein. It has a phospholipid shell. It is full of triglyceride. |
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The smaller cousin to the chylomicron produced by the gut out of dietary lipid is the lipoprotein made in the liver out of denovo synthesized fatty acids which is called...
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VLDL
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The adipocyte delivers fat to the peripheral cells by making...
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Fatty acid/albumin complexes
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In summmary, what lipid transport molecules are made by each tissue?
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Gut=Chylomicrons
Liver=VLDL Adipocytes=fatty acid/albumin complexes. |
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Digestion of dietary triglycerides happens by...
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Gastric lipase (Fragments fats in the stomach)
Pancreatic lipase and colipase create free fatty acids. Bile salt micelles are formed which allow association with the microvillus and absorption into the mucosal cell. Triglycerides are reassembled and self associate (hydrophobicity) as a droplet. The droplet acquires a phospholipid shell and apoprotein B. It squirts out of the liver and into the lymphatic duct where it will be dumped into the blood stream and circulated throughout the body. |
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What is lipoprotein lipase?
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It exists bound to heparin sulfate proteoglycan projections attached to vessel walls.
Chylomicrons that have picked up Apoprotein C in the plasma bind to and are acted upon by lipoprotein lipase. Lipoprotein lipase breaks off fatty acids from triglycerides in the chylomicron core and faciliates transit of the fatty acids into the cells . |
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Defects in Apo C or lipoprotein lipase cause....
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Elevated plasma triglycerides
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How are fatty acids used for energy by the beta oxidation pathway?
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The fatty acid is activated by adding Co-A to it.
It is transported across the mitchondrial membranes by the carnitine shuttle. It is then broken down inside the mitochndrion into Acetyl-CoA which is fed into the TCA cycle. |
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How does the carnitine shuttle work?
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Carnitine circulates through porins and binds to the fatty acid in the cytoplasm.
The Co-A that was bound to the free fatty acid in the cytoplasm get knocked off in the cytoplasm. After the carnitine carries the fatty acid into the mitochndrion, Co-A is regenerated again by the process of uncoupling the fatty acid from carnitine. The enzymes responsible are carnitine-acyl-transferase 1 in the cytoplasm and carnitine-acyl-transferase 2 in the mitochondrial matrix. This process is a major regulator of how much beta oxidation happens. |
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What enzymes are involved in beta oxidation?
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The fatty acid is "prepared" by:
Acyl-CoA-dehydrogenase (FADH2 made) Enoyl-CoA-Hydratase Beta-hydroxyacyl-CoA dehydrogenase (NADH made) Thiolytic cleavage is done by : acyl-CoA-acetyltransferase (thiolase)-ATP is made. |
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Thiolase reduces the length of the fatty acid carbon chain by...
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two carbons each time it acts on it.
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Where are ketone bodies produced?
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Exclusively in the liver.
It is also the only organ that canot use them for energy. |
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What are the two metabolically important ketone bodies?
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Hydroxybutyrate (3)
Acetoacetate (1) Approx. 3:1 ratio in blood |
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When does the liver make ketone bodies?
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When acetyl-CoA is abundant.
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What enzyme is required for ketone body utilization?
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Succinyl-CoA-transferase
Activates the ketone with Co-A NOT found in the liver. |
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What enzyme is required for ketone body synthesis?
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HMG-CoA-Synthase
(prominent in the fasting liver) Shoots up in decompensated diabetics and partially explains the ketoacidosis. |
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What happens in genetic ketoacidotic disease?
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SCOT (Succinyl-CoA-transferase) deficiency.
Acidosis ensues after about 14 hours of fasting. |
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In a normal person, more or less how many calories should we be storing as fat?
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120,000
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What do we need to make complex lipids?
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Acetyl-CoA
Malonyl-CoA Double bonds Essential fatty acids Backbone: Glycerol-3-phosphate (for triglycerides and phsopholipids) Sphingosine (for sphingolipids) Cholesterol nucleus and intermediates. |
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The basic mechanism of fatty acid synthesis is....
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Sequential 2 carbon additions.
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What is the major source of cytosolic acetyl-CoA for fatty acid synthesis?
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Mitochondrial citrate from the TCA cycle.
The acetyl-CoA (as well as ATP) is a byproduct in the conversion of citrate to oxaloacetate by the cytosolic enzyme ATP-citrate-lyase. The oxaloacetate is made into malate and then pyruvate (by NADPH producing malic enzyme) and the pyruvate is sent back into the mitochondrion to rejoin the TCA cycle. |
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What are the two sources of NADPH in the cell?
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HMP shunt
Malic enzyme |
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How is malonyl Co-A made?
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it is synthesized from Acetyl-CoA by the RATE LIMITING ENZYME of fatty acid synthesis, acetyl Co-A carboxylase.
Acetyl Co-A carboxylase is a biotin cofactor requiring enzyme and uses ATP and CO2. Insulin stimulate acetyl Co-A carboxylase by indirectly dephosphorylating it. |
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The sequential addition of malonyl-CoA to the initial acetyl Co-A is done by the enzyme...
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Fatty acid synthase.
At each sequential 2 by 2 carbon addition, 2 NADPH are used and a CO2 is removed from the malonyl. |
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How do we get unsaturated fatty acids?
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Some, like linoleic acid (18C 2 double bonds) and linolenic acid (18C 3 double bonds) are essential and must come from the diet.
Others are made by adding cis double bonds to a saturated fatty acid with the enzyme fatty-acyl-CoA desaturase. The process requires NADPH and oxygen. |
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What is arachidonic acid and why is it important?
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A fatty acid with 20 carbons and 4 double bonds made from linoleic acid by elongase and double bond modification.
It is the precursor for eicosanoids which play a MAJOR role in inflammation. |
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How is fatty acid synthesis regulated?
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The manufacture of malonyl-CoA from Acetyl-CoA by acetyl-Coa carboxylase can be stimulated by increased amounts of insulin and citrate.
It can also be inhibited by increased amount of glucagon or fatty acids. In addition, Malonyl-CoA blocks fatty acids from entering the mitochndrion through the carnitine shuttle so that we don't beta-oxidize fatty acids we are trying to synthesize. |
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Before the action of elongase and desaturase, the product of fatty acid synthesis is..
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16 carbon palmitic acid
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What do we need to make a phospholipid?
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Backbone
Fatty acid Polar head group- Ethanolamine, choline, serine, glycerol or inositol. |
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What are the potential sources of the three carbon backbone of phospholipids; glycerol-3-phosphate (G3P) ?
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Glycerol itself (phosphorylated by Glycerol kinase)
Dihydroxy-acetone-phosphate made at the end of glycolysis can be converted to G3P by G3P dehydrogenase. |
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In phospholipid synthesis, what is the first thing that happens to glycerol-3-phosphate?
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It reacts with fatty acid-CoA and the fatty acid is added by acyl transferase to make phosphatidic acid.
Phosphatidic acid look like a triglyceride that has lost one chain and had a phosphate added instead. |
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Phosphatidic acid is the common starting point for lipid biosynthesis but before it can become anything...
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The phosphate group is removed to make a diglyceride.
The open site can accept a third fatty acid to make a triglyceride or a polar head group to make a phospholipid. It can also turn itnto a high energy derivative called cytidine diphosphate to make phosphatidylinositol or cardiolipin. |
|
|
What is the most important cofactor in the synthesis of phosphotidylcholine?
|
CTP
Cytidine triphophate. It energizes phosphocholine to make CDP-choline which in turn reacts with the diacylglycerol to make phosphatidylcholine, |
|
|
How is Phosphatidylinositol which is important for IP3 signalling and calcium regulation made?
|
CTP energizes the diacylglycerol to make CDP-diacylglycerol (in contrast to phosphotidylcholine synthesis where the choline is energized).
The inositol ring is then added to the energized portion of the molecule. |
|
|
What do we need to make a triglyceride?
|
Backbone
Fatty acids |
|
|
What enzyme converts phosphatidic acid to a diglyceride for lipd synthesis?
|
Phosphohydrolase
|
|
|
What is the effect of insulin on adipocytes?
|
Transcriptionally increases the levels of lipoprotein lipase and the GLUT-4 receptors.
This increases the amount of both fatty acids taken up from chylomicrons and the amount of glucose taken up from the circulation that can make glycerol-3-phosphate. In addition the glucose supports the oxidative leg of the HMP shunt which makes the NADPH necessary for de-novo lipid synthesis. |
|
|
How does glucagon influence adipocytes?
|
Activation of the glucagon receptors causes cyclic AMP to be made through a G-protein coupled receptor which activate protein kinase A.
PKA phosphorylates HORMONE SENSITIVE LIPASE. Hormone sensitive lipase liberates fatty acids from triglyceride droplets. The fatty acids cruise out of the adipocyte and hook up with serum albumin and can be transported pretty much everywhere. The leftover glycerol goes back to the liver where it can be used for gluconeogenesis or be converted back to glycerol-3-phosphate. |
|
|
What are the functions of sphingolipids?
|
Signal transduction
Apoptosis Cell recognition/adhesion Vesicle sorting/trafficking Membrane organization (lipid rafts) Extensive function in disease pathology. |
|
|
What are some of the important sphingolipids?
|
Sphingomyelin
(phosphocholine at C1) Glucosylcerebrosides (glucose at C1) Lactosylceramide (lactose at C1) Ceramide (H at C1) Gangliosides (complex oligosaccharide at C1) Sugar sphingolipids are called glycolipids (neutral or charged types with sialic acid) |
|
|
Cell-cell recognition between presynaptic and postsynaptic cells is dependant upon...
|
Gangliosides (Sphingolipids)
|
|
|
What are some examples of ganglioside deficiencies?
|
Tay-Sachs disease
Gaucher Fabry's disease Niemann pick disease Globoid leukodystrophy Metachromatic leukodystrophy All are associated with mental retardation, short life spans and buildups in cells. |
|
|
Tay Sachs disease, results from...
|
Inclusion bodies filled with GM2 ganglioside and glycosaminoglycans.
The inclusion bodies are there because of a deficiency in lysosomal hexosaminidase. Disturbances in the postnatal maturation of lipid rafts in the neuronal membranes lead to severe neurodegenerative symptoms. |
|
|
What is the role of complex lipids, specifically eicosanoids, in promoting acute and chronic inflammation?
|
Prostaglandins:
Made by most cells and cause increased vascular permebility,pain and fever. Thromboxanes: Made by platelets and macrophages. Cause vasoconstriction and platelet aggregation. Leukotrienes: Made by inflammtory cells (PMN, Macrophages, MAST cells). Cause vasoconstriction, increased vascular permeability, leukocyte attraction and inflammation. |
|
|
All of the eicosanoids are derived from...
|
Arachidonic acid
|
|
|
How are eicosanoids synthesized from arachidonic acid?
|
Arichidonic acid is acted upon by the cyclooxygenase pathway to make prostaglandins and thromboxanes.
Alternatively, it can be acted upon by the lipoxygenase pathway to make leukotrienes. |
|
|
What is phospholipase A2?
|
It is an enzyme that frees arachidonic acid from membrane phospholipids in response to an extracellular stimulus in order to initiate eicosanoid synthesis.
|
|
|
How do glucocorticoids work?
|
They stimulate a protein that blocks phospholipase A2.
|
|
|
How do aspirin, Indomethacin and ibuprofen work?
|
They inhibit cycloxygenase and therefore prevent the synthesis of parent prostanoids.
This prevents the synthesis of both prostaglandins and thromboxanes. |
|
|
What enzyme is responsible for making thromboxanes out of parent prostanoids?
|
Thromboxane synthase.
|
|
|
How do eicosanoids initiate their action?
|
They bind to G coupled receptors on target cells.
|
|
|
What two pathways that lead to platelet activation?
|
Phosphoinositide cycle
Thromboxane synthesis They both facilitate: Cytoskeleton rearrangement Fibrinogen receptor exposure Granule secretion |
|
|
Cyclooxygenase (Cox1, Cox 2) is also commonly called...
|
Prostaglandin H2 synthase
|
|
|
What is the significance of the cytoskeletal changes in plasma cells when they are acted upon by thromboxane?
|
Thromoboxane induces changes in intracellular calcium which cause the cell to acquire projections.
The projections expose the integrin glycoprotein-2b3a which can bind fibrinogen and form bridges with other plasma cells |
|
|
What platelet disorders originate from signal transduction problems?
|
PLA 2 deficiency and decreased thrombin calcium mobilization
Decreased COX activity and thromboxane synthase. Wiskott – Aldrich syndrome : WAS protein mutants Gq deficiency |
|
|
What sort of surface receptors do platelets have that are promising targets for drug therapy?
|
Aggregation molecules like integrins and fibrinogen binding sites.
Adhesion molecules like integrin, collagen and von willebrands factor. Activation sites like thromboxane and ADP binding sites. |
|
|
How does ASA work?
|
It covalently binds the cyclooxygenase site at both COX-1 and COX-2 and inactivates a serine residue.
COX-1 is heavily involved with the production of mucous in the stomach. The COX-2 site of H2 synthase is less involved in gastric stuff and is the target for viox, celebrex etc. |
|
|
Prolonged smooth muscle contraction and mucosal edema in asthma is due to the effect of...
|
Leukotrienes
They become conjugated with glutathione to change to other leukotrienes. |
|
|
Leukotrienes are synthesized by the...
|
Lipooxygenase pathway
Requires arachidonic acid as a substrate. The important enzyme here is 5,lipoxygenase. |
|
|
How do leukotrienes induce smooth muscle contraction?
|
They bind to LT receptors on the cell surface and modify cellular calcium through Gq, phospholipase C, and IP3 mediated series of reactions.
Calcium binds to calmodulin and induces the myosin light chain kinase to phosphorylate myosin which leads to actin/myosin attachment. Contraction then ensues. |
|
|
What are the normal function of cholesterol?
|
Membrane lipid
Steroid hormone precursor Vitamin D Bile acids |
|
|
Cholesterol bound to a fatty acid is called...
|
A cholesterol ester.
|
|
|
What are the intemediates on the path to cholesterol synthesis?
|
Acetate
Mevalonic acid Squalene Cholesterol |
|
|
What is the rate limiting reaction in cholesterol synthesis?
|
HMG-CoA is converted to mevalonic acid by the enzyme HMG-CoA reductase with 2NADPH consumed in the process.
|
|
|
Mevalonic acid is turned into activated isoprene which has two phosphates and how many carbons?
|
5 carbons
Thes 5C fragments are put together into squalene and then cyclyzed to make cholestrol. |
|
|
What do statin drugs do?
|
Inhibit HMG-CoA reductase and thus cholesterol biosynthesis.
|
|
|
Cholesterol synthesis requires the energy molecules...
|
ATP and NADPH
|
|
|
What enzyme turns squalene into cholesterol?
|
Cyclase turns it into lanosterol and then cholesterol in a multistep process.
|
|
|
What elese can be made from the squalene?
|
Stigmasterol or ergosterol
|
|
|
What is cholesterol synthesis regulated by?
|
LDL concentration
Cholesterol ester synthesis Number of LDL receptors HMG-CoA reductase !!Cholestrol directly influences transcription of genes in its own metabolism!! |
|
|
Where is VLDL made and what is it?
|
It is made In the liver. Unlike the chylomicron which is made in the gut.
It carries triglycerides synthesized de novo by the liver. It also contains a phospholipid coating, apoprotein E (which enables endocytosis) and apoprotein B100 which is significantly larger than apoprotein B48 in the chylomicron. VLDL acquires apoprotein C in the plasma which allows it to interact with the lipoprotein lipase on the tissues .After it interacts with lipoprotein lipase it shrinks because triglycerides are removed from it. Fatty acids go into the cell and free glycerol goes back to the liver via the plasma. The shrunken molecule turns into intermediate density lipoprotein (IDL) which now only contains apoproteins B100 and E. |
|
|
What happens to circulating IDL remnants?
|
They are taken up by the liver.
|
|
|
What happens to IDL that is not quickly picked up by the liver and stays in the circulation too long?
|
It is acted upon by hepatic lipase and becomes LDL by losing apoprotein E instead of being broke down and regenerating VLDL. .
|
|
|
What is LDL?
|
It results from further hepatic metabolism of IDL to remove triglycerides.
It does not contain apoprotein E but can still be endocytosed by cells but by a different receptor than the one that binds VLDL. It provides the cells with choesterol. Binding of LDL to cells happens in the clathrin coated pit. |
|
|
What does apoprotein A do?
|
It is found in HDL and has to do with LCAT (lecithin:cholesterol acyl transferase) activation.
|
|
|
What does apoprotein D do?
|
It is the cholesterol ester exchange protein (CETP) of HDL.
|
|
|
What happens to LDL that binds cell LDL receptors in the clathrin coated pit ?
|
The LDL and its receptor are engulfed into an endosome and as the endosome begins to acidify and become a lysosome, a recycling vesicle is formed which carries the receptor back to the clathrin coated pit,
|
|
|
What type of molecule is the LDL receptor?
|
A glycoprotein
|
|
|
What is the significance of LDL rceptors in the clathrin coated pit on regulation?
|
The number of the receptors in the pit at any given time is regulated by controlling their life cycle.
In addition,high cholesterol levels in the cell cause genetic downregulation of the LDL receptors so we pull less LDL out of the blood. |
|
|
What is SREBP?
|
A circulating protein that can enter the cell. It's N terminal acts as a transcription factor for several genes involved in lipid metabolism.
|
|
|
What is familial hypercholestrolemia?
|
A genetic disease of the LDL receptor.
Mutations include: Class 1: Defect in synthesis Class 2: Transport defect Class 3: Ligand binding domain defect (majority of patients) Class 4: Clustering defect Class 5: Recycling defect |
|
|
What is HDL?
|
It is a reverse cholesterol transporter.
It is the smallest of the lipid transport lipoproteins and carries lipids from the cell TO the liver. It is associated with apoprotein A and apoprotein D. Lecitihin:cholesterol acyl transferase is a key HDL associated enzyme. |
|
|
Where is HDL made?
|
In the liver.
It is almost entirely lipoprotein A when it is first synthesized. |
|
|
How does HDL interact with the tissues?
|
It interacts with an ABC like transporter protein in cell membrane lipid rafts.
The transporter protein shuttles cholesterol out of the cell using ATP only when HDL is bound to it. |
|
|
What happens to the HDL after it is loaded with cholesterol from the tissues?
|
It acquires a phospholipid coating.
It converts cholesterol to cholesterol ester using the enzyme LCAT which is part of the HDL particle. The HDL particle can exchange cholesterol ester with remnant particles but it can alsobe taken up into the liver for the synthesis of bile acids. |
|
|
What liver receptor is most selective for picking up mature cholesterol-ester rich HDL from the plasma?
|
SRB1
Scavenger receptor B1 |
|
|
What happens in knockout mutants of SRB1?
|
Severe atherosclerotic disease.
|
|
|
How does atherosclerosis develop?
|
Disruption of laminar flow.
Fatty streak formation by oxidized LDL. Vascular smooth muscle secretes extracellular matrix which attracts immune response and forms foam cells. Foam cells die an attract more inflammatory cells and thrombogenic material. Thrombus forms. |
|
|
What is a foam cell?
|
A macrophage that is harboring LDL.
They can secrete or release by their death plaque promoting elements. |
|
|
What are common types of drugs for hypercholestrolemia?
|
Inhibitors of HMG-CoA reductase (mevalonic acid mimic) that block de novo cholesterol synthesis. (statins)
Cholestyramine therpy to decrease reabsorption of bile salts and thus induce more bile production and cholesterol use. |
|
|
What type of virus is HPV?
|
Icosahedral DNA tumor virus that causes dysplasia and cervical cancer.
It makes E6 protein which ties up the product of the P53 tumor supressor gene and carries it to ubiquitin ligase for degradation by the proteosome. P53 destruction favors HPV survival and transformation of the cell. It also makes viral protein E5 which blocks ATPase in the lysosome and prevents degradation of EGF surface proteins. |
|
|
The average person breaks up how much of their own protein every day?
|
about 300g
In a healthy indivdual we synthesize an equal amount of protein from the amino acid pool daily. |
|
|
What are the demands placed on the amino acid pool at the level the cell?
|
Protein synthesis
Carbon skeletons for ATP, Ketones, Glucose and different amino acids. Manufacture of special products like carnitine, creatine, glutathione etc. Ammonium ions and urea manufacture. |
|
|
What are the essential amino acids for adults that must be supplied by an external source?
|
Isoleucine
Leucine Lysine Methionine Phenylalanine Threonine Tryptophan Valine |
|
|
In addition to the adult essential amino acids what is considered essential for children?
|
Growing child:
Arginine Histidine Premature infant: Cysteine Tyrosine |
|
|
What zymogens are secreted by the pancreas?
|
Chymotrypsinogen
Trypsinogen Procarboxypeptidase Proelastase |
|
|
What is the controlling protease in the pancreas?
|
Trypsinogen
It is activated in the gut by the enzyme enteropeptidase which clips off 7 or 8 carbons from it. Trypsin then activates all the other pancreatic zymogens by clipping off their amino termini. There is even a specific trypsin inhibitor in the pancreas just to make sure active trypsin does not cause pancreatitis. |
|
|
How are amino acids absorbed in the microvilli of the intestinal mucosa?
|
By sodium dependent amino acid symport systems.
|
|
|
The average human protein turnover is about...
|
300-400g/day
some proteins like ornithine decarboxylase (11 minutes) have very short half lives whereas other like adult collagen (300days) have very long half lives. |
|
|
What are the three major protein turnover pathways in the cell?
|
Cathepsins localized in the lysosome by their glycosylation (mannose-6-phosphate residues) which handle large proteins.
Calpains (cysteine containing) in the cytosol which get their name from their calcium sensitivity. They act mostly on cytoskeletal elements. Calcium dysregulation can cause these to do major damage. Ubiquitin proteosome system. A highly specific mechanism for breaking down protein. It tags proteins with ubiquitin for destruction. The regulation of ubiquitin addition is a controlling feature of protein half life. |
|
|
How does the ubiquitin pathway work?
|
Ubiquitin is activated by E1
Ubiquitin is bound to ubiquitin ligase (E3) by the conjugating system E2 The proteosome then recognizes the protein with ubiquitin bound to it and chews it up. |
|
|
The ubiquitin pathway is a common target for....
|
Oncogenic viruses like EBV.
EBV causes ubiquitin tagging of the RB (retinoblastoma inhibitor protein) which causes uncontrolled replication. |
|
|
The backup pathway to the ubiquitin pathway if it doesn't destroy proteins fast enough and tangles form is...
|
Autophagy
It is especially important in the nervous system as demonstrated by Atg (an autophagy related gene) knockout mice. |
|
|
Dysregulation of autophagy has been implicated in...
|
Myopathies
Neurodegeneration Cancer Aging Infection and immunity Heart disease Liver disease |
|
|
What do amino acids break down into?
|
alph ketoacids and ammonium (which is toxic)
|
|
|
What are the nontoxic fates of the toxic ammonium ions produced in the breakdown of amino acids?
|
Glutamate/Glutamine
New amino acids and special products Nitrogen containing metabolites. Urea |
|
|
How does amino acid catabolism start?
|
The transamination reaction which ties the ammmonium ion up with alpha-ketoglutarate to make glutamate and leaves behind the alpha-ketoacid.
|
|
|
What happens to the glutamate made i the tissues by the transamination reaction?
|
It is made into glutamine by the addition of another amino group.
Glutamine is an important carrier of ammonium throughout the body. |
|
|
What functions do glutamate and glutamine have in the body?
|
Neurotransmission.
Nucleotide synthesis. Ammonia transport. Non-essential amino acid synthesis. Fuel for specific cell types. Special products. Both are five carbon structures. Glutamate has one ammonium group and Glutamine has two |
|
|
How do glutamate and glutamine shuttle ammonium between the tissues?
|
Glutamate is conveted into glutamine in the tissues by the ATP dependant glutamine synthetase.
Glutamine can exit the cells and circulate to the liver where it is picked up and converted back into glutamate by glutaminase. Glutamate in the liver is further acted upon by glutamate dehydrogenase to make alpha-ketoglutarate which feeds into the TCA cycle. Mutations in the glutamine synthetase gene cause devastating neurological disease and rapid death. |
|
|
What happens to the alpha keto acids left over from amino acid breakdown and glutamate synthesis?
|
They enter the TCA cycle for energy and/or intermediates by providing precursors for glucose and ketone bodies.
Some alpha-ketoacids from amino acids are said to be glucogenic in that their carbon chains can end up in the synthesis of a new glucose. Others can make ketone bodies. Others still can do a little bit of both. |
|
|
What determines whether an amino acid and consequently its alpha ketoacid is glucogenic or ketogenic?
|
Those alpha ketoacids that can make acety-CoA or acetoacetyl-CoA are potentially ketogenic. Leucine and Lysine for example are exclusively ketogenic.
Glucogenic alpha keto acids are those whose catabolism yields intermediates in the TCA cycle that will eventually become oxaloacetate.This is because oxaloacetate is a substrate for the PEP carboxykinase reaction that leads into gluconeogenesis. |
|
|
What are the branched chain amino acids and why are they important?
|
Valine
Isoleucine Leucine They are 40% of the essential amino acids and 35% of muscle. They are oxidized by most tissues and give rise to Succinyl-CoA and ketones. After the ingestion of proteins, 60% of the rise in plasma free amino acids is from branched chains. Acetyl-CoA made from leucine is used by adipocytes and muscle to make fatty acids and cholesterol. |
|
|
What is maple syrup urine disease?
|
A defect in the ability to carry out the breakdown of branched chain amino acids because of deficient branched chain dehydrogenase complex.
The compostion of this enzyme is much like the PDH complex and alpha ketoglutarate complex and the mutation of the disease is in the ability to bind thiamine pyrophosphate in the type II (thiamine responsive disease). The disease has heavy neurologic characteristics because of poor myelination. The burnt sugar smell in the urine results from ketosis. Treatment is thiamine and withholding branched chain dietary intake within reason. Gelatin does not contain a lot of branched chains and is very useful for this. |
|
|
Where is urea made?
|
The liver
|
|
|
How is carbamolyl phosphate made?
|
Free ammonia, CO2 and ATP are put together by carbamoyl phosphate synthase 1.
|
|
|
What happens to carbamoyl phosphate?
|
It interacts with a very special amino acid called ornithine in a condensation reaction to form citrulline.
The reaction is mediated by ornitihine transcarbamoylase. The majority of defects in the urea cycle are in this ornithine transcarbamoylase enzyme. |
|
|
Citrulline in the urea cycle is converted into...
|
Aspartate which is acted upon by arginosuccinic acid synthase to make arginosuccinic acid (arginosuccinate).
|
|
|
When arginosuccinate is conveted to aspartate by arginosuccinase in the urea cycle, it gives off....
|
A fumarate which feeds the TCA cycle and helps repay the ATP debt incurred in the initial stages of the urea cycle.
|
|
|
Urea is made by...
|
The conversion of arginine to ornithine, the final stage of the urea cycle.
The enzyme arginase is the one that cleaves off the one carbon, two amino urea molecule. |
|
|
The rate limiting reaction of the urea cycle is....
|
The carbamoyl phosphate synthase reaction which is regulated by acetylgutamate.
Interestingly , the synthesis of acetylglutamate by acetylglutamate synthesis is upregulated by high levels of arginine. The genes that encode all the enzymes of the urea cycle are also transcriptionally regulated by protein load (intake). |
|
|
The most sensitive part of the body to hyperammonemia is...
|
The nervous system
|
|
|
What happens in urea cycle disorders?
|
Argininie becomes an essential amino acid.
Plasma free ammonia and glutamine increase. Hyperammonemia results in progressive lethargy, vomitting, irritability, ataxia and bizarre or combative behaviour. |
|
|
What happens to astrocytes in hyperammonemia?
|
They swell.
|
|
|
How are urea cycle defects treated?
|
Provide a diet sufficient in protein, arginine and energy to promote development and prevent hyperammonemia.
Monitor plasma glutamine as indicator of coming crisis. Invoke alternate waste disposal by giving phenylbutyrate, benzoate and arginine. |
|
|
Which amino acids are essentials?
|
Arginine
Histidine (only in newborns. adults can make these) Threonine Methionine Lysine Isoleucine Valine Leucine Phenylalanine Tryptophan Common mnemonic is PVT TIM HALL Cysteine must be made from methionine. Phenylalanine must be made from tyrosine. |
|
|
Transamination is a reversible reaction, which amino acids can be made from which alpha ketoacid TCA intermediates?
|
Alanine from pyruvate
Glutamate, glutamine and proline from alpha-ketoglutarate. Aspartate and asparagine from oxaloacetate. Serine and glycine from 3-phosphoglycerate. |
|
|
When the liver gets circulating alanine from muscle, how does it turn it into pyruvate for gluconeogenesis?
|
Transamination.
|
|
|
How is alanine made by the muscle tissues?
|
When the muscle breaks down amino acids into alphaketoacids, the alphketoglutarate that is made binds to pyruvate to make alanine.
This is why plasma alanine levels escalate in the fasting state. |
|
|
Which types of special products require amino acids as precursors?
|
Neurotransmitters
Neurohormones Hormones and Growth Factors S-adenosylmethionine Glutathione Carnitine Creatine Porphyrins and others. |
|
|
What is the molecule S-adenosylmethionine (also called Adomet or SAM) and what is it the precursor for ?
|
Major methyl donor made from methionine.
Precursor for: Catecholamines Creatine Carnitine Cysteine It is also used for making choline and spermidine as well as DNA and RNA methylation. |
|
|
Where is carnitine made?
|
All over the place.
It starts out in the nucleus, undergoes proteolysis in the lysosome, hydroxylation in the mitochondrion and finally 2 carbon cleavage in the cytoplasm which requires pyridoxal phosphate, NADH and Vitamin C. People with scurvy (vitamin C deficiency) therefore have a defect in fatty acid oxidation (beta oxidation). They have cardiac and skeletal muscle issues with lipid droplets found in the myocytes. Carnitine supplementation can lead to good clinical effects and can be carried into cells by a sodium symport system. |
|
|
What is the purpose of the special amino acid product glutathione?
|
It is a REDOX buffer with an SH group which can bind toxic compunds and remove toxic peroxides.
It is a donor of hydrogens. It is made by the enzymes gluatmyl cystein synthetase and glutathione synthetase from glutamate cysteine and Glysine. !!Synthesis involves ATP requiring reactions!! |
|
|
How does acetaminophen toxicity progress?
|
Preclinical toxic effects
Liver injury Liver failiure (mortality 20-40%) Recovery The highly reactive metabolite of acetaminophen NAPQI made by CP450 acts as a ubiquinone mimic and marks good proteins for proteosome degradation. In early stages boosting glutathione with its n-acetylcysteine precursor can help. n-acetylcysteine has better cell penetration than plain old cysteine. |
|
|
What do creatine and creatine phosphate do?
|
It is a a rapid energy (P) carrier in muscle cells.
It is made by arginine-glycine transmidase which makes ornithine and guanidoacetate as a byproduct. The guanidoacetate is acted upon by guanidoacetate methyl transferase to make the creatine. Phosphorylation comes from S-adenosylmethionine (SAM). A lot of the synthesis of creatine happens in the pancreas and liver and can be taken up by muscles where it is phosphorylated by SAM. Defects in creatine synthesis like Guanidoacetate methyl transferase (GAMT) deficiency lead to a buildup of guanidoacetate, developmental delay, muscle tone issues, epilepsy and/or autism. Creatine supplementation can help these patients. |
|
|
What role do amino acids have in neurotransmission?
|
Dopamine, NE and Epi are derived from Phenylalanine and Tyrosine.
Gluatmate is a neurotransmitter and a component of GABA. Glycine is a neurotransmitter. Arginine is important for NO synthesis. Tryptophan is a component of serotonin. Histidine is a component of histamine. |
|
|
What is phenolketonuria (PKU)?
|
Phenylalanine hydroxylase deficiency causes high serum phenylalanine and these amino acids can block channels across the BBB designed for other amino acids.
Failiure to thrive, retardation and poor myelination ensues if untreated. Routinely screened for and treated with a low phenylalanine diet. |
|
|
What does nitric acid do?
|
Immune mediator
Smooth muscle relaxant Neuronal messenger. It is synthesized from arginine by nitric oxide synthetase (NOS). |
|
|
How does NO cause smooth muscle relaxation?
|
It activates a soluble Guanyl cyclase.
Guanyl cyclase activates cGMP protein kinase. The kinase closes calcium channels and the decreased calcium leads to activation of myosin LC phosphatase The myosin phosphatase dephosphorylates myosin light chains and causes vasorelaxation. Cytokine induced NO sythesis decreases vascular resistance and causes a renal response which leads to renal failure. Renal failiure is highly associated with sepsis mortality. |
|
|
What molecules contain heme as a prosthetic group?
|
Myoglobin
Hemoglobin Catalase Cytochromes Cytochrome p-450 Prostaglandin endoperoxide synthase. Guanylate cyclase |
|
|
Hemes synthesis occurs in all cells but is most appreciable in..
|
Bone marrow (hemoglobin)
The liver (C-P450) |
|
|
There are 8 enzymatic reactions in heme synthesis. Where do they occur?
|
The first one and last three are in the mitochondrion.
The middle four happen in the cytosol. |
|
|
The rate limiting enzyme in heme synthesis is....
|
Aminolevullinic acid synthase
It is the first reaction in Heme synthesis and makes aminolevullinic acid out of glycine and succinyl-CoA substrates. The reaction happens in the mitochondrion but the product is shuttled into the cytosol. |
|
|
What is the fate of aminolevulliic acid in heme synthesis?
|
It is acted upon by amino levullinic acid dehydratase to make the first cyclic structure of heme synthesis, porphobillinogen.
Porphobillinogen deaminase then makes a tetrapurole called hydroxymethylbillane out of the porphobillinogen. Hydroxymethylbillane is then acted upon by uroporphyrinogen III synthase to make uroporphyrinogen III. Uroporphyrinogen III is turned into coproporphyrinogen III by uroporphyrinogen decarboxylase. The enzymes coproporphyrinogen oxidase and protoporphyrinogen oxidase carry the coproporphyrinogen III back into the mitochondrion and convert it to protoporphyrinogen IX Here in the mitochondrion ferrochetalase adds the iron to protoporphyrinogen IX to make the HEME. |
|
|
How is Heme synthesis regulated?
|
High levels of Heme in the mitochondrion inhibit Aminolevullinic acid synthase, the rate limiting enzyme in Heme synthesis.
|
|
|
Why are porphyrias calld porphyrias?
|
Some of them are charcterized by purple urine.
|
|
|
Which enzymes in heme synthesis can cause porphyrias?
|
All of them except the first one, aminolevullinic acid synthase.
The defects are usually only partial because a 100% defect would be fatal. Hepatic Porphyrias cause neurovisceral symptoms and victims are often considered psychiatric patients. Erythropoetic porphyrias are charcterized by a deposit of porphyrins in the skin and cutaneous photosensitivity. |
|
|
What is acute intermittent porphyria?
|
Most common porphyria.
A defect in porphobillinogen deaminase that causes it to be half normal. There is an acumulation of porphobillinogen in these patients. Attacks are brought on by sex streoids, drugs and diet that induce ALA synthase.CP450 drugs cause attacks too because CP450 binds heme outside the mitochondrion and indirectly promotes ALA synthase. Attacks include Severe abdominal pain, tachycardia, anxiety and depression. |
|
|
What is porphyria cutanea tarda?
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Uroporphyrinogen decarboxylase deficiency.
Buildup of oxygen reactive chemicals in the skin and complement activation causes blistering and lysosomal damage. Predisposes patients to severe secondary infections. |
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How is Heme degraded?
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The liver plays a large role in Heme degradation.
Amino acids are pulled off the red blood cell (+- 120 day half life) after being bound to the reticulo endothelial system . The porphyrin ring is broken down into Billiverdin in the plasma. Billiverdin must be broken down by the NADPH dependant billiverdin reductase into billirubin. Billirubin is a very potent neurotoxin though so it must be bound to albumin in the plasma and transferred over to ligandin in the liver. The enzyme !!UDP glucoronyl transferase!! adds the sugar glucoronic acid to the billirubin. The glucoronic acid makes the billirubin more soluble and it then can be secreted ito the bile . |
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What is neonatal jaundice?
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Yellow skin and sclera in about 50% of newborns due to increased billirubin production or delayed metabolic ability of the liver to add glucoronic acid to billirubin because of decreased Billirubin UDP glucuronyl transferase.
Phototherapy at 459nm breaks the billirubin to isomerise to the much more soluble lumirubin. |
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What is kernicterus?
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Severe unconjugated hyperbilirubinemia because of a gentic defect in bilirubin UDP glucoronyl transferase.
Originally called kriegller-najar syndrome. Type 1: Liver transplant, plasmaphoresis, phototherapy. Type 2: Phenobarbitol works here because the inducible form of the enzyme is still realtively okay. Phenobarb induces increased transcription of the enzyme. |
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What is Gilbert syndrome?
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A genetic disorder that results from a chage in the promoter of the gene encoding UDP glucoronyl transferase.
The promoter has some extra TA repeats in it. The enzyme coding is okay though. There is some degree of hemolytic jaundice and hyperbillirubinemia but usually not life threatening. |
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How does drug induce hyperbillirubinemia work?
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Certain hydrophobic drugs like sulfonamides and imaging drugs can displace billirubin from its complex with albumin and pose a toxicity threat.
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Elevated blood glucose leads to...
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Protein glycosylation
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What is a euglycemic blood glucose?
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about 40-50 mg%
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What does the insulin/glucagon reation tell us about the nutritive state?
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0.5 means very well fed.
0.15 is typical after about 12 hours. 0.05 is extreme starvation. |
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What is the effect of increased insulin on metabolic enzymes?
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+Glycogen Synthase
(glycogen synthesis) +Lipoprotein Lipase (pulls fat off chlyomicrons) +Acetyl-CoA Carboxylase (Making malony Co-A for fat storage) +Glucose transporter 4 (taking glucose into the cells) + Protein Synthesis |
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How much do the organs really need a day?
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Brain- about 125g glucose
RBC's-about 50g glucose Muscle- about 50g glucose |
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In an overnight fast, how much of the needed glucose comes from liver glycogen?
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70-80%
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In the overnight fast...
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Glucagon is up, insulin is down.
Glycogenolysis is up, glycogen synthesis is down. |
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About what portion of blood glucose is contributed by gluconeogenesis in the overnight fast ?
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25%
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What do we see metabolically in a 1-3 day fast?
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Decreased insulin.
Increased glucagon. Lower insulin:glucagon ratio. Stable blood glucose. Increased fatty acids. Increased ketones. Carnitine levels in the liver are heightened because the shuttle is very active for beta oxidation and ultimately ketogenesis. |
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What rate does muscle proteolysis proceed at?
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75-100g/day
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What is the metabolic response in a prolonged fast?
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Decreased insulin
Increased glucagon Lower insulin:glucagon ratio Stable glucose Very high fatty acids Very high ketones |
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How does the kidney respond to prolonged fasting?
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Develops the ability to resorb ketones from filtered plasma.
It also becomes an organ for gluconeogenesis like the liver. |
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What happens to muscle proteolysis in prolonged fasting?
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It drops to about 20g/day.
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How does the brain respond to prolonged fasting?
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It develops the ability to use ketones for about 50% of its needs.
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How does glucagon influence transcription during fasting?
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It increases transcription of the gluconeogenic enzymes PEP-CK, G6Pase and F1,6BPase by increasing cAMP.
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How does cAMP influence the genes of the gluconeogenic enzymes?
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A DNA sequence in the promotor, c-AMP response element (CRE) is bound by the protein CREB.
The CREB protein has a kinase inducible domain (KID) with a serine residue, two glutamine rich Q domains that activate the gene and a leucine zipper domain that allows binding to DNA. CREB travels to the nucleus once it is phosphorylated by PKA which is activated by the signalling of glucagon. CREB binding protein or CBP connects CREB to the polymerase once it settles on the genome and transcription ensues. Metformin interferes with the CREB pathway. |
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How do you differentiate between the purine bases; adenine, guanine, hypoxanthine and xanthine?
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Adenine has an ammonium (NH2) sticking straight up from the 6 carbon. All other have an oxygen at this position.
Guanine is the only one that has an ammonium sticking out of the 2 carbon. Xanthine is the only one that has an oxygen sticking out of the 6C. Hypoxanthine is the only one left. So look at the 6 carbon first. If Ammonium, it's adenine. If not, look at the 2 carbon. Ammonium=Guanine, Oxygen=xanthine, nothing=hypoxanthine. |
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Where does the pentose sugar bind to the purine bases?
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The 9 position nitrogen
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Bases and nucleosides can readily cross cell membranes unless they are...
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Phosphorylated to make nucelotides which are trapped by the negative charge of the phosphate ion.
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What sort of concentrations of nucelotides do we find in the cell?
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Millimolars of ribonucleotides.
Micromolars of deoxyribonucleotides. Triphosphates nucelotides are the predominant form in the cell. (over 70%) |
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How do you differentiate between the pyrimidine bases; uracil, cytosine and thymine?
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Look at the 4 position first. If it has an ammonium sticking out of it, its cytosine.
If not, look at the 5 position. If the five position has a methyl its thymine. If not, its uracil. This makes sense since thymine and cytosine are made from activated metabolites of uracil. |
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How is PRPP made and why is it important?
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PRPP is a central molecule in both de novo nucleotide synthesis and nucleotide salvage.
We begin de novo purine biosynthesis with PRPP by building onto the ribose and we end pyrimidine biosynthesis with PRPP by adding the ribose last. In purine biosynthesis, PRPP is made by double phosphorylating ribose 5 phosphate (r-5-p) from the HMP shunt. Both phosphates are added at the same time unlike most phosphorylation reactions. The enzyme is called PRPP synthetase and is importnat because it regulates the amount of reactants available for nucleotide synthesis. PRPP synthetase is activated by phosphate and inhibited by ADP. |
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What is the origin of the atoms in the purine ring of the nucleoside Inosine (hypoxanthine base+sugar)?
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Carbon and oxygen at position 6 (12o'clock) come from CO2.
Nitrogen at position 1 comes from aspartate. Nitrogens at position 3 and 9 (6o'clock on both rings) come from glutamine. Carbons 2 and 8 come from N10-formyl-tetrahydrofolate. Lastly,carbons 4, 5 and nitrogen 7 (12 o'clock on pentose ring) come from glycine. |
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Why is inosine important in purine biosynthesis?
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It is the product of the core pathway of purine synthesis in that synthesis of AMP and GMP branch from IMP.
It requires 7ATP to make it. (including the 2ATP required to resynthesize PRPP) |
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The first commited step in purine de novo biosynthesis and also the most important regulatory step is....
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Making 5-phosphoribosylamine (PRA) from PRPP
The enzyme is called glutamine PRPP amidotransferase because it also turns glutamine into glutamate in the process. Glutamine PRPP amidotransferase (abbreviated PRPP amidotransferase) is allosterically inhibited by IMP, AMP, and GMP (the end products) and activated by PRPP (the reactant). PRPP, IMP, AMP and GMP do this by favoring or disfavoring the active monomeric enzyme state over the inactive dimer. The nitrogen at the 9 position (from glutamine) is added in this step. |
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What else is important about the way AMP, IMP and GMP inhibit glutamine PRPP amidotransferase (PRPP amidotransferase)?
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They can have additive inhibition because of two seperate binding sites.
AMP+(IMP or GMP) |
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During de novo purine synthesis when CAIR becomes SAICAIR, an entire molecule of aspartate is added. Which part of this molecule will be retained in the final purine?
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Only the N1 nitrogen.
The rest are cleaved off as fumarate. |
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What is the reaction that actually makes the first common purine nucleotide IMP?
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FAICAR turns into IMP (hypoxanthine base) by the removal of water.
The phosphate from the very beginning is carried through all steps and is retained on IMP. This ensures that all the intermediates and IMP stay trapped in the cell. |
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Once IMP is formed, the pathway diverges towards either AMP synthesis or GMP synthesis, what defines this divergence?
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The oxidation of C2 by IMP dehydrogenase will lead to GMP.
IMP dehydrogenase is the regulated step on the GMP side of the pathway and is inhibited by the final product, GMP. The substitution of aspartate for the C=O in position 6 by adenylosuccinate synthetase will lead to AMP synthesis. Adenylosuccinate synthetase is the regulating enzyme for the AMP side of the pathway and is inhibited by the final product of the pathway, AMP. |
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The final step in the synthesis of GMP is...
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Substitution of C–NH2 for C=O in the 6 position by the enzyme GMP synthetase.
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The final step in the synthesis of AMP is...
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Removal of fumarate from the 6 position by the enzyme adenylosuccinase.
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How is purine de novo biosynthesis regulated ?
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AMP and GMP inhibit the enzymes that send IMP down their respective pathways. They also inhibit the conversion of PRPP to 5-phosphoribosylamine by PRPP amidotransferase the same way that IMP inhibits it.
AMP energizes the GMP pathway enzyme and GMP energizes the AMP pathway enzyme which means that an abundance of one will cause increased production of the other. Lastly, an abundance of PRPP will upregulate PRPP amidotransferse and cause increased production of IMP. |
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One of the benefits of the purine nucleotide cycle in which we can reverse the branched part of the de novo synthesis in one step with the enzyme AMP deaminase is that it allows conversion of aspartate to fumarate. Why is this important?
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Muscle tissue uses this reaction to increase TCA intermediates during stress.
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What is the clinical consequence of an AMP deaminase deficiency (hereditary)?
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Muscle cramping and fatigue during prolonged excercise.
It is important to note that this is completely different from adenosine deaminase which will not act on the monophosphate. A deficiency of adenosine deaminase will cause severe combined immune deficiency syndrome (SCID). |
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Nucleic acids are broken down by...
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Nucleases (endonuclease or exonuclease).
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Purine nucleosides are broken down by...
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In the case of guanine, nucleotidase to yield guanosine, then purine nucleoside phosphorylase to yield guanine, then guanase to yield hypoxanthine and finally, xanthine oxidase to yield uric acid.
Adenine is a little more complex. It can become inosine by one of two paths. It can either be acted upon nucleotidase to yield adenosine and then by adenosine deaminase to make inosine. or It can be acted upon by AMP deaminase first to make IMP and then nucleotidase to make inosine. Inosine is made into hypoxanthine by purine nucleoside phosphorylase. Hypoxanthine is turned into xanthine and then uric acid by a single OXIDATIVE enzyme, xanthine oxidase. |
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What does allopurinol do?
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Inhibits xanthine oxidase and thus reduces the production of uric acid.
It is a useful treatment for gout which is an accumulation in the joints of the relatively insoluble uric acid. |
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What is the pathology of gout?
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Biochemical defects, necrosis or renal insufficiency lead to an accumulation of uric acid.
(end product of purine breakdown) By far the most common genetic cause is a hereditary decrease in the purine salvage enzyme HGPRT which fails to add PRPP to enzymes. HGPRT is carried on the X chromosome and deficiencies are thus far more common in men. Other forms include an increase in glucose 6 phosphatase, elevated levels of PRPP synthetase or loss of feedback inhibition in PRPP amidotransferase. Uric acid gets trapped in synovial fluid. Uric acid is also phagocytized by macrophages which leads to cell lysis and inflammation. The xanthine oxidase inhibitor allopurinol is a treatment. |
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What is the effect of HGPRT deficiency?
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Partial deficiency=Gout
Complete deficiency =Lesch Nyhan syndrome Severe mental retardation in lesch nyhan and loss of nociceptive function leads to chewing of fingers and lips. |
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Where do the atoms in de novo pyrimidine synthesis come from?
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Carbons 4, 5 and 6 as well as the N1 and oxygen on carbon 4 come from aspartate.
Carbon 2 and its oxygen come from CO2. N3 comes from glutamine. The pathway is NOT branched like de novo purine synthesis and is executed by two multifunctional enzyme complexes. The core pathway product is UMP. !!ribose is added last in this pathway!! Regulation is different in bacteria. In eukaryotes UTP is responsible for feedback regulation whereas in bacteria CTP is the regulatory molecule. |
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Synthesis of which pyrimidine requires a folate cofactor?
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dTMP
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What are the two big multifunctional enzyme complexes in pyrimidine synthesis?
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Carbamoyl phosphate synthetase II complex in the cytosol. (NOT the same as CPS 1 in the mitochondrion which is a TCA cycle enzyme)
It is the principal regulatory site of pyrimidine synthesis in mammalian cells. It is upregulated by PRPP and down regulated by UTP. It consists of three enzymatic components namely the CPS II subunit, the ACTase component and the dihydroorotase subunit. The second complex is bifunctional. It adds the ribose sugar from PRPP to the fully formed pyrimidine ring, orotate. Its second component is OMP decarboxylase and is negatively regulated by its own product UMP. |
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What happens to the carbamoyl phosphate made by CPS II?
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It is acted upon by the enzyme ACTase and forms the first commited intermediate of pyrimidine synthesis (carbamoyl aspartate).
Aspartate carbamoyl transferase is positively regulated by ATP but only inhibited by CTP in bacteria. |
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What enzyme is responsible for closing the pyrimidine ring?
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dihydroorotase which does NOT require ATP.
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What enzyme is responsible for oxidation (double bond formation) in the pyrimidine ring and what cofactors does it need?
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Dihydroorotate
dehydrogenase in the mitochondrion. It requires NAD+ and coenzyme Q. |
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Where does the ribose in pyrimidine synthesis come from?
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PRPP
It's added by phosphoribosyltransferase. |
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The last regulatory point in pyrimidine synthesis is...
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OMP decarboxylase which makes UMP out of OMP.
It is inhibited by its own product UMP. A deficiency in OMP decarboxylase (or in OPRTase) will cause orotic aciduria. |
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How is UMP made into CTP?
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It has to be made at the triphosphate level so it is first phosphorylated and then transaminated at C4 by CTP synthetase.
CTP synthetase is negatively inhibited by its own product CTP. The reaction is not considered part of the core pyrimidine synthesis pathway. In bacteria the CTP inhibits ACTase. |
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How does dTMP synthesis happen any why is it important?
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dTMP is essential for DNA.
dUMP is the substrate and a methyl is added to it at C5. The methyl comes from the cofactor N5,N10-methylene-tetrahydrofolate which forms a covalent complex with the enzyme thymidilate synthase. To make the reaction happen, the H4-folate cofactor is oxidized to an H2-folate. Regeneration of the tetrahydrofolate cofactor is done by the enzyme dihydrofolate reductase. Dihydrofolate reductase is the target of antibiotics and cancer antimetabolites. These work by trapping the folate in its inactive oxidized form thereby preventing dTMP monophosphate and the ability to make DNA for replication. |
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How does pyrimidine degradation proceed?
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Dephosporylation by nucleotidase.
Deamination by cytidine deaminase to uridine in the case of cytidine. Deribosylation by Uridine phosphorylase or thymidine phosphorylase depnding on the base. The resulting uracil or thiamine are further catbolized by irreversible REDUCTIVE steps. The reactions are mediated by DIHYDROURACIL DEHYDROGENASE. They are then degraded even further into amino acids. |
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How are nucleotides for DNA made?
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The enzyme ribonucleotide reductase reduces ribose 2'-OH to 2'H.
The reaction can happen only with a diphosphate (not MP or TP) substrate. The ultimate reducing source is NADPH because it regenerates thioredoxin but the intermediate carrier is Thioredoxin which gets oxidized (glutaredoxin in bacteria) The reaction is inhibited by high dTTP or dATP. |
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What is SCID?
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Deficiency in adenosine - deoxyadenosine deaminase which heavily affects B and T cells.
The deficiency results in high cellular dATP which inhibits ribonucleotide reducatse and thus blocks DNA synthesis and the cell cycle. There is another similar condition which only affects T-cells and results from purine nucleoside phosphorylase deficiency. (not frequently tested) |
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How are nucleotide cofactors synthesized?
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Linkage of essential vitamins to ADP or 1 carbon groups as well as redox interconversions and one carbon transfers.
The cofactors usually have a pyrophosphate linkage (two phosphates) which protects them from nuclease degradation. NAD+ is used for oxidations. NADPH is used for reductions. |
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How is NAD+ synthesized?
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Nicotinamide undergoes a series of reactions.
Nicotinamide phosphoribosyltransferase adds a ribose and a phosphate from PRPP and then ATP is added to the resulting molecule by NAD pyrophosphorylase. NAD pyrophosphorylase creates a PPi linkage between the nicotinamide mononucleotide and ATP. |
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What is pellagra?
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Diarrhea, Dermatitis and dementia caused by niacinamide deficiency.
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How is FAD+ which is required for many redox enzymes synthesized?
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Riboflavin is phosphorylated and then AMP is added to it.
Again there is a PPi linkage involved. |
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How is coenzyme A which is an important carrier of acyl and acetyl groups synthesized?
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Pantothenic acid is phosphorylated, then cysteine is added to it. Finally AMP is added to it by PPi linkage.
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How is vitamin B12 (cobalamin), which functions in one carbon transfers like methionine synthesis from homocysteine acquired?
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It is an essential vitamin but a protein called intrinsic factor is required for its absorption.
In B12 deficiency, 5-methyl-FH4 accumulates, trapping folate in a dead-end form which is called a functional folate deficiency. The functional folate deficiency causes megaloblastic anemia and neurological disorders. Folate deficiency symptoms are treated with both B12 and folate because folate supplementation alone can deplete CNS B12 and worsen symptoms. |
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What is tetrahydrobiopterin?
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A compound made from GTP that is essential for serotonin synthesis.
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What is folic acid?
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An essential vitamin required for many 1 carbon structures but it must be fully reduced to tetrahydrofolate.
Sulfonamide antibiotics mimic the PABA core of tetrahydrofolate and thus block folate biosynthesis in the rapidly dividing bacteria. |
