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374 Cards in this Set
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Anabolic Pathway |
synthesizes macromolecules aka biosynthetic pathway an energy-requiring or energy-consuming pathway use energy derived from catabolic pathways endergonic rxn (delta G > 0) ex: glycogenesis, gluconeogenesis
delta G = +ve |
|
Catabolic pathway |
aka degradative pathway breaking down of complex molecules to simpler ones that results in energy release captured by formation of high energy compounds such as ATP energy-generating or energy-releasing pathway exergonic rxn (delta G < 0) example: glycolysis, complete oxidation of glucose to CO2 and H20
delta G = -ve |
|
metabolism |
the sum of all of the chemical reactions that occur within an organism in order to maintain life |
|
the metabolic activities of cells are dictated by two major goals: |
1) the cell has to synthesize it macromolecules: proteins have to be made from amino acids, carbs from monosaccharides, membrane lipids form fatty acids, nucleic acids from nucleotides 2) the cell has to generate metabolic energy: nutrients must be oxidized to supply the energy for biosynthesis, active membrane transport, cell motility, and muscle contraction. |
|
intermediary/ energy metabolim |
reactions concerned with generating or storing energy; using that energy for biosynthesis of small molecules (maintenance of cellular ATP and blood glucose levels)
combined activities of all the metabolic pathways that inter-convert precursors, metabolites etc
these processes allow organisms to grow and reproduce, maintain their structures, and respond to their environments |
|
most amino acids can be converted to |
glucose |
|
glucose can be converted to |
amino acids and fatty acids |
|
2 alternative fates of a nutrient molecule entering a cell: |
it is either used for the synthesis of a macromolecule or
it is oxidized to CO2 and H2O for the generation of ATP through various metabolic pathways |
|
the direction in which the pathway proceeds depends on... |
the sum of the free energy changes of the individual reactions |
|
a metabolic pathway is a : |
series of chemical reactions occurring within a cell |
|
metabolic pathways are: |
compartmentalized
driven by the net free energy change of the sum of individual reactions
regulated |
|
cytosol/ cytoplasm |
contains both anabolic and catabolic pathways such as glycolysis, glycogen metabolism, pentose phosphate pathway, and it is also the place where glycogen and fat are stored as energy reserves |
|
ER and golgi apparatus |
concerned with the synthesis and processing of proteins and membrane lipids |
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mitochondria |
the powerhouse of the cell, generating >90% of ATP synthesis by oxidate phosphorylation |
|
lysosomes |
are hydrolytic enzymes for the degradation of macromolecules. they hydrolyze cellular macromolecules |
|
peroxisomes |
specialized organelles for oxidative reactions such as reactions forming hydrogen peroxide as a byproduct |
|
Nucleolus |
synthesis of ribosomal RNA, assembly of ribosomal subunits |
|
nucleus |
central databank, DNA and RNA synthesis |
|
Free energy |
the component of the total energy of a system that can do woe at constant temperature and pressure |
|
free energy change |
the amount of free energy released or absorbed in a rxn at constant temperature and pressure |
|
exergonic reaction |
when delta G is negative (the product has lower free energy than the substrate), process or chemical run proceeds spontaneously in the forward direction |
|
endergonic reaction |
when delta G is positive (the reaction does not go spontaneously), the process proceeds spontaneously in the reverse |
|
delta G = zero |
the process is in equilibrium, with no net change taking place over time |
|
under aerobic conditions, [NAD+] is ... |
always higher than [NADH] |
|
in the cell, [GTP] concentration is ... |
almost 100 times higher than [GMP]
|
|
Cells respond to signals from _____ to adjust their metabolism |
nutrients |
|
cells have 3 options for the regulation of their metabolic pathways |
1) long term at the DNA level: the amt of enzyme is adjusted by a change in its synthesis or degradation... SLOW 2) short term at protein level: some enzymes are modified covalently by phosphorylation. this requires a protein kinase and protein phosphatase... FAST 3) allosteric effectors: VERY FAST |
|
phosphorylation |
formation of a phosphate derivative |
|
dephosphorylation |
removal of phosphate groups from a biomolecule |
|
the protein kinases and protein pho sphatases are regulated by: |
metabolites or hormones |
|
metabolic enzymes are also subject to competitive inhibition in the form of : |
product inhibition - meaning the product of the reaction competes with the substrate for the active site of the enzyme. |
|
hormones can regulate both the synthesis and degradation of metabolic enzyme and their phosphorylation by : |
protein kinase |
|
most biosynthetic pathways are inhibited by : |
high concentrations of their end product (feedback inhibition) |
|
regulation of anabolic pathway |
regulation by feedback inhibition |
|
regulation of catabolic pathway |
regulation by ATP and ADP, Pi |
|
regulation of catabolic pathway |
regulation by feedforward stimulation |
|
in energy-producing catabolic pathways, the important product is : |
ATP |
|
the ATP level is inversely related to: |
the concentrations of ADP and AMP. ADP and /or AMP act opposite to ATP in the regulation of many catabolic pathways |
|
feedback inhibition |
the regulated enzyme is inhibited by a product of the pathway |
|
feedforward stimulation |
a substrate stimulates the pathway by which it is utilized |
|
a regulated enzyme must be present in: |
lower activity than the other enzymes in the pathway |
|
the regulated enzyme should serve : |
an essential function in only one metabolic pathway |
|
the regulated enzyme should catalyze: |
the first irreversible reaction ( the committed step) in the pathway |
|
regulation of the committed step ensures: |
that only the substrate of the pathway accumulates when the regulated enzyme is inhibited. if a later reaction would be inhibited, metabolic intermediates would accumulate causing possible toxic effects. |
|
inherited enzyme deficiencies cause |
metabolic diseases |
|
when an enzyme is missing as a result of a genetic defect, the immediate effects are always: |
the accumulation of the substrate in blood and the lack of the product |
|
deficiency of an enzyme in a catabolic pathway, ATP producing pathway causes: |
a serious problem |
|
if the intracellular degradation of a macromolecule by hydrolytic enzymes is blocked... |
"undegraded" macromolecules accumulates mostly within the cells. the result is a "storage disease" |
|
vitamin deficiencies |
can affect multiple metabolic pathways. a vitamin deficiency can prevent a metabolic react by depriving it of an essential coenzyme. most vitaim derived coenzymes (NAD, FAD, CoA), participate in multiple metabolic pathways. al of these pathways are impaired when vitamin deficient |
|
toxins |
act by inhibiting metabolic enzymes
lead: causes the accumulation of toxic intermediates by inhibiting enzymes of heme biosynthesis
cyanide: blocks cell respiration by inhibiting the mitochondrial cytrochrome oxidase |
|
endocrine disorders |
the most complex metabolic diseases because each hormone controls a whole set of metabolic pathways.
diabetes mellitus: insufficient insulin action disrupts a host of pathways in carbohydrate and fat metabolism |
|
bioenergetics |
the quantitative study of every relationships and energy utilization, and conversions in biological systems, or energy transformations in living organisms |
|
metabolism |
the sum of all chemical reactions that occur within an organism in order to maintain life or the entire set of enzyme-catalyzed transformations of organic molecules in living cells (the sum of anabolism and catabolism) |
|
autotrophs |
aka producers can use CO2 from the atmosphere as their major source of carbon, from which they construct all their carbon-containing biomolecules, such as photosynthetic bacteria, green algae, and plants |
|
heterotrophs |
aka consumers
can not use CO2 from the atmosphere and must obtain carbon from their environment in the form of complex organic molecules such as glucose. Multi cellular animals an most micro-organisms are heterotrophic |
|
free energy source |
cells are isothermal systems - function at constant temp and pressure. autotrophic cells acquire free energy form solar radiation, and heterotrophic cells acquire it from nutrient molecules |
|
autotrophic organisms are ____ and obtain their energy from ____ |
photosynthetic
sunlight |
|
heterotrophic organisms obtain their energy from .... |
the degradation of organic nutrients produced by autotorphs |
|
Carbon, oxygen, nitrogen, and water are constantly cycled between the ____ and _____ |
autotrophic producers and heterotrophic consumers |
|
oxidation-reduction |
reactions involving the loss or gain of electrons - one reactant gains electrons and is reduced while the other loses electrons and is oxidized |
|
oxidation reactions generally ______ energy and are important in _____ |
release
catabolism |
|
in many organisms, the oxidation of ____ supplies energy for the production of ____ |
glucose
ATP |
|
NAD+ and FAD |
are a prosthetic group covalently bound in some enzymes
|
|
NAD+ or NADP+ |
soluble co-factors free to diffuse from one enzyme to another. Both accept two electrons and one proton |
|
FAD or FMN |
coenzymes derived from the vitamin riboflavin, often tightly bound to specific enzyme called flavoproteins |
|
great majority of NAD+/NADH is located in |
the mitochondria |
|
most of the NADP+/NADPH is |
in the cytosol |
|
electron carrier |
a biomolecule that can reversibly gain and lose electrons |
|
NAD+ and NADP+ undergo |
reduction to NADH and NADPH by accepting a hydride ion from an oxidizable substrate
the hydride ion is added to either the front or back of the nicotinamide ring |
|
Reduction of nicotinamide ring produces |
a new broad ring
NADH at 340 nm |
|
NAD+ or NADP+ move readily fro one enzyme to another, acting as a water-soluble electron carriers, derived from |
vitamin niacin which is synthesized from tryptophan |
|
Niacin deficiency causes a disease called |
pellagra (rough skin) |
|
Rossmann fold |
most dehydrogenates that use NAD or NADP bid the cofactor in a conserved protein domain
it is an NAD-binding site, consisting of : six stranded parallel beta pleated sheets and four alpha helices |
|
FAD/FADH2 |
flavoproteins are enzymes that catalyze oxidation-reduction reactions using either FMN or FAD as coenzyme |
|
FAD or FMN are coenzyme derived from |
vitamin B2, riboflavin |
|
in a healthy cell: [NAD+]/[NADH] |
>> 1 due to continuous ATP production (rapid utilization of NADH in the mitochondria) |
|
in a healthy cell: [NADP+]/[NADPH] |
= 0.05
maintains reductive environment in the cytosol (NADPH) |
|
ATP is the chemical link between: |
catabolism and anabolism and is the energy currency of the living cell |
|
NAD and NADP, both are the freely diffusible coenzymes of |
dehydrogenases
|
|
total concentration of NAD+ + NADH in tissues is |
10^ -5 M |
|
total concentration of NADP+ + NADPH in tissues is |
10^ -6 M |
|
all major nutrients are degraded to |
acetyl coenzyme A
"activated acetic acid" |
|
in the mitochondria, the two carbons of the acetyl group become oxidized to CO2 and produce reduced coenzymes in the |
tricarboxylic acid (TCA) cycle |
|
the deoxidation of the reduced coenzymes produces the bulk of the cellular ATP in the process of |
oxidative phosphorylation |
|
glucose is not only the most abundant monosaccharide in food, but is |
also produced from other monosaccharides by the breakdown of the storage polysaccharide glycogen
from amino acids and other non-carbohydrate substrates |
|
dietary sources of glucose |
starch- a glucose polymer sugar (dimer of glucose and fructose) milk (lactose, dimer of galactose and glucose) fruit/ vegetables (a source of glucose and fructose) |
|
glucose is the principal |
transported carbohydrate in humans and most abundant monosaccharide in dietary carbohydrates |
|
glucose can be transported by the |
blood |
|
glucose cannot be stored in |
the cells |
|
glucose storage |
to be stored, it has to be converted to the polysaccharide glycogen |
|
glucose is relatively rich in |
potential energy, and thus a good fuel |
|
in many organisms, the oxidation of glucose supplies energy for the production of |
ATP |
|
is glucose lipid soluble |
glucose is not sufficiently lipid soluble to enter in cells by diffusion across the plasma membrane |
|
dietary glucose enters the intestinal mucosal cells mainly by |
sodium co-transport, but the uptake of glucose from blood or interstitial fluid into the cells occurs by so-called "facilitate diffusion" |
|
GLUT 4 |
express in muscle, adipose tissue, heart
function: insulin-dependent glucose uptake |
|
GLUT 4 deposition in the plasma membrane is enhanced by |
insulin |
|
during the well-fed state |
decreased levels of glucagon and elevated levels of insulin
muscle and adipose tissue take up glucose
muscle and adipose do not depend on glucose, but can subsist on fatty acids and other nutrients if needed |
|
durgin starvation |
elevated levels of glucagon and low levels of insulin develops during fasting. this results in a decrease in the overall rate of glycolysis and an increase in gluconeogenesis
glucose is redirected from muscle and adipose tissue to tissues that depend on glucose - brain, RBCs |
|
insulin-independent tissues |
utilize glucose independently of the dietary/nutritional status
includes tissues that depend on glucose as a sole source of energy
RBCs, brain, beta cells of the pancreas |
|
insulin - dependent tissues |
can take up glucose only during the fed state (high insulin) levels
do not depend on glucose as a sole source of energy
muscle, fat |
|
glucose metabolism by the liver depends on |
the insulin/glucagon but insulin is NOT required for the entry of glucose into the liver cell |
|
glucose absorption from diet leads to |
increase in blood glucose concentrations |
|
rising blood glucose levels will |
increase liver-mediated glucose consumption by the liver (insulin-independent) - GLUT 2 transporters |
|
rising glucose triggers the release of |
insulin by the beta cells of the pancreas, which leads to a rapid removal of excess glucose from blood by tissues expressing GLUT 4 transporters (fat and muscle) Insulin-dependent |
|
blood glucose levels never fall below |
4-5 mM |
|
falling glucose leads to |
decreased insulin, increased glucagon and cessation of glucose uptake by most tissues |
|
carbohydrate |
a major source of energy |
|
glucose |
the major product of carbohydrate digestion |
|
some cells depend exclusively on |
glucose for energy |
|
glucose is stored in cells as |
glycogen (animal starch) |
|
glucose can be synthesized by cells from |
other metabolites |
|
the brain always depends on |
glucose supply. |
|
blood glucose level must be maintained at |
4-5.5 mmol/liter (70-100 mg/dL) |
|
the main site for glucose metabolism is |
the liver |
|
glucose degradation begins in the _____ and ends in the _____ |
cytoplasm
mitochondria |
|
glucose oxidation: |
when glucose is oxidized completely to CO2 and H2O, 36 or 38 ATP molecules are generated |
|
glycerol phosphate shuttle |
the transfer of electrons from cytoplasmic NADH to the respiratory chain of mitochondria |
|
malate- aspartate shuttle |
the reversible shuttling of hydrogen, in the form of malate, across the inner mitochondrial membrane |
|
glycolysis |
the catabolic pathway by which a molecule of glucose (6 carbons) is broken down into 2 molecules of 3 carbon compound pyruvate |
|
All cells of the body are capable of |
GLYCOLSIS |
|
glycolysis produces |
ATP without consuming oxygen |
|
glycolysis functions under |
aerobic or anaerobic conditoins |
|
many microorganisms are entirely dependent on |
glycolysis |
|
where does glycolysis take place |
in the cytoplasm of the cells |
|
glycolysis is an essential step for : |
aerobic metabolism of glucose |
|
in the liver _____ is the first step in the conversion of carbohydrate to fat |
glycolysis |
|
during glycolysis, some of the free energy released from glucose is conserved in the form: |
of ATP and NADH |
|
step 1 of glycolysis |
glucose is phosphorylated to glucose 6 phosphate catalyzed by glucokinase in the liver or by hexokinase in muslce/ fat |
|
glycolysis produces a net yield of |
2 molecules of pyruvate, 2 molecules of ATP, and 2 molecules of NADH per molecule of glucose (aerobic)
2 molecules of lactate, 2 molecules of ATP, and no net product of NADH per molecule of glucose (anaerobic glycolysis) |
|
2 phases of glycolysis |
1) energy investment phase (steps 1-5) phosphorylation of glucose and its conversion to glyceraldehyde 3-phosphate
2) energy generation phase (steps 6-10): oxidative conversion of glyceraldehyde 3-phosphate to pyruvate |
|
glucokinase |
(liver and pancreas) highly specific for glucose high but variable Km for glucose (10mM) not saturated at physiological blood glucose [] (4-5mM inhibited by fructose 6 P, but not glucose- 6- phosphate induced by insulin (transcriptionally) |
|
hexokinase |
(peripheral tissues) -low specificity - phosporylates most relevant hexoses -soluble and cytoplasmic protein -low Km (0.1mM); saturated at all plasma glucose concentrations -inhibited by glucose 6 phosphate -activated by fructose 1 phosphate and glucose -insulin has no effect on expression
|
|
during glycolysis, some of the energy of the glucose is conserved in ___ while much remains the product ___ |
ATP
pyruvate |
|
each molecule of glucose is degraded to : |
2 molecules of pyruvate 2 molecules of ATP and 2 molecules of NADH |
|
conversion of glucose to pyruvate is |
exergonic (neg G) |
|
formation of ATP from ADP and Pi is |
endergonic (positive G) |
|
what is the most important regulated enzyme of glycolysis |
phosphofrutokinase (PFK) |
|
PFK is stimulated by ____ and inhibited by _____ |
insulin AMP and ADP
glucagon (in the liver) citrate low pH ATP |
|
what inhibits pyruvate kinase |
ATP |
|
in RBCs, rates of glycolysis are regulated by |
ATP / (AMP + ADP) only |
|
hexokinase, phosphofructokinase, and pyruvate kinase reactions are |
irreversible |
|
aldolase and triose phosphate isomerase have very |
unfavorable equilibria (G>0)
but can still proceed, since fructose 1,6 bisP forms irreversibly, and glyceraldehyde 3P is rapidly consumed in the next react of the pathway bc NAD+ is in excess compared to NADH |
|
committed step of glycolysis |
Phosphofructokinase - commits conversion of glucose to pyruvate |
|
fate of 1,3 BPG |
converted to 3-phosphoglycrerate by phophoglycerate kinase
converted to 2,3- BPG by bisphophoglycerate mutase
2,3 bisphosphoglycerate is converted to 3-phosphoglycerate by bisphophoglycerate phosphatase |
|
pyruvate kinase is more active in |
the fed state than in the fasting state |
|
pyruvate kinase is inhibited by |
ATP acetyl CoA alanine |
|
pyruvate kinase is activated by |
fructose 1,6-bisphosphate |
|
pyruvate formed by glycolysis, is only the first stage in |
the complete degradation of glucose |
|
acetyl - CoA is formed from |
carbohydrates through glycolysis and pyruvate dehydrogenase |
|
the major fate of acetyl CoA is |
oxidation in the TCA cycle |
|
pasteur effect |
the stimulation of glycolysis under anaerobic conditions
this is due to a much higher energy yield from glucose metabolism in the presence of oxygen
pasteur effect NOT observed in red blood cells |
|
flux of glucose through the glycolytic pathway is dramatically reduced uner |
aerobic conditions
oxygen appears to "inhibit" glucose metabolism |
|
lactate is produced under |
anaerobic conditions |
|
anaerobic glycolysis is only useful under what circumstances: |
mature RBCs
vigorously contracting skeletal muscle in which oxygen supply becomes a limiting factor
ischemic tissue |
|
warburg effect |
most cancer cells rely on aerobic glycolysis |
|
fructose metabolism occurs primarily in |
the liver, kidneys, and small intestine |
|
in the liver, fructose is converted to |
fructose 1 phosphate by fructokinase and activates glucokinase |
|
essential fructosuria |
a deficiency of fructokinase |
|
hereditary fructose intolerance |
a deficiency of fructose 1-phosphate metabolism by aldolase B |
|
pyruvate |
produced by glycolysis and further oxidized in the mitochondria under aerobic conditions |
|
cellular respiration |
the aerobic phase of catabolism when cells consume O2 and produce CO2 (and H2O) |
|
transport of pyruvate |
must be transported into the mitochondria, it diffuses through the pores in the outer mitochondrial membrane into the mitochondria matrix to reach the multi-enzyme complex pyruvate dehydrogenase |
|
The TCA cycle is ____ in metabolism |
"hub" |
|
first step of TCA |
conversion of pyruvate to acetyl groups, then acetyl groups are carried into the TCA cylce |
|
3 stages of cellular respiration |
1) oxidation of fatty acids, glucose, and some amino acids yields acetyl COA 2)oxidation of acetyl groups in TCA cycle includes 4 steps in which electrons are transferred ( 4 pairs of electrons are transferred during one turn of the cycle) 3) electrons carried by NADH and FADH2 enter the respiratory chain - ultimately reducing O2 to H2O and the production of ATP |
|
Oxidative Decarboxylation |
the conversion of pyruvate to Acetyl CoA Exergonic reaction catalyzed by pyruvate dehyrogenase complex NAD+ and CoA-SH are needed as co-substrates -vitamins: niacin (NAD) and panthotenic acid (CoA)
co-enzymes are lipoid acid and the vitamins thiamin pyrophosphate and riboflavin |
|
3 enzymes that make up the PDH complex |
1) pyruvate dehydrogenase 2) dihydrolipoyl transacetylase 3)dihydrolipoyl dehydrogenase |
|
pyruvate dehydrogenase |
-inhibited by its product NADH and acetyl CoA -stimulated by AMP -Inactivated but the phosphorylation -reactivated by dephosphorylation |
|
dihydrolipoyl transacetylase |
catalyzes the transfer of the acetyl group to coenzyme A, forming Acetyl - CoA |
|
dihydrolipoyl dehydrogenase |
catalyzes the regeneration of the disulfide form of lipoate |
|
regualtory enzymes of PDH |
phosphorylate/dephosphorylate E1 (a kinase and a phophatase) |
|
5 cofactors required for PDH |
-Thiamin pyrophosphate (TPP) -Lipoic acid (lipase) -Flavin adenine dinuclueotide, FAD (Riboflavin) -Nicotinamide adenine dinucleotide, NAD+ (Niacin) -Coenzyme A, CoA (Pantothenic acid) |
|
4 different vitamins required in human nutrition are vital components of PDH complex |
thiamine (in TPP) riboflavin (in FAD) niacin (in NAD) pantothenate (in CoA) |
|
thiamine pyrophosphate (TPP) |
a coenzyme important in respiration in the TCA cycle, and often plays a role in the removal of carboxyl groups from organic acids
a vitamin B1 derivative produced by the enzyme thiamine |
|
thiamine deficiency leads to |
inability to oxidize pyruvate and thus has a major neurological impact - Beriberi |
|
lipoamide |
lipoate, a prosthetic group of pyruvate dehydrogenase, has two thiol groups that can undergo reversible oxidation to a disulfide bond. because of its capacity to undergo oxidation-reduction reactions, lipase can serve both as an electron carrier and as an acyl carrier. |
|
Coenzyme A |
has a reactive thiol (-SH) group that is critical to the role of CoA as an acyl carrier in metabolic reactions
formed from pantothenic acid and ATP, is necessary for carb, fatty acid synthesis and metabolism, and the oxidation of pyruvate in the TCA cylce |
|
PDH complex carries out __________ in the decarboxylation and dehydrogenation of pyruvate |
five consecutive reactions |
|
sources of acetyl - Co A |
in aerobic organisms, glucose and other sugars, fatty acids, and most amino acids are ultimately oxidized to CO2 and H2O via TCA cycle and respiratory chain
pyruvate, the product of glycolysis is converted to acetyl CoA, the starting material for the TCA cycle, by the PDH complex |
|
Regulation of PDH |
Allosteric: inhibition by ATP, acetyl-CoA and NADH Activation by AMP, CoA and NAD+
Covalent: Inhibition by phosphorylation of E1 (pyruvate dehydrogenase). A specific kinase (co-substrate: ATP) catalyzes this phosphorylation (PDH kinase) Activation by dephospho rylation
|
|
pyruvate is a potent inhibitor of |
pyruvate dehydrogenase kinase |
|
TCA/Krebs cylce |
the final common pathway for the oxidation of all major nutrients, and plays several roles in metabolism |
|
where do TCA and oxidative phosphorylation take place |
in all cells that contain mitochondria |
|
TCA cycle and oxidative phosphorylation are the |
final common pathway for the oxidation of all major nutrients |
|
degradation of acetyl CoA derived form carbs, fatty acids, and amino acids: |
-produces most of the CO2 generated in tissues -is the major source of NADH -allows excess energy to be used for fatty acid biosynthesis -provides precursors for many metabolites |
|
most TCA cycle enzymes are in the |
mitochondrial matrix, some are in the inner mitochondrial matrix |
|
one complete turn of the TCA cycle generates |
only one GTP, 3 molecules of NADH and one molecule of FADH2 from one acetyl residue |
|
TCA: in a series of 7 reactions 2 carbons are released as |
CO2, regenerating oxaloacetate |
|
how many pairs of electrons are transferred during one turn of the TCA cycle |
4 paris 3 pairs of electrons reducing 3 NAD+ to NADH, and one pair reducing FAD to FADH2 |
|
one complete turn of the TCA cycle generates ____ ATP ____ NADH ____ FADH2
|
1 ATP in the conversion of succinyl CoA to succinate 3 NADH 1 FADH2
|
|
oxidation of one NADH leads to formation of ___ ATP |
3 |
|
Oxidation fo FADH2 yields ____ ATP |
2 |
|
Total ATP generated by one round of TCA cycle from one acetyl residue |
12ATP |
|
Total ATP yield from one molecule of glucose (through glycolysis and TCA) |
38 ATP |
|
The TCA cycle activity is responsive to: |
energy state of the cell -redox state of the cell, through flux rate limitation caused when intramitochondrial NAD+ decreses - availability of energy - rich compounds, through inhibition of relevant enzymes by acetyl CoA or succinyl CoA |
|
TCA cycle is an ______ pathway, that serves in ... |
amphibolic pathway that serves in both catabolic and anabolic processes |
|
PDH complex is allosterically inhibited when |
[ATP]/[ADP], [NADH]/[NAD+] and [acetylCoA]/[CoA] ratios are high, indicating an energy sufficient metabolic state
when these ratios decrease, allosteric activation of pyruvate oxidation results |
|
the overall rate of the TCA cycle is controlled by |
the rate of conversion o pyruvate to acetyl CoA |
|
In TCA cycle: Citrate synthase is inhibited by |
ATP citrate NADH succinyl CoA |
|
in TCA: isocitrate dehydrogenase is inhibited by |
ATP and NADH |
|
in TCA: alpha keto glutarate dehydrogenase is inhibited by |
succinyl CoA and NADH |
|
TCA cycle intermediates are also used in |
biosynthetic (anabolic) pathways |
|
Anaplertoic reactions |
biosynthetic reactions tat consume TCA cycle intermediates, must be balanced by reactions that produce them |
|
example of anplerotic reactions |
synthesis of oxaloacetate from pyruvate by pyruvate carboxylase... this is ATP dependent carboxlation reaction, activated by acetyl CoA bound biotin
synthesis of malate form pyruvate by malic enzyme - pro and eukaryotes
synthesis of oxaloacetate from PEP by PEP-CK - heart and skeletal muscle
|
|
pyruvate carboxylase defficiency |
a rare recessively inherited condition
pyruvate accumulates because pyruvate carboxylase is a major consumer of pyruvate
acculated pyruvate is converted to lactate and alanine
|
|
hypoglycemia |
caused by the inability to convert pyruvate to glucose |
|
neurological deficits and mental retardation can be caused by |
dysfunction of TCA cycle due to insufficient oxaloacetate |
|
Antiporters |
transport metabolites across the inner mitochondrial membrane
ex: ADP, ATP, pyruvate, phosphate, alanine, aspartate, glutamate, substrates, intermediates, and products of the TCA cycle : except acetyl CoA, oxaloacetate, fumarate, NAD, NADH |
|
the mitochondrial translocases are |
antiporters
they do not hydrolyze ATP, but energy is consumed whenever active maintained ion gradient or the membrane potential is dissipated |
|
Can TCA function in anaerobic conditions? |
NO, unlike glycolysis, TCA cycle cannot function under anaerobic condition TCA cycles is an aerobic pathway |
|
under aerobic conditions, pyruvate is transported to... |
into the mitochondria, where it is turned into the 2 carbon compound acetyl coenzyme A (CoA) |
|
how does Acetyl CoA enter the TCA cycle |
by reacting with the 4 carbon compound oxaloacetate to form the 6 carbon compound citrate
citrate is converted back to oxaloacetate in the reactions of the TCA cylcw |
|
in aerobic organisms, glucose and other sugars, fatty acids and most amino acids are ultimately oxidized to |
CO2 and H2O via TCA and respiratory chain. |
|
what converts pyruvate to acetyl CoA |
pyruvate dehydrogenase complex |
|
FADH2 |
is not free in solution like NAD+ and NADH; it is tightly bound to enzymes |
|
TCA cycle produces ___ molecules of CO2 for each acetyl residue |
2 |
|
succinate dehyrogenase |
is the only membrane bound enzyme in the TCA cycle |
|
lipoate (lipoid acid) |
a prosthetic group of pyruvate dehyrdogenase |
|
prosthetic group |
a metal ion or an organic compound that is covalently bound to a protein an dis essential for its activity |
|
pantothenic acid (pantothenate) |
an essential constituent of coenzyme A, also called vitamin B5, a water soluble vitamin required to sustain life (essential nutrient) |
|
TPP |
thiamine pyrophosphate, a prosthetic group that transfers carboxyla |
|
acyl carrier |
part of the fatty acid synthesizing enzyme complex, which carries acyl groups, including the acetyl group
|
|
election carriers |
a protein such as flavoprotein or a cytochrome that can reversibly gain and lose electrons |
|
lyase reaction |
an enzymatic reaction that removes a group non hydrolytic ally from its substrate |
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isomerization |
convert form one isomer to another |
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condensation |
a chemical reaction in which two molecules or moieties combine to form one single molecule, with the loss of a small molecule |
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decarboxylation |
a chemical reaction in which a carboxyl group is split off from a compound as CO2 |
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deydration |
a chemical reaction that involves the loss of water from the reacting moleculeh |
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hydration |
a chemical reaction involving the loss of water from the reacting molecule |
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dehyrogenation |
chemical reaction that involves the elimination of H2 |
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the respiratory chain is present in |
the mitochondrial membrane |
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the respiratory chain and oxidative phosphorylation are |
tightly couple processesin |
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inhibition of the electron transport chain also results in |
inhibition of ATP synthesis |
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oxidative phosphorylation |
means ATP synthesis, its the culmination of energy yielding metabolism in aerobic organisms |
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what is the principal source of ATP |
oxidative phosphorylation |
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where do TCA cycle and oxidative phosphorylation take place? |
in all cells that contain mitochondria |
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TCA cycle and oxidative phosphorylation are the final.. |
common pathway for the oxidation of all major nutrients |
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failures of oxidative phosphorylation are caused by |
hypoxia and anoxia |
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oxidative phosphorylation involves the reduction of |
O2 to H2O with electrons donated by NADH and FADH2 |
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oxidative phosphoyrlation involves |
a "flow of electrons" |
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oxidative phosphorylation begins with |
the entry of elections into the respiratory chain |
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NADH |
a water soluble electron carrier that associates reversibly with dehydrogenates |
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energy yields from cytoplasmic NADH depends on |
the shuttle used |
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complete oxidation of glucose molecule to CO2 yields |
36 or 38 ATP
only 4 of them are produced by phosphorylation during glycolysis and the TCA cycle, the rest are from oxidative phosphorylation |
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all major catabolic pathways form |
NADH and or FAHD2
these reduced coenzymes must be re-oxidized to NAD+ and FAD, which are needed as substrates of the pathways and requires the respiratory chain in the inner mitochondria membrane |
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nutrient energy potential (H2) is stored in |
mitchondrial NADH+, H+/FADH2 |
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the transfer of the protons and electrons to oxygen generates the |
energy required for ATP synthesis |
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none of the functional groups in proteins can transfer |
hydrogen or electrons
the components of the respiratory chain have to employ metal and ions and coenzymes |
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the respiratory chain contains: |
flavoproteins iron-sulfur proteins cytochromes ubquinone or coenzyme Q protein bound copper
* with the exception of Coenzyme Q, all members of this chain are proteins |
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FAD or flavin mononucleotide (FMN) in the flavoproteins can transfer: |
either one or two electrons at a time |
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electron transfer occurs because: |
the FAD/FMN has a higher reduction potential than the compound oxidized |
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FAD/FMN accepty hydrogen/electrons from : |
NADH and donate it to the cytochromes |
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flavoproteins |
proteins containing flavin adenine dinucleotide (FAD) or FMN as a prosthetic group, participate in hydrogen transfer reactions |
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reduction potential |
delta E: the measure of tendency of a redox pair reaction
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cytochromes |
heme proteins that functions as electron carriers in respiration, photosynthesis, and other oxidation reduction reactions |
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iron-sulfur proteins |
a large family of electron-transfer proteins in which the electron carrier is one or more iron ions associated with 2 or more sulfur atoms of cysteine residues
aka non-heme proteins anchored in proteins through cysteine both the iron sulfur proteins and flavoproteins are integral membrane proteins |
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iron sulfur complexes in proteins |
iron in these complexes can change its oxidation state reversibly between the ferrous (Fe2+) and ferric (Fe3+) forms |
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cytochromes contain |
red or brown heme proteins the heme iron of the cytochrome switches back and forth between ferrous and ferric one electron carriers mitochondria contain 3 classes of cytochromes based on wavelengths of the spectral absorption peaks (a, b, c) all but one are integral membrane proteins
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cytochrome c |
is a small and water soluble protein. after its single heme accepts an electron from complex III, cytochrome c moves to complex IV to donate electron to a binuclear copper center. |
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cytochromes consist of |
4 five membered nitrogen containing rings in a cyclic structure, called a porphyrin
the 4 nitrogen atoms are coordinated with a central Fe ion, either Fe2+ or Fe3+ |
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ubiquinone or coenzyme Q |
a lipid soluble hydrophobic benzoquinione with a long isoprenoid side chain (a long hydrocarbon tail of 10 isoprene units makes it hydrophobic)
a component of the respiratory chain
a hydrogen carrierp |
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protein bound copper |
participates in the last reaction of the respiratory chain, the transfer of electrons to molecular oxygen. it switches between the Cu+ and Cu 2+ forms during these electron transfers |
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4 components of the respiratory chain are freely diffusible: |
NADH ubiquinone cytochrome c molecular oxygen |
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the respiratory chain contains |
large multi protein four electron carrier complexes, each capable of catalyzing electron transfer: complex I, II, III, IV |
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Complexes I and II |
catalyze electron transfer to ubiquinone from 2 different electron donors: NADH (complex I) and succinate dehydrogenase (complex II) |
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Complex III |
carries electrons from reduced ubiquinone to cytochrome C |
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complex IV |
transferring electrons from cytrochrome c to O2 |
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the respiratory proteins are located in |
the inner mitochondrial membrane
cells with high rates of respiration (heart muscle) have mitochondria with many densely packed cristae.
liver cells have much fewer cristae |
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for each pair of electrons transferred to O2, ___ protons are pumped out by Complex I, ___ by Complex III, and ___ by complex IV |
4 protons by complex 1 4 protons by complex III 2 protons by complex IV |
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electron transport |
progressive transport of electrons for NADH+H+/FADH2 through various electron acceptors with increasing reduction potentials, ultimately to O2 |
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Complex I |
aka NADH: ubiquinone oxidoreductase or NADH dehydrogenase, transfers electrons from NADH to ubiquinone, is a large enzyme composed of 42 different polypeptide chains, including FMN-containing flavoprotein and at least 6 iron sulfur centers
electrons are transferred from NADH to flavoprotein (FMN) then iron sulfur centers to ubiquinone |
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amytal, rotenone, and piericidin A inhibit: |
electron flow from the Fe-S centers of complex I to ubiquinone, and therefore block the overall process of oxidative phosphorylation |
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complex II |
aka succinate dehyrogenase is the only membrane-bound enzyme in the TCA cycle
contains only 5 cofactors and 4 different protein subunits (A, B, C, D) contains 3 Fe-S centers, bound FAD electrons from succinate pass through a flavoprotein and several Fe-S centers to ubiquinone |
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glycerol 3-phosphate donates electrons to |
a flavoprotein on the outer face of the inner mitochondrial membrane, then pass to ubiquinone |
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acyl CoA dehyrogenase transfers |
electrons to ETF from which they pass to ubiquinonec |
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complex III |
(ubiquinone to cytochrome c) aka cytochrome c oxidoreductase or cytochrome bc1 complex, couples the transfer of electrons from ubiquinol (QH2) to cytochrome c
it contains cytochrome b, an Fe-S protein, and cytochrome c1.
its a dimer of identical monomers, each with 11 different subunits |
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Complex IV |
(cytochrome c to O2) the final step of the respiratory chain. aka cytochrome oxidase, carries electrons from cytochrome c to molecular oxygen, reducing it to H2O
a large enzyme of the inner mitochondrial membrane
contains 2 heme groups, each located near a copper ion
oxygen is tightly bound between heme a3, and copper to be released after its reduction to H20 by the transfer of 4 electrons
cytochrome oxidase has a very high affinity for oxygen. |
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complex IV inhibitoin |
acute cyanide poisoning |
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both iron and copper has been shown |
to bind cyanide |
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oxidative phosphorylation proceeds in 2 steps |
1) protons are pumped out of the mitochondria: driven by the redox reactions in resp chain 2)protons are admitted back into the mitochondria via a proton channel: this process drives ATP synthesis |
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ATP is synthesized only when |
protons flow, and protons can only flow when ATP is synthesized |
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inner mitochondrial membrane acts like a |
storage battery, is charged by the proton pumps of the respiratory chain |
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proton pumping out of the mitochondria matrix is fueled by |
the exergonic reactions in the respiratory chain |
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protons move back into the matrix through a proton channel. This proton channel is coupled to |
an ATP- synthesizing enzyme (ATP synthase). ATP synthesis is field by the flow of protons down their electrochemical gradient. |
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there is no rate limiting step in: |
oxidative phosphorylation |
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what does the rate of oxidative phosphorylation depend on |
substrates availability and an oxidizable metabolite, like NADH and or FADH2 |
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ATP synthesis absolutely dependent on |
continuous electron flow and electron transport occurs only during ATP synthesis |
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what produces most of the ATP |
oxidative phosphorylation |
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in healthy cells, the level of ATP exceeds that of ADP by a factor of: |
4-10 |
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high demand for ATP, generates: |
ADP, which stimulates respiration |
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At rest, accumulation of ATP depletes |
ADP levels and suppresses respiration |
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uncoupler |
any substance that inhibits ATP synthesis but have no effect on electron transport
means the dissociation of oxidative phosphorylation (not reduction) from ATP synthesis. wh |
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at is the most common uncoupler |
2,4-dinitrophenol (DNP) |
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Valinomycin |
an antibiotic that makes the inner mitochondrial membrane permeable for potassium |
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oxygen utilization is maintained as |
electron transport (H+ pumping) continues |
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ATP synthesis is diminished or inhibited as |
proton gradient is weak, disrupted, or non-existentt |
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thyroxin |
a hormone produced by the thyroid glands to regulate metabolism by controlling the rate of oxidation in cells |
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thermogenin |
a protein of the inner mitochonrial membrane that allows trans-membrane movement of protons, called uncoupling protein, a membrane-spanning protein that forms a natural channel to allow proton return
-increases heat generation -found in specialized tissues (hairless, hibernators, cold-adapted) -brown fat (particularly high content of cytrochromes) localized in the neck and upper back |
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oxidative phosphorylation is inhibited by: |
by many poisons; electron flow through the respiratory chain, can be blocked by: -rotenone -amytal -antimycin A -cyanide |
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rotenone |
an insecticide, blocks flow of electrons from Fe-S complexes in the NADH-Q reductase complex to ubiquinone through complex I. blocks transfer of electrons associated with NADH |
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amytal |
(a barbituate), site of action same as rotenone, also inhibits electron flow through the NADH-Q redutase compile (complex I) |
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antimycin A |
an antibiotic, that blocks electron flow from cytochrom b to c1 through the cytochrome c oxido-reductase complex (complex III) |
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cyanide |
binds to cytochrome oxidase (complex IV) and prevents electron transfer ot oxygen. hydrogen sulfide, carbon monoxide and azide also act as cyanide. |
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mitochondrial genome consists of |
16,569 base pairs that encode: 13 polypeptides 7 subunits of complex I 1 subunit of complex II 3 subunits of complex IV 2 subunits of ATP synthase 22 transfer RNAs 2 RNAs of the mitochondrial ribosomes |
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mutation in mitochondrial DNA can cause |
-Lebers hereditary optic neuropathy (LHON): blindness, caused by degeneration of the optic nerve -myoclonic epilepsy and ragged-red fiber disease (MERRF) -mitochondrial DNA has a higher mutation rate than nuclear DNA |
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reactive oxygen species are formed when? |
during oxidative metabolism
electrons may "leak out" of the respiratory chain |
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what is the most harmful radical |
hydroxyl radical |
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enzymes evolved to destroy ROS |
superoxide dismutase (SOD)
catalase - a heme containing enzyme that destroys H2O2)
peroxidases: glutathione peroxidase |
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examples of metabolites, vitamins, hormones,and phytochemicals that can eliminate free radicals |
bilirubin uric acid ascorbate (vitamin C) estrogens |
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heart muscle obtains nearly all its ATP from |
oxidative phosphorylation |
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oxidative phosphorylation and photo-phosphorylation account for |
most of the ATP synthesized by organisms |
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mitochondria have ___ membranes |
2: the outer membrane is readily permeable to small molecules, which move freely through transmembrane channels. The inner membrane is impermeable to small molecules and bears the components of the respiratory chain and the ATP synthase. |
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can NADH and NADPH cross the inner mitochondrial membrane |
NO |
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respiratory chain creates |
a proton gradient |
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inhibition of ATP synthesis blocks: |
electron transfer in intact mitochondria |
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glycolysis under anaerobic conditions yields only |
2 ATP per glucose |
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ATP consumption increases... |
the rate of electron transfer and oxidative phosphorylation increases |
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mitochondria of heart muscle |
have much larger are of inner membrane, contain more than 3 times the electron transport systems compared to liver mitochondria |
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electron transport system: |
movement of electrons from electron donor to electron acceptor molecules, especially from substrates to oxygen, via carriers such as components of the respiratory chain |
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cytochromes |
heme proteins that functions as electron carriers in respiration, photosynthesis and other oxidation - reduction reactions |
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proton pump |
proton pumps are integral membrane proteins capable of moving protons across the membrane of a cell, mitochondrion, or other sub-cellular compartment |
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iron-sulfur proteins |
non-heme iron proteins that participate in electron transfer reactions |
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ATP synthase |
an enzyme complex that forms ATP from ADP and phosphate during oxidative phosphorylation in the inner mitochondria membrane, and during phosphorylation in chloroplast |
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uncouplers |
also called uncoupling agents substances tha uncouple phosphorylatin of ADP from electron transfer, ex; 2,4 dinitrophenol |
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free radicals |
molecules with an unpaired electron; most of them are highly reactive |
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the brain alone consumes ____ of glucose |
120 grams of glucose per day |
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what blood glucose level must be maintained at all times |
4-5.5 mmol/liter |
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only ____ glycogen can be used to maintain the blood glucose level |
liver |
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gluconeogenesis produces |
glucose from amino acids, lactic acid, and glycerol
it is the only source of glucose during prolonged fasting |
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only the liver and kidneys have a .. |
complete gluconeogenic pathway |
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liver produces ___ times more glucose than kidney, because... |
10 x bc the liver is this much larger than the kidney |
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where is glucose stored |
in the liver and muscle, in the form of glycogen |
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where does gluconeogenesis occur |
primarily in the cytosol, although some precursors are generated in the mitochondria |
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glucose is a universal |
fuel and building block in humans, some tissues depend almost completely on glucose for their metabolic energy |
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what is the major gluconeogenic organ of the body |
LIVER |
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does muscle contribute to gluconeogenesis |
muscle does NOT contribute, because it has no glucose-6-phospatase and no glucagon receptors |
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gluconeogenesis |
synthesis of carbohydrate from non carbohydrates such as oxaloacetate or pyruvate |
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gluconeogenesis and glycolysis run in |
oposite directions |
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3 reactions of glycolysis are irreversible and cannot be used in gluconeogenesis: |
1. conversion of glucose to glucose 6 phosphate (hexokinase/glucokinase)
2. phosphorylation of fructose 6 phosphate to fructose 1,6 bisphosphate (PFK-1)
3. Conversion of PEP to pyruvate (pyruvate kinase) |
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3 reactions bypassing irreversible reactions of glycolysis in gluconeogenesis |
1) bypass from pyruvate to PEP. Pyruvate is carboxylated to oxaloacetate by pyruvate carboxylase. 2) the PFK rxn is bypassed by fructose 1,6 bisphosphate which hydrolyzes the phosphate from carbon 1 3) hexokinase reaction is bypassed by glucose 6 phosphate |
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where is glucose 6 phosphate |
located in the ER and present only i the liver. |
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glucose |
is an important metabolic substrate for most tissues, and is required fuel for brain and RBCs. normal blood glucose level: 70 to 100 mg/dL |
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in the fasting state, the liver... |
has to produce glucose by gluconeogenesis and glycogen degradation |
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for each molecule of glucose formed by pyruvate, ___ high-energy phosphate groups are required, ___ from ATP and ___ from GTP |
6 4 2 |
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___ molecules of NADH is required for the reduction of 2 molecules of 1,3 bisphosphoglycerate to glyceraldehyde 3 phosphate |
2 |
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gluconeogenic substrates |
glucogenic amino acids - all except leucine and lysine
lactate - cori cycle
glycerol
all TCA intermediates except Acetyl CoA |
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Acetyl CoA cannot be converted to glucose, because |
the PDH reaction is irreversible |
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gluconeogenesis depends on |
amino acids, lactate, and glycerol |
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fatty acids that are released from adipose tissue during fasting cannot |
be turned into glucose |
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most important substrates of gluconeogenesis |
lactate and alanine bc they are readily converted to pyruvate by lactate dehydrogenase and by transamination |
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cori cycle |
shuttling of glucose and lactate between muscle/ RBC and liver during physical exercise |
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after vigorous exercise, lactate produced by anaerobic glycolysis returns to |
the liver and is converted to glucose, which moves back to muscle and is converted to glycogen (core cycle) |
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regulation of gluconeogenesis |
insulin and glucagon epinephrine and norepinephrine glucocorticoids pyruvate kinase phosphofructokinase and fructose 1,6 bisphosphate |
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insulin |
released from pancreatic Beta cells in response to hyperglycemia
insulin lower blood glucose level
insulin is needed to convert sugar, starches, and other food into glucose or regulates storage of glycogen in the liver and accelerates oxidation of sugar in cells |
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glucagon |
a polypeptide hormone from the alpha cells of the pancreas that stimulates the glucose producing pathways of the liver. it is released in response to hyperglycemia
glucagon raises blood glucose level |
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the release of glucagon and insulin is inhibited by |
somatostatin that is secreted by the pan created delta cells |
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epinephrine and norepinephrine |
stress hormones that released during physical exertion and cold exposure. in the liver, they promote gluconeogenesis over glycolysis by inducing cAMP |
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glucocorticoids |
also stress hormones that affect gene transcription. stimulate gluconeogenesis by inducing gluconeogenic enzymes |
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pyruvate kinase |
the most important regulated enzyme in the PEP-pyruvate cycle. it is inhibited by ATP and activated by fructose 1,6 bisphosphate |
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phosphofructokinase and fructose 1,6 bisphosphatase |
in the liver are oppositely regulated. ATP and citrate stimulate fructose 1,6 bisphosphatase but inhibit phosphofructokinase |
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glucose-phosphorylating enzymes in the liver are: |
hexokinase and glucokinase |
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fructose 2,6 bisphosphate |
the most potent modulator of phosphofructokinase and fructose 1,6 bisphosphatase |
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fatty acid oxidation is less controlled by _______ _______ than is glucose oxidation |
feedback inhibition
therefore, levels of ATP and acetyl CoA in the liver are actually elevated during fasting |
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fatty acid oxidation provides the necessary energy required by |
gluconeogenesis |
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feedback inhibition |
inhibition of a metabolic pathway by its end product |
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fatty acid oxidation |
the burning of stored fat |
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gluconeogenesis is inhibited by: and stimulated by: |
inhibited by fructose 2,6 bisphospate
stimulated by acetyl CoA |
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liver consumes _____ to maintain _____ |
glucose to maintain blood glucose level |
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muscle consumes |
glucose for energy production |
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lactate is transported from muscle to... |
liver for the re-synthesis of glucose in the Cori cycle |
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glycolysis |
conversion of glucose to pyruvate |
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gluconeogenesis |
conversation of 2 molecules of pyruvate to one molecule of glucose |
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glycogenesis |
synthesis of glycogen |
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glycogenolysis |
breakdown of stored glycogen |