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Biochem: TCA Cycle and ETC

What are the reducing molecules used in the ETC to make ATP? NADH, FADH2
Where are the enzymes of the PDH and TCA cycle found? pyruvate dehydrogenase, dihydrolipoyl transacetylase, dihydrolipoyl dehydrogenase, in the mito matrix
Which membrane of the mito is leaky, which is the major barrier? outer: leaky, inner:barrier
How does pyruvate enter the mito? pryuvate translocase transports pyruvate across the inner mito membrane in symport with H+
WHat converts pyruvate to Acetyl CoA? the pyruvate dehydrogenase complex does and produces NADH in the process
Describe the PDC 3 enzymes: E1:pyruvate dehydrogenase, E2:dihydrolipoyl transacetylase, E3:dihydrolipoyl dehydrogenase and 5 co-enzymes
What products/coenzymes are required for the action of PDH? pyruvate, CoA-SH, NAD+, TPP, lipoate, FAD
Describe the properties of Acetyl-CoA high energy compound, hydolysis of the thioester is very high (greater than ATP hydrolysis)
Functions of Acetyl-CoA input into TCA cycle where the acetate moiety is further degraded to CO2, donor of C2 for synthesis of fatty acids, ketone bodies, cholesterol, amino acids
Why is there such a large complex of enzymes for the PDC? enzyme complex can direct substrate from one enzyme to the next, channeling intermediates minimizes side reactions, the reactions can be coordinately controlled
What is the prosthetic group of Pyruvate dehydrogenase? thiamine pyrophosphate (TTP)
What is the prosthetic group of Dihydrolipoyl transacetylase? lipoamide
What is the prosthetic group of dihydrolipoyl dehydrogenase? FAD
What is the function of E1? pruvate is decarboxylated to form hydroxyethyl derivative bound to TPP
Describe the function of E2? hydroxyethyl is oxidized by transfer to the disulfide form of lipoic acid (E2 prosthetic), the acetyl group bound as a thioester to the side chain of lipoic acid is transferred to CoA
Describe the function of E3? sulfhydryl form of lipoic acid oxidized by FAD-dependent E3 leading to the formations of oxidized lipoic acid making FADH2. FADH2 is oxidized by E3 as NAD is reduced to NADH
What are all the vitamens in the PDC? panthothenic acid:coenzyme A, Thiamine:TPP, lipoic acid:lipoamide, riboflavin:FAD, Niacin:NAD
What are the prosthetic groups of PDC? TPP, FAD, lipoamide
What are the cosubstrates of PDC? CoA, NAD
Describe Beriberi nutritional deficiency of thiamine, especially affects the brain because of it's dependence on glucose metabolism, prolonged deficiency causes multiple system effects, occurs with alcohol abuse
What is Wernicke-Korsakoff? Also known as wet brain, thiamine deficiency due to alcohol abuse
What is genetic beriberi? ppl who can't absorb thiamine
How is the PDC inhibited? NADH competes with NAD+ for binding to E3, Acetyl CoA competes with CoA for binding to E2
How is the PDC activated? by NAD to E3 and CoA to E2, phosphorylation state of E1, PDH kinase/PDH phosphatase
How many copies of each enzyme are there per complex? E1:20-30, E2:1, E3:6
How is E1 regulated? PDC kinases catalyze E1 phosphorylation thereby inhbiting it
How are the PDC Kinases activated? they are activated by NADH and acetyl CoA, PDH kinases interact with E2 to sense changes in oxidation state and acetylation of lipoamide by NADH and acetyl CoA
How do PDH kinases work during the fasted state? in muscle PDH kinase increases which inhibits msucle from using glucose that is more needed for brain
How is PDH kinase inhibited? in the presence of high pyruvate concentration it is inhibited by ADP
What is the function of PDH phosphatases? removes Pi from E1, in skeletal muscle it is activated by Ca allowing mito metabolism to be stimulated during exercise
What is arsenite? trivalent arsenic
How does it regulate PDH? forms a stable complex with lipoic acid and inhibits the E2 enzyme causing lactate to accumulate and a significant reduction of energy
Describe Leigh syndrome inherited disorder that affects infants caused by mutation in PDH complex resulting in reduced ATP production. Degradation of motor skills and episodes of lactic acidosis
Describe E2 enzyme deficiency hyperammonemia, non-specific amino acid elevation, discrete lesions on the globus pallidus
Describe E3 enzyme deficiency branched chain amino acid elevation in serum, alpha ketoglutarate in serum and urine, TPP inhibitors can be detected in urine and blood
What reactions replenish intermediates of the TCA cycle? anapleurotic reactions
What does the amphibolic nature of the TCA cycle refer to? anabolic reactions to generate energy and anabolic reactions that generate intermediates for biosynthesis occur in the TCA cycle
What kind of intermediates are in the TCA cycle? carbohydrates, lipids, amino acids, as well as nucleotides and porphyrins
What is produced in the TCA cycle? 3NADH, 1FADH2, 1GTP
How many ATP produced when glucose is fully oxidized to CO2 and H20? (34) 36
How many ATP are contributed by the TCA cycle and by which coenzyme? 24 ATP in total, 2 ATP by substrate level phosphorylation, 18 ATP from 6 NADH, 4 ATP from 2 FADH2
which enzyme in the TCA cycle catalyzes the highest free energy reaction? citrate synthase
Which enzyme in the TCA cycle catalyzes the lowest free energy reaction? malate dehydrogenase
1st step of TCA? Condensation of Acetyl CoA with oxaloacetate produces citrate, reaction is irreversible, catalyzed by citrate synthase
Properties of citrate? can be exported out of the mito, can be broken down by ATP-citrate lyase to yield oxaloacetate and acetyl-CoA, it inhibits PFK1 and activates acetyl-CoA carboxylase of fatty acid synthesis
Properties of citrate synthase? Oxaloacetate binds citrate synthase, conformational change generates acetyl-CoA Inhibited by citrate, NADH, succinyl-CoA, ATP. Activated by ADP
What happens to citrate in the TCA cycle? isomerized by aconitase to isocitrate
Inhibition of aconitase? inhibited by fluoroacetate
Where is fluoroacetate found? compound in rat poison
Describe the action of fluoroacetate. converted to fluoroacetyl CoA and condenses with oxaloacetate to form fluorocitrate which inhibits aconitase causing citrate build up
What happens to isocitrate in TCA cycle? irreversible reaction, catalyzed by isocitrate dehydrogenase, produces alpha-ketoglutarate and NADH and CO2
Describe alpha ketoglutarate transaminated to make glutamate which can be used to synthesize other amino acids or donate nitrogen groups to other syntheses
Regulation of isocitrate dehydrogenase? inhibited by ATP and NADH, activated by Ca2+, ADP
What are the functions of the two forms of isocitrate dehydrogenase? one uses NAD and the other uses NADP, ONLY THE NAD linked enzyme is used in the TCA cycle
What is the reaction catalyzed by alpha-ketoglutarate dehydrogenase? production of succinyl CoA, NADH, and CO2 from alpha-ketoglutarate
Regulation of alpha-ketoglutarate dehydrogenase? inhibited by succinyl CoA, NADH and activated by Ca
What is special about the reaction by alpha-ketoglutarate dehydrogenase? second oxidative decarboxylation producing a very high energy thioester, it is a key regulatory step, similar to the PDC: E1, E2 and E3 enzyme units
What is the main difference between PDC and alpha-ketoglutarate dehydrogenase? not affected by reversible protein phosphorylation, NB: it can be affected by thiamine deficiency
What happens to succinyl CoA in the TCA cycle? cleavage of high energy thioester bond to produce GTP, catalyzed by succinyl-CoA synthetase
Describe the transfer of the phosphate to GTP by succinyl-CoA synthase succinyl CoA has a thioester bond with very negative free energy when hydrolyzed which is transferred to phosphoester bond with inorganic phosphate. The phosphate is transferred to histidine of enzyme and then GDP
Succinate reaction in TCA? succinate is converted to fumarate when it is oxidized by succinate dehyrogenase, produces FADH2
Describe succinate dehydrogenase located in inner mito membrane, inhibited by malonate which is similar to succinate and competitively inhibits it. Malonate is a metabolic inhibitor and decreases ATP levels
Properties of Fumurate used to make amino acids and pyrimidine nucleotides, it is also made in the urea cyce during purine synthesis and catabolism of certain amino acids
Fumurate in the TCA cycle? fumarase converts it to Malate, reaction is reversible
Malate in the TCA cycle? oxidation of malate to produce oxaloacetate + NADH, catalyzed by malate dehydrogenase
Malate dehydrogenase forward reaction has a positive delta G, how does it proceed forward? there is a lot of substrate and the product, oxaloacetate is constantly being removed
Properties of oxaloacetate? also produced by transaination of aspartic acid, can be used to make amino acids and pyrimidines
Regulation of TCA cycle? high ATP=negative feedback, first 3 steps inhibited by high [ATP], reactions with high negative delta G's are regulated
Which are the rate controlling enzymes of the TCA cycle? citrate synthase, isocitrate dehydrogenase, alpha-ketoglutarate dehydrogenase
NADH & FADH2 are reducing or oxidizing agents? strong reducing agents
What is the order of enzymes in the ETC from high redox potential to low? NADH-CoQ reductase, succinate-CoQ reductase, CoQH2-cytochrome c reductase and cytochrome c oxidase
Why is energy transfer from glucose to ATP not 100% efficient? because some of the energy is consumed in other reactions such as Ca2+ transport or released as heat
How much ATP does a regular body synthesize per day? 50 grams
What are the electron carriers of the ETC? NADH, FADH2, coenzyme Q, cytochrome C, O2
Function of electron carriers? move electrons from complex 1-4 until combining with oxygen
How many domains does the ATP synthase/complex 5 have? F0 in the inner membrane and F1 in the matrix
What is the function of NADH Dehydrogenase? takes the proton and hydride ion carried by NADH
Is NADH tightly associated with their proteins? NO, loosely associated
Function of NADH? water-soluble electron carriers
Under aerobic conditions what regenerates the NAD from glycolysis reactions? aspartate-malate and glycerophosphate shuttles
Describe the aspartate malate shuttle NADH reduces OAA in the cytosol to make malate which is moved into the mito matrix by alpha-ketoglutarte-malate transporter. In the matrix malate reconverted to OAA then transaminated to aspartate which is transported back into cytosol
Describe the glycerophosphate shuttle oxidizes NADH converting it to DHAP to G3P, G3P transfers electrons to FAD to make FADH2 in the inner mito membrane, FADH2 transfers electrons to make 2ATP
Complex I:NADH Dehydrogenase action FMN (riboflavin) accepts electrons and protons from NADH+H to become FMNH2, FMNH2 contains an iron/sulphur center which takes two hydrogen and transfers them to coenzyme Q = QH2 (4 protons transferred into intermembrane space of mito)
How are flavin derivatives reduced? by sequential addition of 2 hydrogen atoms (2 e- and 2 p+)
How does coenzyme Q/ubiquinone carry electrons? reduced to ubiquinol from 2 electrons
HOw many electrons does semiquinone carry? 1
HOw many redox states are there is coenzyme Q? 3
Action of complex II:succinate dehydrogenase electrons passed from succinate to FAD in TCA cycle, electrons are transferred from FADH2 to three Fe-S centers and then to Q, two protons are taken up to from QH2
Describe cytochromes contains a heme group that fluctuates between Fe3+ and Fe2+, on the outer face of the inner membrane and is mobile
How do the cytochromes bc1 and c/a+a3 receive electrons? from CoQ
Describe the reactions at cytochrome C oxidoreductase/complex III Q bind CytoB and heme accepts e-, e- transferred to CytoC1, CytoC1 (membrane bound) transfers e- to CytoC (water soluble/mobile) which can diffuses and donate it's electrons to complex IV, 4 protons pumped
Complex IV/cytochrome oxidase reaction iron atoms of the heme groups in the cytochromes and copper atoms are oxidized and reduced as electrons flow from cyto C to O2 to make water, 2 protons pumped
When are ROS produced during the ETC? when O2 is not fully reduced to water but instead produces a ROS:O2-, H2O2, OH-
Where does superoxide USUALLY come from? leaks from complex I
What is the effect of ROS on the cell? DNA damage, membrane damage, oxidation of amino acids, inactivation of enzymes, initiation of apoptosis signalling
What enzymes destroy ROS? superoxide dismutase, catalase
What is the free-radical theory? oxidateive damage initiated by ROS is a major contributor to the functional decline that characterizes aging
What occurs during Alzheimer's disease? degenerative disease caused by accumulation of oxidative damage much faster than would occur naturally, patients have a deficiency in the terminal complex of the mito ETC at complex IV, inherited forms are autosomal dominant
How do you identify the location of ETC inhibition? look at redox states of different complexes, carriers before block are reduced and those after are oxidized
Which ETC inhibitors block NADH dehydrogenase/complex I? amytal and rotenone, piericidin (same mechanism as antimycin)
Which ETC inhibitors block complex III and by what mechanism? antimycin A, preventing the oxidation of ubiquinol
Which ETC inhibitors block complex IV and by what mechanism? cyanide, carbon monoxide, sodium azide, bind to heme groups of the cytochromes, hydrogen sulfide - binds Fe2+ in heme groups
Describe amytal barbiturate: CNS drug, acts on GABA sensitive ion channels enhancing GABA concentrations in the brain, used for insomnia-ideally causing drowsiness
Describe rotenone insecticide: used to catch fish, high doses cause impaired ETC effects such as increase in ROS, decrease in ATP and cell death
Describe carbon monoxide affect on cytochrome oxidase inhibits it
Describe cyanide reversible inhibitor of cytochrom oxidase, binds to Fe3+ heme group
Created by: mnoronha



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