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82 Cards in this Set
- Front
- Back
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What is the PURPOSE of the TCA cycle?
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To oxidize AcCoA to CO2 and capture the energy as NADH, FADH2, and GTP.
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Where does AcCoA mainly come from for TCA?
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Pyruvate + Fatty acids
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What are other sources of substrate for the TCA cycle?
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-Amino acid carbon skeletons
-Phe, Tyr -Methylmalonyl coA |
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# of carbons converted to CO2 by one full turn of the TCA:
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2
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Why is the indirect TCA pathway used to convert AcCoA to CO2, when other more direct ones could be used?
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-TCA path releases energy of oxidation in APPROPRIATE amts
-Allows other molecules to be catabolized too. |
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What 4 other molecules can also be catabolized by the TCA cycle?
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1. a-ketoglutarate
2. Succinate 3. Fumarate 4. Oxaloacetate |
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Where are all the enzymes for the TCA cycle located?
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IN the mitochondrion
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So what cells are unique in not having a TCA?
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RBCs
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What enzyme catalyzes 2 reactions in TCA? How?
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Aconitase - the intermediate cis-Aconitate is tightly bound.
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What is Enzyme #1 of TCA?
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Citrate Synthase
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What does Citrate Synthase do?
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Condenses AcCoA + Oxaloacetate.
-Both are Achiral -But Citrate Product is Prochiral |
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What pulls the Citrate synthase reaction to the right?
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Hydrolysis of CoA -> CoASH
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Why is it good that Citrate is prochiral?
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Aconitase distinguishes its CH2-COOH groups
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What 2 reactions does Aconitase catalyze?
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1. Citrate -> cis-aconitate
2. Cis-aconitate -> Isocitrate |
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What is the thing to remember about Aconitase?
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It has an Iron-sulfur center
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So what will result from oxidative stress?
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Citrate will build up because the Iron sulfur center will be inactivated.
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What is the purpose of Aconitase?
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It moves the hydroxyl group on Citrate from C3 to C4, where it is better situated for oxidation to a ketone.
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What is the enzyme after aconitase?
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Isocitrate Dehydrogenase
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What does Isocitrate Dehydrogenase do?
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OXIDATIVE DECARBOXYLATION
-Oxidizes C4 OH to a C=O with concomitant reduction of NAD+ -Decarboxylates at C3 |
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Where does the CO2 lost in the Isocitrate oxidative carboxylation come from?
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Oxaloacetate
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What drives the Isocitrate dehydrogenase rxn forward?
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Loss of CO2 to form a-ketoglutarate
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3 things accomplished by Isocitrate Dehydrogenase:
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1. NADH formed
2. CO2 lost 3. Product is easier to metabolize further |
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What is the enzyme that acts on a-ketoglutarate? What does it do?
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a-ketoglutarte dehydrogenase:
catalyzes a reaction identical to pyruvate dehydrogenase. |
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So what are the 3 cofactors required by a-KGDehydrogenase?
What Substrates? |
-FAD
-TPP -Lipoic acid Substrates: CoASH, NAD+ |
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What does a-Ketoglutarate dehydrogenase accomplish?
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1. NADH formed
2. CO2 lost 3. Hi-energy Co-A thioester bond is made |
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Where does the CO2 lost in this step come from?
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Oxaloacetate C4
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Where does the CO2 lost in the Isocitrate dehydrogenase step come from?
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Oxaloacetate C1
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What is the name of the product of a-ketoglu dehydrogenase?
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Succinyl-CoA
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What is the next enzyme?
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Succinyl-Coa Synthetase
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What's weird about that?
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It doesn't synthesize Succinyl-CoA, but breaks it down
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What is accomplished by Succinyl CoA Synthetase?
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Harvests the hi-energy thioester as GTP and forms Succinate.
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What is the GTP formed in the Succinyl CoA Synthetase step an example of?
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Substrate level phosphorylation
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How good is GTP in terms of energy? Why?
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Just as good as ATP; b/c NiDiKi will convert it to ATP
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What do we know about the structure of Succinate?
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Well it has a plane of symmetry: Sooo all we know is
-One CH2 comes from the methyl of AcCoA -One COO- comes from C1 of AcCoA |
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What is the purpose of the final 3 reactions of TCA?
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To convert Succinate back to Oxaloacetate
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What do these 3 steps resemble?
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Fatty acid oxidation
-Dehydrogenation -Rehydration -Oxidation |
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What enzyme acts on Succinate?
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Succinate Dehydrogenase
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What what takes place in the Succinate dehydrogenase rxn?
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FAD is used to make Fumarate
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Why is FAD used to make Fumarate?
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Because the oxidation of succinate doesn't release enough energy to form NADH.
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What is unique about Succinate Dehydrogenase?
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-Not just in the mito matrix; bound to its inner membrane
-Contains Iron-Sulfur Centers |
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So 2 enzymes so far contain Iron-Sulfur centers:
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-Aconitase
-Succinate dehydrogenase |
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What enzyme acts on Fumarate?
What does it do? |
Fumarase - adds water to form Malate
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What is an interesting point about Malate?
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It has a chiral center and only one enantiomer is formed.
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What enzyme acts on Malate?
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Malate dehydrogenase
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What reaction does that of Malate Dehydrogenase resemble?
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LDH - lactate dehydrogenase; reversible and does not favor the forward rxn in vivo.
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How does the Malate Dehydrogenase reaction proceed if it is unfavorable in vivo?
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Oxaloacetate (the product of MDH) reacts with AcCoA and its depletion pulls the rxn along.
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What is the yield of the TCA cycle (starting with pyruvate)?
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-3 CO2
-4 NADH -1 FADH2 -2 GTP |
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What is the overall deltaG of TCA?
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-18 kcal/mol
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What is the deltaG of the equivalent reaction of Pyruvate in a calorimeter?
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-285!!! wow we got a lot of energy invested in NADH/FADH2 and GTP.
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What is the overall efficiency of pyruvate oxidation?
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94%
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What did Alexander Ogston figure out?
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That the active site of Aconitase only recognizes one configuration of prochiral Citrate
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Why does Aconitase only recognize one configuration of citrate?
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B/c it has an IronSulfur center that makes it situate that way.
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How many TCA turns are required to fully convert the methyl group of AcCoA to CO2?
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Infinite
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What are the principal regulatory signals of TCA cycle?
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ATP, ADP, NAD+ and NADH
(their ratios) |
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What is an additional regulator?
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Succinyl-CoA
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What will happen if the cellular metabolic need for E is low?
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TCA intermediates will shuttle to other pathways.
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At what 3 steps is the TCA cycle regulated?
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Irreversible ones:
1. Citrate synthase 2. Isocitrate dehydrogenase 3. a-Ketoglutarate dehydrogenase |
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What is regulation of Citrate synthase similar to? How is it different?
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That of PDH - product inhibition -BUT it is not regulated by phosphorylation
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What products inhibit Citrate synthase? What else?
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-ATP and NADH
-Succinyl CoA |
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What inhibits and activates Isocitrate dehydrogenase?
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Negative: ATP/NADH
Positive: ADP/NAD+ |
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What inhibits a-Ketoglutarate Dehydrogenase?
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Succinyl CoA and NADH
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What are the 4 sources of AcCoA for the TCA Cycle?
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1. PDH - its whole purpose!
2. FA oxidation 3. Amino acids (Ile/Leu/Trp 4. Ethanol |
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How many steps are involved in converting Ethanol to Pyruvate?
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4
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What are the intermediates in converting Ethanol to Pyruvate?
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1. Alcohol goes to
2. Acetaldehyde, goes to 3. Acetic acid, goes to 4. Acetyl CoA |
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What are the enzymes used to convert Ethanol to Pyruvate?
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1. Alcohol dehydrogenase (NAD+)
2. Aldehyde Dehydrogenase (NAD+) 3. Acetyl CoA Synthetase (ATP and CoASH) |
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What enzyme is Acetyl coA comparable to? How are they different?
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Succinyl CoA; except it makes GTP by splitting apart the thioester in Succinyl CoA; AcCoA synthetase MAKES an ATP.
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What is Alcohol an inhibitor of? How? What results clinically?
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Gluconeogenesis; it increases NADH, which inhibits LDH;
No lactate converts -> pyruvate. So: alcoholics = hypoglycemic |
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What are cataplerotic reactions?
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Ones that deplete intermediates of other cycles/pathways.
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What are the 4 Cataplerotic pathways that deplete TCA intermediates?
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1. Gluconeogenesis
2. Lipid biosynthesis 3. Amino acid biosynthesis 4. Porphyrin synthesis |
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What does Gluconeogenesis use thats an intermediate in TCA?
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-Malate (-> OAA -> PEP)
-Aspartate (both can get out of mito) -Oxaloacetate (can't) |
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What does lipid biosynthesis use thats an intermediate in TCA?
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-Citrate
-AcCoA |
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What does Amino Acid Biosynth use thats an intermediate in TCA?
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-OAA to make Asp -> Asparagine
-a-KG to make Glu -> Gln |
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What does Porphryin synthesis use?
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Succinyl CoA
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What are Anaplerotic reactions?
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Ones that replenish TCA cycle intermediates.
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What are the 4 Anaplerotic reactions?
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1. Pyruvate carboxylase
2. AA degradation 3. Fatty acid degradation 4. Purine NT cycle |
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What does Pyruvate carboxylase do?
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Makes OAA from pyruvate by incorporating CO2 and cleaving ATP
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What cofactor does Pyruvate carboxylase require?
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Biotin
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What activates Pyruvate carboxylase?
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Acumulation of AcCoA
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Does high ATP/ADP ratio inhibit pyruvate carboxylase?
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NO - if pyruvate has accumulated PC will still kick in; the OAA made will instead go to Malate or Aspartate to form glucose inst of TCA.
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How is the conversion from AcCoA making Citrate to making Malate accomplished?
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ATP will inhibit citrate synthase and PDH
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What FA metabolism can produce TCA intermediates?
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Propionyl CoA -> Succinyl CoA
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What does the Purine NT cycle contribute to TCA intermediates?
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Aspartate -> fumarate
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