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82 Cards in this Set

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  • Back
What is the PURPOSE of the TCA cycle?
To oxidize AcCoA to CO2 and capture the energy as NADH, FADH2, and GTP.
Where does AcCoA mainly come from for TCA?
Pyruvate + Fatty acids
What are other sources of substrate for the TCA cycle?
-Amino acid carbon skeletons
-Phe, Tyr
-Methylmalonyl coA
# of carbons converted to CO2 by one full turn of the TCA:
Why is the indirect TCA pathway used to convert AcCoA to CO2, when other more direct ones could be used?
-TCA path releases energy of oxidation in APPROPRIATE amts
-Allows other molecules to be catabolized too.
What 4 other molecules can also be catabolized by the TCA cycle?
1. a-ketoglutarate
2. Succinate
3. Fumarate
4. Oxaloacetate
Where are all the enzymes for the TCA cycle located?
IN the mitochondrion
So what cells are unique in not having a TCA?
What enzyme catalyzes 2 reactions in TCA? How?
Aconitase - the intermediate cis-Aconitate is tightly bound.
What is Enzyme #1 of TCA?
Citrate Synthase
What does Citrate Synthase do?
Condenses AcCoA + Oxaloacetate.
-Both are Achiral
-But Citrate Product is Prochiral
What pulls the Citrate synthase reaction to the right?
Hydrolysis of CoA -> CoASH
Why is it good that Citrate is prochiral?
Aconitase distinguishes its CH2-COOH groups
What 2 reactions does Aconitase catalyze?
1. Citrate -> cis-aconitate
2. Cis-aconitate -> Isocitrate
What is the thing to remember about Aconitase?
It has an Iron-sulfur center
So what will result from oxidative stress?
Citrate will build up because the Iron sulfur center will be inactivated.
What is the purpose of Aconitase?
It moves the hydroxyl group on Citrate from C3 to C4, where it is better situated for oxidation to a ketone.
What is the enzyme after aconitase?
Isocitrate Dehydrogenase
What does Isocitrate Dehydrogenase do?
-Oxidizes C4 OH to a C=O with concomitant reduction of NAD+
-Decarboxylates at C3
Where does the CO2 lost in the Isocitrate oxidative carboxylation come from?
What drives the Isocitrate dehydrogenase rxn forward?
Loss of CO2 to form a-ketoglutarate
3 things accomplished by Isocitrate Dehydrogenase:
1. NADH formed
2. CO2 lost
3. Product is easier to metabolize further
What is the enzyme that acts on a-ketoglutarate? What does it do?
a-ketoglutarte dehydrogenase:
catalyzes a reaction identical to pyruvate dehydrogenase.
So what are the 3 cofactors required by a-KGDehydrogenase?
What Substrates?
-Lipoic acid
Substrates: CoASH, NAD+
What does a-Ketoglutarate dehydrogenase accomplish?
1. NADH formed
2. CO2 lost
3. Hi-energy Co-A thioester bond is made
Where does the CO2 lost in this step come from?
Oxaloacetate C4
Where does the CO2 lost in the Isocitrate dehydrogenase step come from?
Oxaloacetate C1
What is the name of the product of a-ketoglu dehydrogenase?
What is the next enzyme?
Succinyl-Coa Synthetase
What's weird about that?
It doesn't synthesize Succinyl-CoA, but breaks it down
What is accomplished by Succinyl CoA Synthetase?
Harvests the hi-energy thioester as GTP and forms Succinate.
What is the GTP formed in the Succinyl CoA Synthetase step an example of?
Substrate level phosphorylation
How good is GTP in terms of energy? Why?
Just as good as ATP; b/c NiDiKi will convert it to ATP
What do we know about the structure of Succinate?
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
What is the purpose of the final 3 reactions of TCA?
To convert Succinate back to Oxaloacetate
What do these 3 steps resemble?
Fatty acid oxidation
What enzyme acts on Succinate?
Succinate Dehydrogenase
What what takes place in the Succinate dehydrogenase rxn?
FAD is used to make Fumarate
Why is FAD used to make Fumarate?
Because the oxidation of succinate doesn't release enough energy to form NADH.
What is unique about Succinate Dehydrogenase?
-Not just in the mito matrix; bound to its inner membrane
-Contains Iron-Sulfur Centers
So 2 enzymes so far contain Iron-Sulfur centers:
-Succinate dehydrogenase
What enzyme acts on Fumarate?
What does it do?
Fumarase - adds water to form Malate
What is an interesting point about Malate?
It has a chiral center and only one enantiomer is formed.
What enzyme acts on Malate?
Malate dehydrogenase
What reaction does that of Malate Dehydrogenase resemble?
LDH - lactate dehydrogenase; reversible and does not favor the forward rxn in vivo.
How does the Malate Dehydrogenase reaction proceed if it is unfavorable in vivo?
Oxaloacetate (the product of MDH) reacts with AcCoA and its depletion pulls the rxn along.
What is the yield of the TCA cycle (starting with pyruvate)?
-3 CO2
-1 FADH2
-2 GTP
What is the overall deltaG of TCA?
-18 kcal/mol
What is the deltaG of the equivalent reaction of Pyruvate in a calorimeter?
-285!!! wow we got a lot of energy invested in NADH/FADH2 and GTP.
What is the overall efficiency of pyruvate oxidation?
What did Alexander Ogston figure out?
That the active site of Aconitase only recognizes one configuration of prochiral Citrate
Why does Aconitase only recognize one configuration of citrate?
B/c it has an IronSulfur center that makes it situate that way.
How many TCA turns are required to fully convert the methyl group of AcCoA to CO2?
What are the principal regulatory signals of TCA cycle?
(their ratios)
What is an additional regulator?
What will happen if the cellular metabolic need for E is low?
TCA intermediates will shuttle to other pathways.
At what 3 steps is the TCA cycle regulated?
Irreversible ones:
1. Citrate synthase
2. Isocitrate dehydrogenase
3. a-Ketoglutarate dehydrogenase
What is regulation of Citrate synthase similar to? How is it different?
That of PDH - product inhibition -BUT it is not regulated by phosphorylation
What products inhibit Citrate synthase? What else?
-Succinyl CoA
What inhibits and activates Isocitrate dehydrogenase?
Negative: ATP/NADH

Positive: ADP/NAD+
What inhibits a-Ketoglutarate Dehydrogenase?
Succinyl CoA and NADH
What are the 4 sources of AcCoA for the TCA Cycle?
1. PDH - its whole purpose!
2. FA oxidation
3. Amino acids (Ile/Leu/Trp
4. Ethanol
How many steps are involved in converting Ethanol to Pyruvate?
What are the intermediates in converting Ethanol to Pyruvate?
1. Alcohol goes to
2. Acetaldehyde, goes to
3. Acetic acid, goes to
4. Acetyl CoA
What are the enzymes used to convert Ethanol to Pyruvate?
1. Alcohol dehydrogenase (NAD+)
2. Aldehyde Dehydrogenase (NAD+)
3. Acetyl CoA Synthetase (ATP and CoASH)
What enzyme is Acetyl coA comparable to? How are they different?
Succinyl CoA; except it makes GTP by splitting apart the thioester in Succinyl CoA; AcCoA synthetase MAKES an ATP.
What is Alcohol an inhibitor of? How? What results clinically?
Gluconeogenesis; it increases NADH, which inhibits LDH;
No lactate converts -> pyruvate.
So: alcoholics = hypoglycemic
What are cataplerotic reactions?
Ones that deplete intermediates of other cycles/pathways.
What are the 4 Cataplerotic pathways that deplete TCA intermediates?
1. Gluconeogenesis
2. Lipid biosynthesis
3. Amino acid biosynthesis
4. Porphyrin synthesis
What does Gluconeogenesis use thats an intermediate in TCA?
-Malate (-> OAA -> PEP)
(both can get out of mito)
-Oxaloacetate (can't)
What does lipid biosynthesis use thats an intermediate in TCA?
What does Amino Acid Biosynth use thats an intermediate in TCA?
-OAA to make Asp -> Asparagine

-a-KG to make Glu -> Gln
What does Porphryin synthesis use?
Succinyl CoA
What are Anaplerotic reactions?
Ones that replenish TCA cycle intermediates.
What are the 4 Anaplerotic reactions?
1. Pyruvate carboxylase
2. AA degradation
3. Fatty acid degradation
4. Purine NT cycle
What does Pyruvate carboxylase do?
Makes OAA from pyruvate by incorporating CO2 and cleaving ATP
What cofactor does Pyruvate carboxylase require?
What activates Pyruvate carboxylase?
Acumulation of AcCoA
Does high ATP/ADP ratio inhibit pyruvate carboxylase?
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.
How is the conversion from AcCoA making Citrate to making Malate accomplished?
ATP will inhibit citrate synthase and PDH
What FA metabolism can produce TCA intermediates?
Propionyl CoA -> Succinyl CoA
What does the Purine NT cycle contribute to TCA intermediates?
Aspartate -> fumarate