TCA Cycle Process-Function Links

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TCA cycle cross products (also known as: Nothing is simple) My textbook of choice has been Biochemistry, by Abeles, Frey, and Jencks (Jones and Bartlett, 1992), a text that has a more mechanistic slant.


Before we get to the actual TCA cycle, pyruvate (from glycolysis) is first converted into acetyl-CoA by the pyruvate dehydrogenase complex:

pyruvate + NAD + CoASH == Acetyl-COA + CO2+ NADH

This is multistep reaction carried out by a large complex; Reactome breaks this down into5 steps.


  1. pyruvate + TPP => 2-(alpha-hydroxÄyethyl)-TPP + CO2 REACT_466.2
  2. 2-(alpha-hydroxyethyl)-TPP + lipoamide => S-acetyldihydrolipoamide + TPP REACT_1449.1
  3. S-acetyldihydrolipoamide + CoA => acetyl-CoA + dihydrolipoamide REACT_1323.1
  4. dihydrolipoamide + FAD => lipoamide + FADH2 [pyruvate dehydrogenase] REACT_601.1
  5. FADH2 + NAD+ => FAD + NADH + H+ [pyruvate dehydrogenase] REACT_1397.1
This is multistep reaction carried out by a large complex; Reactome breaks this down into several steps.


GO:0050243 has NADP+

I have at least 4 textbooks in front of me indicating that this reaction uses NAD, not NADP.

But, I see a lot of papers indicating NADP;

So, I suggest the def be altered to

pyruvate + NAD/NADP + CoASH==Acetyl-CoA +CO2+NADPH

 comment from Midori: GO got its definition from EC 1.2.1.51, and I'm a bit reluctant to diverge,
 since EC, MetaCyc, KEGG, BRENDA all have just NADP. We could add another term or two, though.
comment from Peter E: I've poked around some more and found published data for 
oxidative decarboxylation reactions in which the reducing equivalents are finally
transferred to   NADP+ and not to NAD+:
PMID: 3110154 - pyruvate dehydrogenase from Euglena gracilis
PMID: 11319255 - same enzyme from Euglena and from Cryptosporidium parvum
PMID: 14526024 - alpha-ketoglutarate dehydrogenase from Azoarcus evansii
In all cases the authors appear to be asserting that the overall process in which
the enzyme complex functions is an anaerobic  counterpart to the aerobic mammalian
one. However, that aerobic - anaerobic distinction is fairly basic, so it could be
the basis for splitting GO:0050243 into two, one with NAD as the acceptor and one
with NADP as the acceptor, as has already been done for other children of GO:0016620
Alternatively,  split and take advantage of ChEBI, and use  ChEBI:13390 NAD(P)+ 
"A  coenzyme that may be NAD+ or NADP+" as the cofactor for a single molecular 
function term.

GO:0004738 has no reaction:appears to be a place holder

 comment from Midori: It's a grouping term for all of the pyruvate dehydrogenases, no  matter
 which cofactor they use.


 comment from Harold: actually, if it is meant to convey the steps listed above,then it seems
 to me to be a process term having "has_part" relationships to the activities listed above. 

Anyways, here we go

GO term:tricarboxylic acid cycle

Synonym: citric acid cycle,Krebs cycle, TCA cycle

GO id:GO:0006099

Definition:A nearly universal metabolic pathway in which the acetyl group of acetyl coenzyme A is effectively oxidized to two C02 and four pairs of electrons are transferred to coenzymes. The acetyl group combines with oxaloacetate to form citrate, which undergoes successive transformations to isocitrate, 2-oxoglutarate, succinyl-CoA, succinate, fumarate, malate, and oxaloacetate again, thus completing the cycle. In eukaryotes the tricarboxylic acid is confined to the mitochondria. See also glyoxylate cycle.


ATTENTION!

This term has child,

GO term:reductive tricarboxylic acid cycle

Synonym: reductive carboxylate cycle, reductive carboxylic acid cycle,reductive citric acid pathway,reductive Kreb's cycle, reductive TCA cycle

GO id:GO:0019643

Definition:A pathway leading to the fixation of two molecules of CO2 and the production of one molecule of acetyl-CoA; essentially the oxidative TCA cycle running in reverse. Acetyl-CoA is reductively carboxylated to pyruvate, from which all other central metabolites can be formed. Most of the enzymes of reductive and oxidative TCA cycle are shared, with the exception of three key enzymes that allow the cycle to run in reverse: ATP citrate lyase, 2-oxoglutarate:ferredoxin oxidoreductase, and fumarate reductase. 2-oxoglutarate:ferredoxin oxidoreductase catalyzes the carboxylation of succinyl-CoA to 2-oxoglutarate, ATP citrate lyase the ATP-dependent cleavage of citrate to acetyl-CoA and oxaloacetate, and fumarate reductase the reduction of fumarate forming succinate.


Because this uses different enzymes for certain steps, I do not think this should be a child of TCA, but a sib of THE TCA cycle. It's strictly not a reverse of THE TCA cycle.


I only consider the the TCA cycle in what follows.


The cycle has 8 or 9 steps (depending on textbook), but 14 reactions. Step 1.5 consists of 5 carried out by a large alpha-ketoglutaric acid dehydrogenase complex, analogous to the pyruvate dehydrogenase complex above.


1. TCA cycle part1:CO2 production

  1. condensation of oxaloaceate + acetyl-CoA to give citric acid (citrate); GO:0004108,citrate (Si)-synthase activity, REACT_1282.2 , Acetyl-CoA + H2O + Oxaloacetate => Citrate + CoA
  2. change citrate to isocitrate using GO:0003994, aconitate hydratase activity (water off, water on), REACT_1898.2 Citrate <=> cis-Aconitate + H2O; REACT_1898.2,cis-Aconitate + H2O <=> Isocitrate
  3. oxidize isocitrate to oxalosuccinate (NAD) GO:0004449, isocitrate dehydrogenase (NAD+) activity (see note 1 at end). REACT_1068.2 Isocitrate + NAD+ => alpha-ketoglutarate + CO2 + NADH + H+
  4. decarboxylate oxalosuccinate to make alpha-ketoglutaric acid (glutarate) (note 2)
  5. (Note 3) decarboxylate alpha ketoglutarate (and condense acetyl-CoA) to give succinyl- CoA,REACT_140.2 . This is very complex; catalyzed by an entire complex:
    1. (Note 4) alpha-ketoglutarate + TPP => 3-carboxy-1-hydroxypropyl-TPP + CO2 ;REACT_1137.1;GO:0004591, oxoglutarate dehydrogenase (succinyl-transferring) activity
    2. 3-carboxy-1-hydroxypropyl-TPP + lipoamide => S-succinyldihydrolipoamide + TPPREACT_1085.1;GO:0004591, oxoglutarate dehydrogenase (succinyl-transferring) activity
    3. S-succinyldihydrolipoamide + CoA => succinyl-CoA + dihydrolipoamide REACT_248.1 GO:0004149, dihydrolipoyllysine-residue succinyltransferase activity
    4. dihydrolipoamide + FAD => lipoamide + FADH2 [alpha-ketoglutarate dehydrogenase] REACT_2087.2; GO:0004148 dihydrolipoyl dehydrogenase activity
    5. FADH2 + NAD+ => FAD + NADH + H+ [alpha-ketoglutarate dehydrogenase]R REACT_140.2, GO:0004148, dihydrolipoyl dehydrogenase activity


2. TCA cycle part2: Regeneration of Oxaloacetate

  1. Get rid of the CoA to give succinate (succinic acid) + GTP[1]; GO:0004776, succinate-CoA ligase (GDP-forming) activity REACT_337.1

GDP + Orthophosphate + Succinyl-CoA <=> GTP + Succinate + CoA

  1. Oxidize succinate to fumarate (using FAD); Succinate <=> Fumarate (with FAD redox reaction on enzyme); REACT_1667.3; GO:0000104, succinate dehydrogenase activity
  2. Add water to fumarate to give L-malate; REACT_1656.2; Fumarate + H2O <=> (S)-Malate; GO:0004333, fumarate hydratase activity
  3. oxididize malate to oxaloacetate (NAD). ; REACT_2172.2; (S)-Malate + NAD+ <=> Oxaloacetate + NADH + H+; Go to Part 1.1; GO:0030060, L-malate dehydrogenase activity (has several sibs, all children of GO:0016615.malate dehydrogenase activity. however, GO:0030060 is the one for TCA cycle



Notes

1 There is also GO:0004450, isocitrate dehydrogenase (NADP+) activity
2.Isocitrate dehydrogenase catalyzes both 1.3 and1.4 Reactome combines 1.3 and1.4 into one
 reaction, with oxalosuccinate as in intermediate
3.From Reactome:The conversion of alpha-ketoglutarate (2-oxoglutarate) to succinyl-CoA exactly
 parallels that for the oxidative decarboxylation of pyruvate to acetyl CoA. The pyruvate
 dehydrogenase and alpha-ketoglutarate dehydrogenase complexes are structurally homologous,
 containing homologous E1 and E2 proteins, and identical E3 proteins and cofactors.
4.GO:0004591, oxoglutarate dehydrogenase (succinyl-transferring) activity,appear to include step
 1.5.1 and 1.5.2


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