Download TCA cycle cross products (also known as “nothing is simple” My

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 (from Jencks)
Before we get to the actual 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 into 5 steps.
(a)
(b)
(c)
(d)
(e)
pyruvate + TPP => 2-(alpha-hydroxyethyl)-TPP + CO2 REACT_466.2
2-(alpha-hydroxyethyl)-TPP + lipoamide => S-acetyldihydrolipoamide + TPP REACT_1449.1
S-acetyldihydrolipoamide + CoA => acetyl-CoA + dihydrolipoamide REACT_1323.1
dihydrolipoamide + FAD => lipoamide + FADH2 [pyruvate dehydrogenase] REACT_601.1
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
GO:0004738 has no reaction:appears to be a place holder
Anyways,
GO term:
tricarboxylic acid cycle
Synonym:
citric acid cycle
Synonym:
Krebs cycle
Synonym:
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,
O term:
reductive tricarboxylic acid cycle
Synonym:
reductive carboxylate cycle
Synonym:
reductive carboxylic acid cycle
Synonym:
reductive citric acid pathway
Synonym:
reductive Kreb's cycle
Synonym:
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 “forward” 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+)
activity1 REACT_1068.2 Isocitrate + NAD+ => alpha-ketoglutarate + CO2 + NADH + H+
4. decarboxylate oxalosuccinate to make alpha-ketoglutaric acid (glutarate)2
5.
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.
4
alpha-ketoglutarate + TPP => 3-carboxy-1-hydroxypropyl-TPP + CO2 ;REACT_1137.1;
2. 3-carboxy-1-hydroxypropyl-TPP + lipoamide => S-succinyldihydrolipoamide + TPP
REACT_1085.1;
3. S-succinyldihydrolipoamide + CoA => succinyl-CoA + dihydrolipoamide REACT_248.1
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
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) + GTP5; GO:0004776, succinate-CoA ligase
(GDP-forming) activity REACT_337.1
GDP + Orthophosphate + Succinyl-CoA <=> GTP + Succinate + CoA
2. Oxidize succinate to fumarate (using FAD); Succinate <=> Fumarate (with FAD redox reaction
on enzyme); REACT_1667.3;
GO:0000104, succinate dehydrogenase activity
3. Add water to fumarate to give L-malate; REACT_1656.2; Fumarate + H2O <=> (S)-Malate;
GO:0004333, fumarate hydratase activity
4. oxididize malate to oxaloacetate (NAD). ; REACT_2172.2; (S)-Malate + NAD+ <=>
Oxaloacetate + NADH + H+; Go to Part 1.1; GO:0030060,
activity (has several sibs, all children of
L-malate dehydrogenase
GO:0016615.malate dehydrogenase activity.
however, GO:0030060 is the one for TCA cycle
5 There is also GO:0004775, succinate-CoA ligase (ADP-forming) activity; ADP + Orthophosphate + Succinyl-CoA <=>
ATP + Succinate + CoA; REACT_629.1 both can contribute;
Both are children of GO:0004774, succinate-CoA
ligase activity