Pathway · 11 proteins
Reductive TCA machinery
CO2 incorporation and regeneration of carbon acceptors.
How it works
- The module holds the reductive TCA enzymes VF5 actually encodes: malate dehydrogenase, fumarate hydratase, a succinate dehydrogenase/fumarate reductase pair, an ADP-forming succinate--CoA ligase, an NADP-dependent isocitrate dehydrogenase and a citryl-CoA lyase.
- Read in the carbon-fixing direction, oxaloacetate is reduced to malate, dehydrated to fumarate, reduced to succinate and activated to succinyl-CoA before two carboxylations rebuild the six-carbon acid (2-oxoglutarate:ferredoxin oxidoreductase and isocitrate dehydrogenase).
- Citrate is then cleaved by the citryl-CoA route rather than by ATP-citrate lyase, releasing oxaloacetate and acetyl-CoA. The list shows which enzymes are present; it does not establish flux, and several of these assignments are contested in the databases — see the system page.
Grouped by the atlas’s curated pathway map. The table order is not a proven reaction order.
Its proteins
| Protein | EC | Reaction (UniProt) | Metal or cluster | Amino acids | Certainty |
|---|---|---|---|---|---|
| Succinyl-CoA ligase beta subunit | — | oxaloacetate + acetyl-CoA + ADP + phosphate = citrate + ATP + CoA | — | 436 | Step named |
| citrate synthase (unknown stereospecificity) | 2.3.3.16 | — | — | 259 | Step named |
| Isocitrate dehydrogenase [NADP] | 1.1.1.42 | D-threo-isocitrate + NADP(+) = 2-oxoglutarate + CO2 + NADPH | Mg(2+), Mn(2+) | 426 | Step named |
| Succinate--CoA ligase [ADP-forming] subunit beta | 6.2.1.5 | succinate + ATP + CoA = succinyl-CoA + ADP + phosphate | Mg(2+) | 385 | Step named |
| Succinate--CoA ligase [ADP-forming] subunit alpha | 6.2.1.5 | succinate + ATP + CoA = succinyl-CoA + ADP + phosphate | — | 305 | Step named |
| Fumarate hydratase (Fumarase) | — | — | — | 281 | Step named |
| Malate dehydrogenase 1 | 1.1.1.37 | (S)-malate + NAD(+) = oxaloacetate + NADH + H(+) | — | 335 | Step named |
| Aconitate hydratase A | 4.2.1.3 | citrate = D-threo-isocitrate | [4Fe-4S] cluster | 659 | Step named |
| Succinyl-CoA ligase alpha subunit | — | — | — | 368 | Step named |
| succinate dehydrogenase | 1.3.5.1 | — | [2Fe-2S] cluster, [3Fe-4S] cluster, [4Fe-4S] cluster | 230 | Step named |
| Succinate dehydrogenase flavoprotein subunit | 1.3.5.1 | a menaquinone + succinate = a menaquinol + fumarate | — | 571 | Step named |
Origins
Could a carbon-fixing cycle like this one run before there were enzymes to drive it?
Günter Wächtershäuser proposed that a reductive citric acid cycle, powered by the formation of pyrite from iron and hydrogen sulfide on mineral surfaces, was the first metabolism. Garrett and Grisham explain that such models were sought because key compounds, including arginine, lysine, histidine, straight-chain fatty acids, porphyrins and coenzymes, had not been convincingly made under simulated prebiotic conditions.
Some single steps have experimental support, but each under very different conditions. Whether those conditions are geologically plausible is not established, and none of the proposed schemes has been shown to sustain itself.
A review of prebiotic systems chemistry notes that without enzymes this chemistry would not be robust, and that side reactions would drain the intermediates until the cycle stopped.
In the cell the cycle runs in the carbon-fixing direction only because enzymes that spend ATP push three of its steps backwards. Eleven proteins in the minimal set serve this cycle, and it turns only when all of them are present.
From the books: Garrett & Grisham, Biochemistry, p. 665; Ruiz-Mirazo et al., Prebiotic Systems Chemistry, PDF p. 27; Ribas de Pouplana (ed.), The Genetic Code and the Origin of Life, p. 11; Slonczewski & Foster, Microbiology, p. 580.
The wider question for this part of the cell: origins for building carbon into molecules.
Sources
- Atlas pathway grouping from the VF5 reference-genome system map (Deckert et al. 1998; Braakman & Smith 2014)
Other pathways in this group: Sugar-phosphate supply · Pyruvate and acetyl-CoA · Lipid A and outer envelope · Ribose and PRPP supply · Glycolysis / Gluconeogenesis · Amino sugar and nucleotide sugar metabolism · Pentose phosphate pathway · Not yet placed in a pathway