Reductive tricarboxylic acid cycle

The reductive TCA cycle (reverse Krebs, Arnon-Buchanan cycle), which fixes CO2 by running the oxidative TCA cycle backwards. Three steps are not simply the reverse of their oxidative counterparts, and they are what define the cycle: citrate is cleaved by an ATP-dependent citrate lyase rather than made by citrate synthase; 2-oxoglutarate is formed by reductive carboxylation of succinyl-CoA by a ferredoxin-dependent 2-oxoglutarate synthase; and fumarate is reduced rather than succinate oxidized. A fourth ferredoxin-dependent carboxylation, pyruvate synthase, converts the acetyl-CoA released by citrate cleavage into pyruvate for biosynthesis. The cycle fixes two CO2 per turn and is markedly cheaper per carbon than the Calvin cycle, which is why it dominates in green sulfur bacteria and several Aquificae and epsilonproteobacteria; the price is that its ferredoxin-dependent carboxylases are oxygen-sensitive, confining it to anaerobic and microaerophilic niches. A sibling of MODULE:wood_ljungdahl_pathway, MODULE:hydroxypropionate_bicycle and MODULE:calvin_benson_bassham_cycle.

MODULE:reductive_tca_cycleDRAFTABSTRACTMetabolic Pathwaymodules/reductive_tca_cycle.yaml
reductive tricarboxylic acid cycleGO:0019643 carbon fixationGO:0015977
GO:0019643
reductive tricarboxylic acid cycle
Defines the process this module decomposes.
UniProtKB:Q9AJC4
ATP-citrate lyase alpha-subunit (Chlorobium limicola)
The citrate-cleaving enzyme whose presence distinguishes the reductive cycle from the oxidative one, from a green sulfur bacterium in which the cycle was characterized.
UniProtKB:Q9AQH6
ATP-citrate lyase beta-subunit (Chlorobium limicola)
The second subunit of the same heteromeric enzyme.

The GO:0008177 assertion on rtca_frd sits under GO:0000104, which interpro/panther/PTHR11632/PTHR11632-review.yaml scopes SUBFAMILY_ONLY to SF51/SF53/SF72 while P00363 is in SF82; that scope_reason reads as a guard against root-level propagation rather than a claim about member capability, and saying so in the family review's own scope_reason would settle it there. Grounded on Chlorobium limicola, a green sulfur bacterium in which the cycle was characterized; the ATP-citrate lyase and 2-oxoglutarate synthase entries are unreviewed (TrEMBL), which is stated here because no reviewed entries exist for them in this organism. The shared steps that the cycle runs simply in reverse - aconitase, malate dehydrogenase, fumarase, citrate/isocitrate interconversion - are real parts of the cycle but are not modelled as separate parts, because they are not diagnostic and are shared with the oxidative cycle; the module models the three reversal-defining steps plus pyruvate synthase. Some organisms use a citryl-CoA synthetase plus citryl-CoA lyase pair in place of ATP-citrate lyase, which is a realization difference at the citrate-cleavage step rather than a different cycle. 2-oxoglutarate synthase (GO:0047553) and pyruvate synthase (GO:0019164) are the GO terms for the ferredoxin-dependent carboxylations; both enzymes also run oxidatively in other organisms, so direction is a property of the metabolic context rather than of the protein. The reverse oxidative TCA cycle is modelled elsewhere in this corpus if at all; this module is specifically the carbon-fixing direction.

6Nodes
5Parts
0Variant Sets
0Variants
5Annotons
5Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:reductive_tca_cycle deep-research report alongside the module YAML.

Leaf nodes lacking representative members

✓ representative grounding skipped for abstract module.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Reaction chaining (advisory)

✓ every PRECEDES step chains, or its break is acknowledged via chaining_status.

  • rtca_citrate_cleavage → rtca_fumarate_reduction [NOT_CHECKED]
  • rtca_fumarate_reduction → rtca_succinyl_coa [NOT_CHECKED]
  • rtca_oxoglutarate_synthase → rtca_citrate_cleavage [VERIFIED]
    shared: coa

Function consistency and core coverage

0 gene-function check(s) reflected in core functions · 0 conflict(s) · 5 evidence or coverage gap(s) (8 comparison(s))

Retained noncore functions are reported separately; they do not require promotion to core functions. Support from representative genes does not establish conservation across the whole family. Missing reviews or identifiers leave a claim unverified.

AnnotonParticipantFunctionAssessment
rtca_acl PROTEIN_COMPLEX
Gene 		ATP citrate synthase activity
GO:0003878 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
rtca_frd sdhA (Chlorobium limicola; unreviewed)
UniProtKB:A0A101JUB8
Family Representative 		succinate dehydrogenase (quinone) activity
GO:0008177 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
rtca_frd frdA (Escherichia coli K-12)
UniProtKB:P00363
Family Representative 		succinate dehydrogenase (quinone) activity
GO:0008177 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
rtca_sucCD ANY_WITH_FUNCTION
Gene 		succinate-CoA ligase (ADP-forming) activity
GO:0004775 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
rtca_ogor A0A101JN76 (2-oxoglutarate:ferredoxin oxidoreductase alpha subunit, Chlorobium limicola; unreviewed, no gene symbol in UniProt)
UniProtKB:A0A101JN76
Family Representative 		2-oxoglutarate synthase activity
GO:0047553 		Review Missing
No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
rtca_pfor ANY_WITH_FUNCTION
Gene 		pyruvate synthase activity
GO:0019164 		Participant Unchecked
No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
rtca_frd FAD-dependent oxidoreductase 2 flavoprotein subunit of the SdhA/FrdA class (EC 1.3.5.1), run reductively here
Family 		succinate dehydrogenase (quinone) activity
GO:0008177 		Family Id Missing
The family has no identifier linking it to a curated family review.
rtca_ogor 2-oxoacid:ferredoxin oxidoreductase, 2-oxoglutarate-specific
Family 		2-oxoglutarate synthase activity
GO:0047553 		Family Id Missing
The family has no identifier linking it to a curated family review.

Gene-review completeness (0/5 grounded genes reviewed)

0 complete review(s) · 0 with deep research · 5 missing review · 0 reviewed but lacking deep research

Gene Review Complete Deep research
A0A101JN76 (2-oxoglutarate:ferredoxin oxidoreductase alpha subunit, Chlorobium limicola; unreviewed, no gene symbol in UniProt) A0A101JN76 ✗ — —
sdhA (Chlorobium limicola; unreviewed) A0A101JUB8 ✗ — —
frdA (Escherichia coli K-12) P00363 ✗ — —
aclA (Chlorobium limicola; unreviewed) Q9AJC4 ✗ — —
aclB (Chlorobium limicola; unreviewed) Q9AQH6 ✗ — —

Details

Reductive tricarboxylic acid cycleMetabolic Pathwayreductive_tca_cycle
reductive tricarboxylic acid cycleGO:0019643 carbon fixationGO:0015977

Connections

The acetyl-CoA released by citrate cleavage is the substrate for reductive carboxylation to pyruvate.
The oxaloacetate released by citrate cleavage reaches fumarate through the shared reductive steps (malate dehydrogenase and fumarase), which the module does not decompose because they are not diagnostic of the reductive direction, and treated here as one undecomposed stretch, as the 2-oxoglutarate to citrate span below is.
Succinate is activated to its CoA thioester.
Succinyl-CoA is the acceptor for the ferredoxin-dependent carboxylation.
2-oxoglutarate is carried on to citrate through the shared steps (isocitrate and aconitase), which the module does not decompose, and the cycle closes at citrate cleavage.
Part 1: citrate cleavage (the reversal-defining step)
ATP-citrate lyase cleavage of citrate to acetyl-CoA and oxaloacetateReactionrtca_citrate_cleavage

Annotons

ATP-citrate lyase (AclAB)
rtca_acl
Participant: Protein Complex: ATP-citrate lyase (AclAB)
Protein Complex:
ATP-citrate lyase (AclAB)
Active units:
AclA
Participant: Gene Product: aclA (Chlorobium limicola; unreviewed)
Gene Product:
aclA (Chlorobium limicola; unreviewed)UniProtKB:Q9AJC4
AclB
Participant: Gene Product: aclB (Chlorobium limicola; unreviewed)
Gene Product:
aclB (Chlorobium limicola; unreviewed)UniProtKB:Q9AQH6

Function

ATP citrate synthase activityGO:0003878
Substrates: citrate coenzyme A ATP
Products: acetyl-CoA oxaloacetate ADP phosphate

Replaces citrate synthase, which is effectively irreversible in the synthetic direction. Spending ATP here is what lets the cycle close. The GO term is named for the reverse (synthase) direction; in this cycle the enzyme runs as a lyase.

Part 2: fumarate reduction
Fumarate reductase reduction of fumarate to succinateReactionrtca_fumarate_reduction

Annotons

Fumarate reductase
rtca_frd
Participant: Family: FAD-dependent oxidoreductase 2 flavoprotein subunit of the SdhA/FrdA class (EC 1.3.5.1), run reductively here
Family:
FAD-dependent oxidoreductase 2 flavoprotein subunit of the SdhA/FrdA class (EC 1.3.5.1), run reductively here
Representative Members: sdhA (Chlorobium limicola; unreviewed)UniProtKB:A0A101JUB8 frdA (Escherichia coli K-12)UniProtKB:P00363
The flavoprotein subunit carrying the succinate/fumarate half-reaction against a quinone pool, run reductively at this step. The two members deliberately span the family's two documented subfamilies rather than sitting on one side of it: A0A101JUB8 is in PTHR11632:SF53 (SUCCINATE DEHYDROGENASE FLAVOPROTEIN SUBUNIT) and P00363 in PTHR11632:SF82 (FUMARATE REDUCTASE FLAVOPROTEIN SUBUNIT, which interpro/panther/PTHR11632/PTHR11632-review.yaml marks diverged_from_family with "Physiologically reduce fumarate"). That spread is the point, and it is the principle this module already states for the ferredoxin carboxylases: direction is a property of the metabolic context, not of the protein. A0A101JUB8's UniProt entry cannot place it on either side of that split, which is why the preferred_term names family membership rather than a direction. Its RecName "Fumarate reductase flavoprotein subunit" and its EC are both ARBA-only ({ECO:0000256|ARBA:ARBA00014044} and ARBA00012792) on an unreviewed TrEMBL entry at PE 3, which CLAUDE.md classes as an unvetted prediction and not support; its gene name sdhA is submitter-supplied ({ECO:0000313|EMBL:KUL33152.1}), equally unvetted. So nothing on that entry establishes a physiological direction either way, and the EC anchor rests on P00363, which is reviewed. The entry's one curated line, "Belongs to the FAD-dependent oxidoreductase 2 family", is family membership, which is what the preferred_term states. EC 1.3.5.4, which once named the quinol:fumarate reductase separately, is a transferred entry merged into 1.3.5.1 (ExPASy: "Transferred entry: 1.3.5.1"), so a two-EC anchor would cite a class that no longer exists. No PANTHER term is asserted, and the reason is granularity rather than breadth. UniProt places A0A101JUB8 in PTHR11632:SF53 and P00363 in PTHR11632:SF82, so no subfamily contains both members. SF82 is unusable for a second reason: it sits outside the reviewed SUBFAMILY_ONLY scope for GO:0000104, so declaring it makes module_family_conformance raise FAMILY_CONFLICT at error level (module_family_conformance.py:131-139), not a warning. The shared base family PTHR11632 does contain both members, and declaring it yields FAMILY_SCOPE_RESTRICTED: "GO:0000104 is SUBFAMILY_ONLY; this family grounding does not establish the allowed subfamily scope" (:143-151). That complaint is about precision: the term is reviewed as valid for SF51/SF53/SF72 only, and a base-family id does not say which subfamily a member falls in. Since the two members fall in different subfamilies and only one is in the allowed set, no single id states the truth, so the descriptor keeps its free-text intent and its members and asserts no family id. NADH-dependent fumarate reductases (GO:0016156, EC 1.3.1.6) occupy this same position in other organisms. That is recorded as context rather than modelled, because both members here are quinone-coupled rather than NAD(P)-coupled - which the curated "FAD-dependent oxidoreductase 2 family" line supports as membership evidence, and which is a separate axis from the physiological direction the ARBA text cannot establish.

Function

succinate dehydrogenase (quinone) activityGO:0008177 Reduction of fumarate to succinate with a quinol as electron donor, run in the reductive direction here. The term's name reads oxidatively, which is not a reason to refuse it: GO defines it by the reversible equation and carries "fumarate reductase (menaquinone)" as an exact synonym, and it xrefs the same EC 1.3.5.1 that P00363 carries on a reviewed entry. A name that reads oxidatively is not a semantic mismatch. This is not the cofactor-over-specificity error corrected elsewhere in this module set: that applies where a node spans both cofactors, as cam_malic_enzyme does, whereas the electron acceptor here is a quinone for both members and the quinone-specific term is the precise one. GO:0016156 would have been wrong, being NADH-specific (EC 1.3.1.6). One tension is worth recording rather than resolving silently. GO:0008177 is_a GO:0000104 succinate dehydrogenase activity, which PTHR11632-review.yaml scopes SUBFAMILY_ONLY to SF51/SF53/SF72 because propagating it from the family root would over-annotate the fumarate reductase branches. P00363 sits outside that set, so asserting GO:0008177 on a descriptor including it entails a term this repo keeps off fumarate reductases. That scope statement guards against family-level propagation of a directionally named parent; it is not a claim that a quinol:fumarate reductase cannot catalyse the succinate/quinone reaction, which it demonstrably does - hence GO:0008177's exact synonym "fumarate reductase (menaquinone)" and its shared EC. So the scope statement does not exclude a member that genuinely runs the reaction in reverse, and no GO change is called for: GO:0000104 is named oxidatively in the same way GO:0008177 is, so by the argument above its parentage is no more defective than the child's name.
Substrates: fumarate
Products: succinate

Replaces succinate dehydrogenase. Running this step reductively requires a donor at a lower potential than the quinone pool used in the oxidative direction.

Part 3: succinyl-CoA formation
Succinate-CoA ligase activation of succinateReactionrtca_succinyl_coa

Annotons

Succinate--CoA ligase
rtca_sucCD
Participant: Any With Function: succinate-CoA ligase (ADP-forming) activity
Required Function:
succinate-CoA ligase (ADP-forming) activityGO:0004775

Function

succinate-CoA ligase (ADP-forming) activityGO:0004775
Substrates: succinate coenzyme A ATP
Products: succinyl-CoA ADP phosphate

Supplies the thioester substrate for the carboxylation step; the second ATP cost of the cycle.

Part 4: reductive carboxylation of succinyl-CoA
2-oxoglutarate synthase carboxylation of succinyl-CoAReactionrtca_oxoglutarate_synthase

Annotons

2-oxoglutarate:ferredoxin oxidoreductase
rtca_ogor
Participant: Family: 2-oxoacid:ferredoxin oxidoreductase, 2-oxoglutarate-specific
Family:
2-oxoacid:ferredoxin oxidoreductase, 2-oxoglutarate-specific
Representative Members: A0A101JN76 (2-oxoglutarate:ferredoxin oxidoreductase alpha subunit, Chlorobium limicola; unreviewed, no gene symbol in UniProt)UniProtKB:A0A101JN76

Function

2-oxoglutarate synthase activityGO:0047553
Substrates: succinyl-CoA CO2 reduced ferredoxin
Products: 2-oxoglutarate coenzyme A oxidized ferredoxin

One of the two CO2-fixing steps. Thiamine-diphosphate and iron-sulfur dependent, and reliant on low-potential ferredoxin, which is the main reason the cycle is restricted to anoxic conditions.

Part 5: pyruvate synthesis from the acetyl-CoA product
Pyruvate synthase carboxylation of acetyl-CoAReactionrtca_pyruvate_synthase

Annotons

Pyruvate:ferredoxin oxidoreductase
rtca_pfor
Participant: Any With Function: pyruvate synthase activity
Required Function:
pyruvate synthase activityGO:0019164

Function

pyruvate synthase activityGO:0019164
Substrates: acetyl-CoA CO2 reduced ferredoxin
Products: pyruvate coenzyme A oxidized ferredoxin

Takes the acetyl-CoA released by citrate cleavage into central biosynthesis. Strictly an outlet from the cycle rather than a step of the ring, but it is what makes the cycle autotrophic, and it fixes a further CO2.