3-Hydroxypropionate/4-hydroxybutyrate CO2 fixation cycle (Sulfolobales)

The autotrophic CO2 fixation cycle of the Sulfolobales. Acetyl-CoA is carboxylated to malonyl-CoA and reduced through malonate semialdehyde and 3-hydroxypropionate to propionyl-CoA, which is carboxylated a second time and rearranged to succinyl-CoA. Succinyl-CoA is reduced through succinate semialdehyde to 4-hydroxybutyrate, which is activated, dehydrated to crotonyl-CoA and converted through acetoacetyl-CoA into two molecules of acetyl-CoA. One acetyl-CoA restarts the cycle, so each turn fixes two bicarbonate molecules into one acetyl-CoA. Several enzymes act twice: one carboxylase acts on acetyl-CoA and propionyl-CoA, one reductase on malonyl-CoA and succinyl-CoA, and one crotonase-family enzyme dehydrates 3-hydroxypropionyl-CoA and hydrates crotonyl-CoA.

MODULE:hydroxypropionate_hydroxybutyrate_cycleDRAFTCONCRETEMetabolic Pathwaymodules/hydroxypropionate_hydroxybutyrate_cycle.yaml

carbon fixationGO:0015977

PMID:18079405

A 3-hydroxypropionate/4-hydroxybutyrate autotrophic carbon dioxide assimilation pathway in Archaea

Defines the cycle in Metallosphaera sedula.

PMID:19684143

Malonic semialdehyde reductase, succinic semialdehyde reductase, and succinyl-coenzyme A reductase from Metallosphaera sedula: enzymes of the autotrophic 3-hydroxypropionate/4-hydroxybutyrate cycle in Sulfolobales.

Identifies Msed_1993 as malonic semialdehyde reductase, Msed_1424 as succinic semialdehyde reductase and Msed_0709 as the succinyl-CoA reductase, each by purification or heterologous expression.

PMID:19429610

3-hydroxypropionyl-coenzyme A dehydratase and acryloyl-coenzyme A reductase, enzymes of the autotrophic 3-hydroxypropionate/4-hydroxybutyrate cycle in the Sulfolobales

Identifies Msed_2001 as 3-hydroxypropionyl-CoA dehydratase and Msed_1426 as acryloyl-CoA reductase.

PMID:21169482

Identification of missing genes and enzymes for autotrophic carbon fixation in crenarchaeota

Identifies Msed_0399 as the bifunctional crotonyl-CoA hydratase/(S)-3-hydroxybutyryl-CoA dehydrogenase and points to the beta-ketothiolase gene Msed_0656.

PMID:24532060

Conversion of 4-hydroxybutyrate to acetyl coenzyme A and its anapleurosis in the Metallosphaera sedula 3-hydroxypropionate/4-hydroxybutyrate carbon fixation pathway

Names the acetyl-CoA/propionyl-CoA carboxylase subunits Msed_0147, Msed_0148 and Msed_1375 among the genes most strongly upregulated under autotrophic growth.

PMID:33472982

Convergent Evolution of a Promiscuous 3-Hydroxypropionyl-CoA Dehydratase/Crotonyl-CoA Hydratase in Crenarchaeota and Thaumarchaeota

Shows that Msed_2001 supplies most of the crotonyl-CoA hydratase activity of M. sedula and that Msed_0399 is not the main crotonyl-CoA hydratase.

GO:0015977

carbon fixation

The cycle is an autotrophic carbon fixation pathway; GO has no term for the 3HP/4HB cycle itself.

PMID:22752162

Epimerase (Msed_0639) and mutase (Msed_0638 and Msed_2055) convert (S)-methylmalonyl-coenzyme A (CoA) to succinyl-CoA in the Metallosphaera sedula 3-hydroxypropionate/4-hydroxybutyrate cycle.

Shows that Msed_0639 (epimerase) and the two-subunit mutase Msed_0638/Msed_2055 are upregulated autotrophically and, as recombinant enzymes, together convert (S)-methylmalonyl-CoA to succinyl-CoA.

PMID:32218776

Enzymes Catalyzing Crotonyl-CoA Conversion to Acetoacetyl-CoA During the Autotrophic CO(2) Fixation in Metallosphaera sedula.

The dehydrogenase Msed_1423, not the bifunctional Msed_0399, appears to be the main (S)-3-hydroxybutyryl-CoA dehydrogenase of the cycle; the paper also lists beta-ketothiolase paralogs of Msed_0656.

PMID:12581213

Characterization of acetyl-CoA/propionyl-CoA carboxylase in Metallosphaera sedula. Carboxylating enzyme in the 3-hydroxypropionate cycle for autotrophic carbon fixation.

Purified M. sedula acetyl-CoA/propionyl-CoA carboxylase carboxylates both acetyl-CoA and propionyl-CoA.

Concrete module for the crenarchaeal (Sulfolobales) form of the cycle, with M. sedula DSM 5348 proteins as representative members. GO:0043427 carbon fixation by 3-hydroxypropionate cycle is deliberately not used: it is defined as the Chloroflexus pathway that fixes CO2 into glyoxylate, which is a different cycle. The gene reviews propose 'carbon fixation by 3-hydroxypropionate/4-hydroxybutyrate cycle' and four missing activity terms; four steps therefore carry a function descriptor without a GO id. Thaumarchaeota run a related cycle with partly convergent enzymes (PMID:33472982) and are outside this module.

19Nodes

18Parts

0Variant Sets

0Variants

16Annotons

16Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

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

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

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.

methylmalonyl_coa_rearrangement → succinyl_coa_reduction [NOT_CHECKED]
acetoacetyl_coa_thiolysis → acetyl_coa_carboxylation [NOT_CHECKED]

Function consistency and core coverage

15 gene-function check(s) reflected in core functions · 0 conflict(s) · 17 evidence or coverage gap(s) (35 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.

Annoton	Participant	Function	Assessment
acc_acetyl	PROTEIN_COMPLEX Gene	acetyl-CoA carboxylase activity GO:0003989	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
acc_acetyl/acc_bc	Msed_0147 (Metallosphaera sedula biotin carboxylase) UniProtKB:A4YD22 Complex Unit	biotin carboxylase activity GO:0004075	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
acc_acetyl/acc_ct	Msed_1375 (Metallosphaera sedula carboxyltransferase) UniProtKB:A4YGI1 Complex Unit	carboxyl- or carbamoyltransferase activity GO:0016743	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mcr_malonyl	Msed_0709 (Metallosphaera sedula) UniProtKB:A4YEN2 Family Representative	malonyl-CoA reductase (NADP+) activity No function ID	No Function Id A gene review exists, but this function lacks a GO identifier. Free-text chemistry is not automatically compared.
msr	Msed_1993 (Metallosphaera sedula) UniProtKB:A4YI81 Family Representative	3-hydroxypropionate dehydrogenase (NADP+) activity GO:0035527	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hpcs	Msed_1456 (Metallosphaera sedula) UniProtKB:A4YGR1 Family Representative	3-hydroxypropionyl-CoA synthetase activity GO:0043955	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hpcd	Msed_2001 (Metallosphaera sedula) UniProtKB:A4YI89 Family Representative	3-hydroxypropionyl-CoA dehydratase activity GO:0043956	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
acr	Msed_1426 (Metallosphaera sedula) UniProtKB:A4YGN2 Family Representative	acryloyl-CoA reductase (NADPH) activity GO:0043957	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
acc_propionyl	PROTEIN_COMPLEX Gene	propionyl-CoA carboxylase activity GO:0004658	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
acc_propionyl/acc_bc	Msed_0147 (Metallosphaera sedula biotin carboxylase) UniProtKB:A4YD22 Complex Unit	biotin carboxylase activity GO:0004075	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
acc_propionyl/acc_ct	Msed_1375 (Metallosphaera sedula carboxyltransferase) UniProtKB:A4YGI1 Complex Unit	carboxyl- or carbamoyltransferase activity GO:0016743	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mce	Msed_0639 (Metallosphaera sedula) UniProtKB:A4YEG2 Family Representative	methylmalonyl-CoA epimerase activity GO:0004493	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mcm	PROTEIN_COMPLEX Gene	methylmalonyl-CoA mutase activity GO:0004494	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
mcm/mcm_small	Msed_2055 (Metallosphaera sedula B12-binding small subunit) UniProtKB:A4YIE3 Complex Unit	cobalamin binding GO:0031419	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mcr_succinyl	Msed_0709 (Metallosphaera sedula) UniProtKB:A4YEN2 Family Representative	succinyl-CoA reductase (NADP+) activity No function ID	No Function Id A gene review exists, but this function lacks a GO identifier. Free-text chemistry is not automatically compared.
ssr	Msed_1424 (Metallosphaera sedula) UniProtKB:A4YGN0 Family Representative	succinate-semialdehyde reductase (NADPH) activity No function ID	No Function Id A gene review exists, but this function lacks a GO identifier. Free-text chemistry is not automatically compared.
hbcs	Msed_0406 (Metallosphaera sedula) UniProtKB:A4YDT1 Family Representative	4-hydroxybutyrate-CoA ligase activity No function ID	No Function Id A gene review exists, but this function lacks a GO identifier. Free-text chemistry is not automatically compared.
hbcd	Msed_1321 (Metallosphaera sedula) UniProtKB:A4YGC7 Family Representative	4-hydroxybutanoyl-CoA dehydratase activity GO:0043721	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cch	Msed_2001 (Metallosphaera sedula) UniProtKB:A4YI89 Family Representative	(2E)-butenoyl-CoA hydratase activity GO:0120092	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hbdh	Msed_1423 (Metallosphaera sedula, main enzyme) UniProtKB:A4YGM9 Family Representative	(3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity GO:0003857	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
hbdh	Msed_0399 (Metallosphaera sedula, bifunctional crotonase/dehydrogenase, minor) UniProtKB:A4YDS4 Family Representative	(3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity GO:0003857	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
thl	Msed_0656 (Metallosphaera sedula) UniProtKB:A4YEH9 Family Representative	acetyl-CoA C-acetyltransferase activity GO:0003985	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mcr_malonyl	archaeal malonyl-CoA/succinyl-CoA reductase (aspartate-semialdehyde dehydrogenase-derived) Family	malonyl-CoA reductase (NADP+) activity No function ID	No Function Id The family function has no GO identifier for comparison; prose is not matched.
msr	NADPH-dependent malonic semialdehyde reductase Family	3-hydroxypropionate dehydrogenase (NADP+) activity GO:0035527	Family Id Missing The family has no identifier linking it to a curated family review.
hpcs	AMP-forming 3-hydroxypropionyl-CoA synthetase Family	3-hydroxypropionyl-CoA synthetase activity GO:0043955	Family Id Missing The family has no identifier linking it to a curated family review.
hpcd	crenarchaeal 3-hydroxypropionyl-CoA dehydratase/crotonyl-CoA hydratase (crotonase family) Family	3-hydroxypropionyl-CoA dehydratase activity GO:0043956	Family Id Missing The family has no identifier linking it to a curated family review.
acr	NADPH-dependent acryloyl-CoA reductase (zinc alcohol dehydrogenase family) Family	acryloyl-CoA reductase (NADPH) activity GO:0043957	Family Id Missing The family has no identifier linking it to a curated family review.
mce	methylmalonyl-CoA epimerase Family	methylmalonyl-CoA epimerase activity GO:0004493	Family Id Missing The family has no identifier linking it to a curated family review.
mcr_succinyl	archaeal malonyl-CoA/succinyl-CoA reductase (aspartate-semialdehyde dehydrogenase-derived) Family	succinyl-CoA reductase (NADP+) activity No function ID	No Function Id The family function has no GO identifier for comparison; prose is not matched.
ssr	NADPH-dependent succinic semialdehyde reductase (zinc alcohol dehydrogenase family) Family	succinate-semialdehyde reductase (NADPH) activity No function ID	No Function Id The family function has no GO identifier for comparison; prose is not matched.
hbcs	AMP-forming 4-hydroxybutyrate-CoA ligase Family	4-hydroxybutyrate-CoA ligase activity No function ID	No Function Id The family function has no GO identifier for comparison; prose is not matched.
hbcd	radical 4-hydroxybutyryl-CoA dehydratase Family	4-hydroxybutanoyl-CoA dehydratase activity GO:0043721	Family Id Missing The family has no identifier linking it to a curated family review.
cch	crenarchaeal 3-hydroxypropionyl-CoA dehydratase/crotonyl-CoA hydratase (crotonase family) Family	(2E)-butenoyl-CoA hydratase activity GO:0120092	Family Id Missing The family has no identifier linking it to a curated family review.
hbdh	NAD+-dependent (S)-3-hydroxybutyryl-CoA dehydrogenase Family	(3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity GO:0003857	Family Id Missing The family has no identifier linking it to a curated family review.
thl	acetoacetyl-CoA beta-ketothiolase Family	acetyl-CoA C-acetyltransferase activity GO:0003985	Family Id Missing The family has no identifier linking it to a curated family review.

Gene-review completeness (17/17 grounded genes reviewed)

16 complete review(s) · 0 with deep research · 0 missing review · 17 reviewed but lacking deep research

Gene	Review	Complete	Deep research
Msed_0147 A4YD22	✓	✓	✗
Msed_0148 A4YD23	✓	✓	✗
Msed_0399 A4YDS4	✓	7/8	✗
Msed_0406 A4YDT1	✓	✓	✗
Msed_0638 A4YEG1	✓	✓	✗
Msed_0639 A4YEG2	✓	✓	✗
Msed_0656 A4YEH9	✓	✓	✗
Msed_0709 A4YEN2	✓	✓	✗
Msed_1321 A4YGC7	✓	✓	✗
Msed_1375 A4YGI1	✓	✓	✗
Msed_1423 A4YGM9	✓	✓	✗
Msed_1424 A4YGN0	✓	✓	✗
Msed_1426 A4YGN2	✓	✓	✗
Msed_1456 A4YGR1	✓	✓	✗
Msed_1993 A4YI81	✓	✓	✗
Msed_2001 A4YI89	✓	✓	✗
Msed_2055 A4YIE3	✓	✓	✗

Tree

3-Hydroxypropionate/4-hydroxybutyrate cycleMetabolic Pathwayhydroxypropionate_hydroxybutyrate_cycle

Parts
1. 1. acetyl-CoA to succinyl-CoA
2. 3-Hydroxypropionate branchMetabolic Pathwayhydroxypropionate_branch
  
  Parts
  1. 1. acetyl-CoA carboxylation
  2. Acetyl-CoA carboxylationReactionacetyl_coa_carboxylation
    
    Annotons
    
    Acetyl-CoA carboxylase Protein Complex: archaeal acetyl-CoA/propionyl-CoA carboxylase (biotin carboxylase, biotin carboxyl carrier protein and carboxyltransferase subunits)
  3. 2. malonyl-CoA reduction
  4. Malonyl-CoA reductionReactionmalonyl_coa_reduction
    
    Annotons
    
    Malonyl-CoA reductase Family: archaeal malonyl-CoA/succinyl-CoA reductase (aspartate-semialdehyde dehydrogenase-derived)
  5. 3. malonate semialdehyde reduction
  6. Malonate semialdehyde reductionReactionmalonate_semialdehyde_reduction
    
    Annotons
    
    Malonic semialdehyde reductase Family: NADPH-dependent malonic semialdehyde reductase
  7. 4. 3-hydroxypropionate activation
  8. 3-Hydroxypropionate activationReactionhydroxypropionate_activation
    
    Annotons
    
    3-hydroxypropionyl-CoA synthetase Family: AMP-forming 3-hydroxypropionyl-CoA synthetase
  9. 5. 3-hydroxypropionyl-CoA dehydration
  10. 3-Hydroxypropionyl-CoA dehydrationReactionhydroxypropionyl_coa_dehydration
    
    Annotons
    
    3-hydroxypropionyl-CoA dehydratase Family: crenarchaeal 3-hydroxypropionyl-CoA dehydratase/crotonyl-CoA hydratase (crotonase family)
  11. 6. acryloyl-CoA reduction
  12. Acryloyl-CoA reductionReactionacryloyl_coa_reduction
    
    Annotons
    
    Acryloyl-CoA reductase Family: NADPH-dependent acryloyl-CoA reductase (zinc alcohol dehydrogenase family)
  13. 7. propionyl-CoA carboxylation
  14. Propionyl-CoA carboxylationReactionpropionyl_coa_carboxylation
    
    Annotons
    
    Propionyl-CoA carboxylase Protein Complex: archaeal acetyl-CoA/propionyl-CoA carboxylase (biotin carboxylase, biotin carboxyl carrier protein and carboxyltransferase subunits)
  15. 8. methylmalonyl-CoA epimerization
  16. Methylmalonyl-CoA epimerizationReactionmethylmalonyl_coa_epimerization
    
    Annotons
    
    Methylmalonyl-CoA epimerase Family: methylmalonyl-CoA epimerase
  17. 9. methylmalonyl-CoA rearrangement
  18. Methylmalonyl-CoA rearrangementReactionmethylmalonyl_coa_rearrangement
    
    Annotons
    
    Methylmalonyl-CoA mutase Protein Complex: coenzyme B12-dependent methylmalonyl-CoA mutase (alpha2beta2)
3. 2. succinyl-CoA to two acetyl-CoA
4. 4-Hydroxybutyrate branchMetabolic Pathwayhydroxybutyrate_branch
  
  Parts
  1. 1. succinyl-CoA reduction
  2. Succinyl-CoA reductionReactionsuccinyl_coa_reduction
    
    Annotons
    
    Succinyl-CoA reductase Family: archaeal malonyl-CoA/succinyl-CoA reductase (aspartate-semialdehyde dehydrogenase-derived)
  3. 2. succinate semialdehyde reduction
  4. Succinate semialdehyde reductionReactionsuccinate_semialdehyde_reduction
    
    Annotons
    
    Succinic semialdehyde reductase Family: NADPH-dependent succinic semialdehyde reductase (zinc alcohol dehydrogenase family)
  5. 3. 4-hydroxybutyrate activation
  6. 4-Hydroxybutyrate activationReactionhydroxybutyrate_activation
    
    Annotons
    
    4-hydroxybutyrate-CoA ligase Family: AMP-forming 4-hydroxybutyrate-CoA ligase
  7. 4. 4-hydroxybutyryl-CoA dehydration
  8. 4-Hydroxybutyryl-CoA dehydrationReactionhydroxybutyryl_coa_dehydration
    
    Annotons
    
    4-hydroxybutyryl-CoA dehydratase Family: radical 4-hydroxybutyryl-CoA dehydratase
  9. 5. crotonyl-CoA hydration
  10. Crotonyl-CoA hydrationReactioncrotonyl_coa_hydration
    
    Annotons
    
    Crotonyl-CoA hydratase Family: crenarchaeal 3-hydroxypropionyl-CoA dehydratase/crotonyl-CoA hydratase (crotonase family)
  11. 6. (S)-3-hydroxybutyryl-CoA oxidation
  12. (S)-3-Hydroxybutyryl-CoA oxidationReactionhydroxybutyryl_coa_oxidation
    
    Annotons
    
    (S)-3-hydroxybutyryl-CoA dehydrogenase Family: NAD+-dependent (S)-3-hydroxybutyryl-CoA dehydrogenase
  13. 7. acetoacetyl-CoA thiolysis
  14. Acetoacetyl-CoA thiolysisReactionacetoacetyl_coa_thiolysis
    
    Annotons
    
    beta-Ketothiolase Family: acetoacetyl-CoA beta-ketothiolase

Details

Context

SulfolobalesNCBITaxon:2281

cytoplasmGO:0005737

3-Hydroxypropionate/4-hydroxybutyrate cycleMetabolic Pathwayhydroxypropionate_hydroxybutyrate_cycle

carbon fixationGO:0015977

Context

SulfolobalesNCBITaxon:2281

cytoplasmGO:0005737

Connections

methylmalonyl_coa_rearrangement -> succinyl_coa_reduction Precedes

Succinyl-CoA links the two branches.

acetoacetyl_coa_thiolysis -> acetyl_coa_carboxylation Precedes

One of the two acetyl-CoA molecules restarts the cycle.

Part 1: acetyl-CoA to succinyl-CoA

3-Hydroxypropionate branchMetabolic Pathwayhydroxypropionate_branch

Two carboxylations and the reductions that turn acetyl-CoA into succinyl-CoA.

Connections

acetyl_coa_carboxylation -> malonyl_coa_reduction Precedes

malonyl_coa_reduction -> malonate_semialdehyde_reduction Precedes

malonate_semialdehyde_reduction -> hydroxypropionate_activation Precedes

hydroxypropionate_activation -> hydroxypropionyl_coa_dehydration Precedes

hydroxypropionyl_coa_dehydration -> acryloyl_coa_reduction Precedes

acryloyl_coa_reduction -> propionyl_coa_carboxylation Precedes

propionyl_coa_carboxylation -> methylmalonyl_coa_epimerization Precedes

methylmalonyl_coa_epimerization -> methylmalonyl_coa_rearrangement Precedes

Part 1: acetyl-CoA carboxylation

Acetyl-CoA carboxylationReactionacetyl_coa_carboxylation

Annotons

Acetyl-CoA carboxylase

acc_acetyl

Participant: Protein Complex: archaeal acetyl-CoA/propionyl-CoA carboxylase (biotin carboxylase, biotin carboxyl carrier protein and carboxyltransferase subunits)

Protein Complex:

archaeal acetyl-CoA/propionyl-CoA carboxylase (biotin carboxylase, biotin carboxyl carrier protein and carboxyltransferase subunits)

Active units:

Biotin carboxylase subunit

Participant: Gene Product: Msed_0147 (Metallosphaera sedula biotin carboxylase)

Gene Product:

Msed_0147 (Metallosphaera sedula biotin carboxylase)UniProtKB:A4YD22

Role: ATP-dependent carboxylation of the biotin carried by the BCCP subunit.

Function:

biotin carboxylase activityGO:0004075

Biotin carboxyl carrier protein subunit

Participant: Gene Product: Msed_0148 (Metallosphaera sedula biotin carboxyl carrier protein)

Gene Product:

Msed_0148 (Metallosphaera sedula biotin carboxyl carrier protein)UniProtKB:A4YD23

Role: Carries the covalently bound biotin between the two half-reactions; GO has no carrier activity term.

Carboxyltransferase subunit

Participant: Gene Product: Msed_1375 (Metallosphaera sedula carboxyltransferase)

Gene Product:

Msed_1375 (Metallosphaera sedula carboxyltransferase)UniProtKB:A4YGI1

Role: Transfers the carboxyl group from carboxybiotin to acetyl-CoA or propionyl-CoA.

Function:

carboxyl- or carbamoyltransferase activityGO:0016743

Function

acetyl-CoA carboxylase activityGO:0003989

Substrates: acetyl-CoA bicarbonate ATP

Products: malonyl-CoA ADP phosphate

Fixes the first bicarbonate onto acetyl-CoA. The same three-subunit enzyme also carboxylates propionyl-CoA later in the cycle.

PMID:12581213

Characterization of acetyl-CoA/propionyl-CoA carboxylase in Metallosphaera sedula. Carboxylating enzyme in the 3-hydroxypropionate cycle for autotrophic carbon fixation.

Purified M. sedula acetyl-CoA/propionyl-CoA carboxylase carboxylates both acetyl-CoA and propionyl-CoA.

PMID:24532060

Conversion of 4-hydroxybutyrate to acetyl coenzyme A and its anapleurosis in the Metallosphaera sedula 3-hydroxypropionate/4-hydroxybutyrate carbon fixation pathway

Names the acetyl-CoA/propionyl-CoA carboxylase subunits Msed_0147, Msed_0148 and Msed_1375 among the genes most strongly upregulated under autotrophic growth.

PMID:19684143

Notes that most archaea carry a single set of acetyl-CoA/propionyl-CoA carboxylase genes, indicating one promiscuous enzyme for both carboxylations.

Part 2: malonyl-CoA reduction

Malonyl-CoA reductionReactionmalonyl_coa_reduction

Annotons

Malonyl-CoA reductase

mcr_malonyl

Participant: Family: archaeal malonyl-CoA/succinyl-CoA reductase (aspartate-semialdehyde dehydrogenase-derived)

Family:

archaeal malonyl-CoA/succinyl-CoA reductase (aspartate-semialdehyde dehydrogenase-derived)

Representative Members: Msed_0709 (Metallosphaera sedula)UniProtKB:A4YEN2

Function

malonyl-CoA reductase (NADP+) activity No GO term exists (RHEA:26446, EC 1.2.1.75); proposed in the Msed_0709 gene review.

Substrates: malonyl-CoA NADPH

Products: malonate semialdehyde CoA NADP+

Reduces malonyl-CoA to malonate semialdehyde. The same enzyme reduces succinyl-CoA in the second half of the cycle.

file:genes/METS5/Msed_0709/Msed_0709-ai-review.yaml

METS5 Msed_0709 gene review

Msed_0709 is the bifunctional malonyl-CoA/succinyl-CoA reductase, derived from aspartate-semialdehyde dehydrogenase.

Part 3: malonate semialdehyde reduction

Malonate semialdehyde reductionReactionmalonate_semialdehyde_reduction

Annotons

Malonic semialdehyde reductase

msr

Participant: Family: NADPH-dependent malonic semialdehyde reductase

Family:

NADPH-dependent malonic semialdehyde reductase

Representative Members: Msed_1993 (Metallosphaera sedula)UniProtKB:A4YI81

Function

3-hydroxypropionate dehydrogenase (NADP+) activityGO:0035527

Substrates: malonate semialdehyde NADPH

Products: 3-hydroxypropionate NADP+

Reduces malonate semialdehyde to 3-hydroxypropionate.

PMID:19684143

Identifies Msed_1993 as malonic semialdehyde reductase, Msed_1424 as succinic semialdehyde reductase and Msed_0709 as the succinyl-CoA reductase, each by purification or heterologous expression.

Part 4: 3-hydroxypropionate activation

3-Hydroxypropionate activationReactionhydroxypropionate_activation

Annotons

3-hydroxypropionyl-CoA synthetase

hpcs

Participant: Family: AMP-forming 3-hydroxypropionyl-CoA synthetase

Family:

AMP-forming 3-hydroxypropionyl-CoA synthetase

Representative Members: Msed_1456 (Metallosphaera sedula)UniProtKB:A4YGR1

Function

3-hydroxypropionyl-CoA synthetase activityGO:0043955

Substrates: 3-hydroxypropionate CoA ATP

Products: 3-hydroxypropionyl-CoA AMP diphosphate

Activates 3-hydroxypropionate to its CoA thioester.

file:genes/METS5/Msed_1456/Msed_1456-ai-review.yaml

METS5 Msed_1456 gene review

Msed_1456 is the 3-hydroxypropionyl-CoA synthetase of the cycle; its acetyl-CoA synthetase annotation is family-level over-annotation.

Part 5: 3-hydroxypropionyl-CoA dehydration

3-Hydroxypropionyl-CoA dehydrationReactionhydroxypropionyl_coa_dehydration

Annotons

3-hydroxypropionyl-CoA dehydratase

hpcd

Participant: Family: crenarchaeal 3-hydroxypropionyl-CoA dehydratase/crotonyl-CoA hydratase (crotonase family)

Family:

crenarchaeal 3-hydroxypropionyl-CoA dehydratase/crotonyl-CoA hydratase (crotonase family)

Representative Members: Msed_2001 (Metallosphaera sedula)UniProtKB:A4YI89

Function

3-hydroxypropionyl-CoA dehydratase activityGO:0043956

Substrates: 3-hydroxypropionyl-CoA

Products: acryloyl-CoA H2O

Dehydrates 3-hydroxypropionyl-CoA to acryloyl-CoA. The same enzyme hydrates crotonyl-CoA in the second half of the cycle.

PMID:19429610

3-hydroxypropionyl-coenzyme A dehydratase and acryloyl-coenzyme A reductase, enzymes of the autotrophic 3-hydroxypropionate/4-hydroxybutyrate cycle in the Sulfolobales

Identifies Msed_2001 as 3-hydroxypropionyl-CoA dehydratase and Msed_1426 as acryloyl-CoA reductase.

file:genes/METS5/Msed_2001/Msed_2001-ai-review.yaml

METS5 Msed_2001 gene review

Msed_2001 is the 3-hydroxypropionyl-CoA dehydratase and also the main crotonyl-CoA hydratase of M. sedula.

Part 6: acryloyl-CoA reduction

Acryloyl-CoA reductionReactionacryloyl_coa_reduction

Annotons

Acryloyl-CoA reductase

acr

Participant: Family: NADPH-dependent acryloyl-CoA reductase (zinc alcohol dehydrogenase family)

Family:

NADPH-dependent acryloyl-CoA reductase (zinc alcohol dehydrogenase family)

Representative Members: Msed_1426 (Metallosphaera sedula)UniProtKB:A4YGN2

Function

acryloyl-CoA reductase (NADPH) activityGO:0043957

Substrates: acryloyl-CoA NADPH

Products: propionyl-CoA NADP+

Reduces acryloyl-CoA to propionyl-CoA.

PMID:19429610

3-hydroxypropionyl-coenzyme A dehydratase and acryloyl-coenzyme A reductase, enzymes of the autotrophic 3-hydroxypropionate/4-hydroxybutyrate cycle in the Sulfolobales

Identifies Msed_2001 as 3-hydroxypropionyl-CoA dehydratase and Msed_1426 as acryloyl-CoA reductase.

Part 7: propionyl-CoA carboxylation

Propionyl-CoA carboxylationReactionpropionyl_coa_carboxylation

Annotons

Propionyl-CoA carboxylase

acc_propionyl

Participant: Protein Complex: archaeal acetyl-CoA/propionyl-CoA carboxylase (biotin carboxylase, biotin carboxyl carrier protein and carboxyltransferase subunits)

Protein Complex:

archaeal acetyl-CoA/propionyl-CoA carboxylase (biotin carboxylase, biotin carboxyl carrier protein and carboxyltransferase subunits)

Active units:

Biotin carboxylase subunit

Participant: Gene Product: Msed_0147 (Metallosphaera sedula biotin carboxylase)

Gene Product:

Msed_0147 (Metallosphaera sedula biotin carboxylase)UniProtKB:A4YD22

Role: ATP-dependent carboxylation of the biotin carried by the BCCP subunit.

Function:

biotin carboxylase activityGO:0004075

Biotin carboxyl carrier protein subunit

Participant: Gene Product: Msed_0148 (Metallosphaera sedula biotin carboxyl carrier protein)

Gene Product:

Msed_0148 (Metallosphaera sedula biotin carboxyl carrier protein)UniProtKB:A4YD23

Role: Carries the covalently bound biotin between the two half-reactions; GO has no carrier activity term.

Carboxyltransferase subunit

Participant: Gene Product: Msed_1375 (Metallosphaera sedula carboxyltransferase)

Gene Product:

Msed_1375 (Metallosphaera sedula carboxyltransferase)UniProtKB:A4YGI1

Role: Transfers the carboxyl group from carboxybiotin to acetyl-CoA or propionyl-CoA.

Function:

carboxyl- or carbamoyltransferase activityGO:0016743

Function

propionyl-CoA carboxylase activityGO:0004658

Substrates: propionyl-CoA bicarbonate ATP

Products: (S)-methylmalonyl-CoA ADP phosphate

Fixes the second bicarbonate onto propionyl-CoA, using the same enzyme as step 1.

PMID:12581213

Characterization of acetyl-CoA/propionyl-CoA carboxylase in Metallosphaera sedula. Carboxylating enzyme in the 3-hydroxypropionate cycle for autotrophic carbon fixation.

Purified M. sedula acetyl-CoA/propionyl-CoA carboxylase carboxylates both acetyl-CoA and propionyl-CoA.

PMID:24532060

Conversion of 4-hydroxybutyrate to acetyl coenzyme A and its anapleurosis in the Metallosphaera sedula 3-hydroxypropionate/4-hydroxybutyrate carbon fixation pathway

Names the acetyl-CoA/propionyl-CoA carboxylase subunits Msed_0147, Msed_0148 and Msed_1375 among the genes most strongly upregulated under autotrophic growth.

PMID:19684143

Notes that most archaea carry a single set of acetyl-CoA/propionyl-CoA carboxylase genes, indicating one promiscuous enzyme for both carboxylations.

Part 8: methylmalonyl-CoA epimerization

Methylmalonyl-CoA epimerizationReactionmethylmalonyl_coa_epimerization

Annotons

Methylmalonyl-CoA epimerase

mce

Participant: Family: methylmalonyl-CoA epimerase

Family:

methylmalonyl-CoA epimerase

Representative Members: Msed_0639 (Metallosphaera sedula)UniProtKB:A4YEG2

Function

methylmalonyl-CoA epimerase activityGO:0004493

Substrates: (S)-methylmalonyl-CoA

Products: (R)-methylmalonyl-CoA

Converts (S)- to (R)-methylmalonyl-CoA.

PMID:22752162

Epimerase (Msed_0639) and mutase (Msed_0638 and Msed_2055) convert (S)-methylmalonyl-coenzyme A (CoA) to succinyl-CoA in the Metallosphaera sedula 3-hydroxypropionate/4-hydroxybutyrate cycle.

Shows that Msed_0639 (epimerase) and the two-subunit mutase Msed_0638/Msed_2055 are upregulated autotrophically and, as recombinant enzymes, together convert (S)-methylmalonyl-CoA to succinyl-CoA.

Part 9: methylmalonyl-CoA rearrangement

Methylmalonyl-CoA rearrangementReactionmethylmalonyl_coa_rearrangement

Annotons

Methylmalonyl-CoA mutase

mcm

Participant: Protein Complex: coenzyme B12-dependent methylmalonyl-CoA mutase (alpha2beta2)

Protein Complex:

coenzyme B12-dependent methylmalonyl-CoA mutase (alpha2beta2)

Active units:

Catalytic large subunit2

Participant: Gene Product: Msed_0638 (Metallosphaera sedula catalytic large subunit)

Gene Product:

Msed_0638 (Metallosphaera sedula catalytic large subunit)UniProtKB:A4YEG1

Role: Holds the substrate-binding TIM barrel and active site.

B12-binding small subunit2

Participant: Gene Product: Msed_2055 (Metallosphaera sedula B12-binding small subunit)

Gene Product:

Msed_2055 (Metallosphaera sedula B12-binding small subunit)UniProtKB:A4YIE3

Role: Supplies the coenzyme B12-binding domain that the large subunit lacks.

Function:

cobalamin bindingGO:0031419

Function

methylmalonyl-CoA mutase activityGO:0004494

Substrates: (R)-methylmalonyl-CoA

Products: succinyl-CoA

Rearranges (R)-methylmalonyl-CoA to succinyl-CoA, closing the 3-hydroxypropionate half. Activity requires both subunits.

PMID:22752162

Epimerase (Msed_0639) and mutase (Msed_0638 and Msed_2055) convert (S)-methylmalonyl-coenzyme A (CoA) to succinyl-CoA in the Metallosphaera sedula 3-hydroxypropionate/4-hydroxybutyrate cycle.

Shows that Msed_0639 (epimerase) and the two-subunit mutase Msed_0638/Msed_2055 are upregulated autotrophically and, as recombinant enzymes, together convert (S)-methylmalonyl-CoA to succinyl-CoA.

Part 2: succinyl-CoA to two acetyl-CoA

4-Hydroxybutyrate branchMetabolic Pathwayhydroxybutyrate_branch

Conversion of succinyl-CoA through 4-hydroxybutyrate into two acetyl-CoA.

Connections

succinyl_coa_reduction -> succinate_semialdehyde_reduction Precedes

succinate_semialdehyde_reduction -> hydroxybutyrate_activation Precedes

hydroxybutyrate_activation -> hydroxybutyryl_coa_dehydration Precedes

hydroxybutyryl_coa_dehydration -> crotonyl_coa_hydration Precedes

crotonyl_coa_hydration -> hydroxybutyryl_coa_oxidation Precedes

hydroxybutyryl_coa_oxidation -> acetoacetyl_coa_thiolysis Precedes

Part 1: succinyl-CoA reduction

Succinyl-CoA reductionReactionsuccinyl_coa_reduction

Annotons

Succinyl-CoA reductase

mcr_succinyl

Participant: Family: archaeal malonyl-CoA/succinyl-CoA reductase (aspartate-semialdehyde dehydrogenase-derived)

Family:

archaeal malonyl-CoA/succinyl-CoA reductase (aspartate-semialdehyde dehydrogenase-derived)

Representative Members: Msed_0709 (Metallosphaera sedula)UniProtKB:A4YEN2

Function

succinyl-CoA reductase (NADP+) activity No GO term exists (EC 1.2.1.76); proposed in the Msed_0709 gene review.

Substrates: succinyl-CoA NADPH

Products: succinate semialdehyde CoA NADP+

Reduces succinyl-CoA to succinate semialdehyde; the second activity of the malonyl-CoA reductase.

PMID:19684143

Identifies Msed_1993 as malonic semialdehyde reductase, Msed_1424 as succinic semialdehyde reductase and Msed_0709 as the succinyl-CoA reductase, each by purification or heterologous expression.

Part 2: succinate semialdehyde reduction

Succinate semialdehyde reductionReactionsuccinate_semialdehyde_reduction

Annotons

Succinic semialdehyde reductase

ssr

Participant: Family: NADPH-dependent succinic semialdehyde reductase (zinc alcohol dehydrogenase family)

Family:

NADPH-dependent succinic semialdehyde reductase (zinc alcohol dehydrogenase family)

Representative Members: Msed_1424 (Metallosphaera sedula)UniProtKB:A4YGN0

Function

succinate-semialdehyde reductase (NADPH) activity No GO term exists (RHEA:26381); proposed in the Msed_1424 gene review. The UniProt name of the representative member describes the preceding step and is disputed there.

Substrates: succinate semialdehyde NADPH

Products: 4-hydroxybutyrate NADP+

Reduces succinate semialdehyde to 4-hydroxybutyrate.

PMID:19684143

Identifies Msed_1993 as malonic semialdehyde reductase, Msed_1424 as succinic semialdehyde reductase and Msed_0709 as the succinyl-CoA reductase, each by purification or heterologous expression.

file:genes/METS5/Msed_1424/Msed_1424-ai-review.yaml

METS5 Msed_1424 gene review

Msed_1424 is the NADPH succinic semialdehyde reductase, not the succinyl-CoA reductase its UniProt name states.

Part 3: 4-hydroxybutyrate activation

4-Hydroxybutyrate activationReactionhydroxybutyrate_activation

Annotons

4-hydroxybutyrate-CoA ligase

hbcs

Participant: Family: AMP-forming 4-hydroxybutyrate-CoA ligase

Family:

AMP-forming 4-hydroxybutyrate-CoA ligase

Representative Members: Msed_0406 (Metallosphaera sedula)UniProtKB:A4YDT1

Function

4-hydroxybutyrate-CoA ligase activity No GO term exists (EC 6.2.1.40); proposed in the Msed_0406 gene review. The paralog Msed_0394 (A4YDR9) has the same activity at lower rates and is unlikely to contribute much (PMID:24532060).

Substrates: 4-hydroxybutyrate CoA ATP

Products: 4-hydroxybutyryl-CoA AMP diphosphate

Activates 4-hydroxybutyrate to its CoA thioester.

file:genes/METS5/Msed_0406/Msed_0406-ai-review.yaml

METS5 Msed_0406 gene review

Msed_0406 is the physiological 4-hydroxybutyrate-CoA ligase, although 4-hydroxybutyrate is its poorest in-vitro substrate.

Part 4: 4-hydroxybutyryl-CoA dehydration

4-Hydroxybutyryl-CoA dehydrationReactionhydroxybutyryl_coa_dehydration

Annotons

4-hydroxybutyryl-CoA dehydratase

hbcd

Participant: Family: radical 4-hydroxybutyryl-CoA dehydratase

Family:

radical 4-hydroxybutyryl-CoA dehydratase

Representative Members: Msed_1321 (Metallosphaera sedula)UniProtKB:A4YGC7

Function

4-hydroxybutanoyl-CoA dehydratase activityGO:0043721

Substrates: 4-hydroxybutyryl-CoA

Products: crotonyl-CoA H2O

Dehydrates 4-hydroxybutyryl-CoA to crotonyl-CoA. By analogy to the clostridial enzyme it may also isomerize vinylacetyl-CoA, as its UniProt name implies; this has not been tested.

PMID:24532060

Conversion of 4-hydroxybutyrate to acetyl coenzyme A and its anapleurosis in the Metallosphaera sedula 3-hydroxypropionate/4-hydroxybutyrate carbon fixation pathway

Names the acetyl-CoA/propionyl-CoA carboxylase subunits Msed_0147, Msed_0148 and Msed_1375 among the genes most strongly upregulated under autotrophic growth.

PMID:21169482

Identification of missing genes and enzymes for autotrophic carbon fixation in crenarchaeota.

Assigns the 4-hydroxybutyryl-CoA dehydratase gene in M. sedula.

Part 5: crotonyl-CoA hydration

Crotonyl-CoA hydrationReactioncrotonyl_coa_hydration

Annotons

Crotonyl-CoA hydratase

cch

Participant: Family: crenarchaeal 3-hydroxypropionyl-CoA dehydratase/crotonyl-CoA hydratase (crotonase family)

Family:

crenarchaeal 3-hydroxypropionyl-CoA dehydratase/crotonyl-CoA hydratase (crotonase family)

Representative Members: Msed_2001 (Metallosphaera sedula)UniProtKB:A4YI89

Function

(2E)-butenoyl-CoA hydratase activityGO:0120092

Substrates: crotonyl-CoA H2O

Products: (S)-3-hydroxybutyryl-CoA

Hydrates crotonyl-CoA; the second activity of the 3-hydroxypropionyl-CoA dehydratase.

PMID:33472982

Convergent Evolution of a Promiscuous 3-Hydroxypropionyl-CoA Dehydratase/Crotonyl-CoA Hydratase in Crenarchaeota and Thaumarchaeota

Shows that Msed_2001 supplies most of the crotonyl-CoA hydratase activity of M. sedula and that Msed_0399 is not the main crotonyl-CoA hydratase.

Part 6: (S)-3-hydroxybutyryl-CoA oxidation

(S)-3-Hydroxybutyryl-CoA oxidationReactionhydroxybutyryl_coa_oxidation

Annotons

(S)-3-hydroxybutyryl-CoA dehydrogenase

hbdh

Participant: Family: NAD+-dependent (S)-3-hydroxybutyryl-CoA dehydrogenase

Family:

NAD+-dependent (S)-3-hydroxybutyryl-CoA dehydrogenase

Representative Members: Msed_1423 (Metallosphaera sedula, main enzyme)UniProtKB:A4YGM9 Msed_0399 (Metallosphaera sedula, bifunctional crotonase/dehydrogenase, minor)UniProtKB:A4YDS4

Function

(3S)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activityGO:0003857

Substrates: (S)-3-hydroxybutyryl-CoA NAD+

Products: acetoacetyl-CoA NADH

Oxidizes (S)-3-hydroxybutyryl-CoA to acetoacetyl-CoA with NAD+. Msed_1423 is the main enzyme; the bifunctional Msed_0399 contributes little and may serve fatty acid metabolism.

PMID:32218776

Enzymes Catalyzing Crotonyl-CoA Conversion to Acetoacetyl-CoA During the Autotrophic CO(2) Fixation in Metallosphaera sedula.

The dehydrogenase Msed_1423, not the bifunctional Msed_0399, appears to be the main (S)-3-hydroxybutyryl-CoA dehydrogenase of the cycle; the paper also lists beta-ketothiolase paralogs of Msed_0656.

PMID:21169482

Identification of missing genes and enzymes for autotrophic carbon fixation in crenarchaeota

Identifies Msed_0399 as the bifunctional crotonyl-CoA hydratase/(S)-3-hydroxybutyryl-CoA dehydrogenase and points to the beta-ketothiolase gene Msed_0656.

PMID:34290692

(S)-3-Hydroxybutyryl-CoA Dehydrogenase From the Autotrophic 3-Hydroxypropionate/4-Hydroxybutyrate Cycle in Nitrosopumilus maritimus.

Restates that Msed_1423 is the main (S)-3-hydroxybutyryl-CoA dehydrogenase in M. sedula, with a kcat/Km about 20-fold higher than Msed_0399.

Part 7: acetoacetyl-CoA thiolysis

Acetoacetyl-CoA thiolysisReactionacetoacetyl_coa_thiolysis

Annotons

beta-Ketothiolase

thl

Participant: Family: acetoacetyl-CoA beta-ketothiolase

Family:

acetoacetyl-CoA beta-ketothiolase

Representative Members: Msed_0656 (Metallosphaera sedula)UniProtKB:A4YEH9

Function

acetyl-CoA C-acetyltransferase activityGO:0003985

Substrates: acetoacetyl-CoA CoA

Products: acetyl-CoA

Cleaves acetoacetyl-CoA into two acetyl-CoA, regenerating the starting molecule and releasing one acetyl-CoA as the product of the cycle. Several beta-ketothiolase paralogs (for example Msed_0386) may share the reaction in vivo (PMID:32218776).

PMID:21169482

Identification of missing genes and enzymes for autotrophic carbon fixation in crenarchaeota

Identifies Msed_0399 as the bifunctional crotonyl-CoA hydratase/(S)-3-hydroxybutyryl-CoA dehydrogenase and points to the beta-ketothiolase gene Msed_0656.

PMID:24532060

Conversion of 4-hydroxybutyrate to acetyl coenzyme A and its anapleurosis in the Metallosphaera sedula 3-hydroxypropionate/4-hydroxybutyrate carbon fixation pathway

Names the acetyl-CoA/propionyl-CoA carboxylase subunits Msed_0147, Msed_0148 and Msed_1375 among the genes most strongly upregulated under autotrophic growth.