Folate one-carbon carrier-state interconversion

A taxon-neutral module for interconversion of the substituted tetrahydrofolate carrier states 5,10-methylene-THF, 5,10-methenyl-THF, 10-formyl-THF, 5-methyl-THF, and the salvaged 5-formyl-THF pool. The module separates four chemically distinct transformations: pyridine-nucleotide-linked oxidation of 5,10-methylene-THF to 5,10-methenyl-THF, hydrolysis of 5,10-methenyl-THF to 10-formyl-THF, reduction of 5,10-methylene-THF to 5-methyl-THF, and ATP-dependent salvage of 5-formyl-THF to 5,10-methenyl-THF. Fused FolD/MTHFD architectures and NAD(H)- versus NADP(H)-linked variants are represented as alternative implementations of the same carrier-state conversions; eukaryotes such as yeasts add trifunctional C1-tetrahydrofolate synthases in the cytosol and mitochondria and, in some fungi, a monofunctional NAD-specific dehydrogenase that lacks cyclohydrolase activity. The dehydrogenase and cyclohydrolase operations form the required coupled core; MTHFR reduction and 5-formyl-THF salvage are independent optional branches. Upstream one-carbon loading by serine hydroxymethyltransferase, glycine cleavage, or formate-tetrahydrofolate ligase and downstream use by purine, thymidylate, or methionine synthesis are outside this module.

MODULE:folate_one_carbon_interconversionDRAFTCONCRETEMetabolic Pathwaymodules/folate_one_carbon_interconversion.yaml

tetrahydrofolate interconversionGO:0035999

GO:0035999

tetrahydrofolate interconversion

GO:0035999 is the specific biological-process term for interconversion of one-carbon-substituted tetrahydrofolate carrier states.

UniPathway:UPA00193

tetrahydrofolate interconversion

UniPathway UPA00193 provides the pathway route used by the selected Pseudomonas putida FolD and MetF proteins.

KEGG:ppu00670

One carbon pool by folate - Pseudomonas putida KT2440

KEGG ppu00670 supplies the organism-specific pathway context; broad members that only produce or consume one-carbon folates are outside the curated module boundary.

RHEA:22812

methylenetetrahydrofolate dehydrogenase (NADP+) reaction

RHEA:22812 specifies reversible oxidation of (6R)-5,10-methylene-THF by NADP+ to (6R)-5,10-methenyl-THF and NADPH.

file:genes/METEA/mtdA/mtdA-ai-review.yaml

Curated review of Methylorubrum extorquens AM1 MtdA (P55818)

The existing mtdA review and reviewed P55818 record ground an experimentally characterized monofunctional NADP-dependent implementation of RHEA:22812. THF is a secondary substrate, with lower catalytic efficiency than MtdA's primary H4MPT substrate, and MtdA does not supply the cyclohydrolase operation.

UniProtKB:Q49135

Methylorubrum extorquens AM1 FchA

Reviewed UniProt entry Q49135 identifies the separate monofunctional FchA that catalyzes RHEA:23700 in the same organism as the MtdA exemplar.

RHEA:22892

methylenetetrahydrofolate dehydrogenase (NAD+) reaction

RHEA:22892 specifies the corresponding reversible NAD+-linked carrier-state oxidation.

RHEA:23700

methenyltetrahydrofolate cyclohydrolase reaction

RHEA:23700 specifies reversible hydrolysis of (6R)-5,10-methenyl-THF to (6R)-10-formyl-THF.

RHEA:19821

methylenetetrahydrofolate reductase (NADH) reaction

RHEA:19821 specifies reversible NADH-linked reduction of 5,10-methylene-THF to 5-methyl-THF.

UniProtKB:O80585

Arabidopsis methylenetetrahydrofolate reductase (NADH) 2

Reviewed O80585 experimentally supports RHEA:19821 in a plant MTHFR with the eukaryotic catalytic and C-terminal regulatory domains. It is an explicit NADH-linked regulatory-architecture counterexample to assigning MTHFR cofactor specificity from taxonomic kingdom.

RHEA:19817

methylenetetrahydrofolate reductase (NADPH) reaction

RHEA:19817 specifies the corresponding reversible NADPH-linked carrier-state reduction represented here by human P42898.

UniProtKB:P42898

Human methylenetetrahydrofolate reductase (NADPH)

Reviewed P42898 assigns RHEA:19817 to an NADPH-dependent MTHFR with a C-terminal regulatory region, grounding this implementation without generalizing its cofactor preference to all proteins with that architecture.

RHEA:10488

5-formyltetrahydrofolate cyclo-ligase reaction

RHEA:10488 specifies ATP-dependent conversion of 5-formyl-THF to 5,10-methenyl-THF, the salvage reaction catalyzed by Fau/MTHFS.

YeastPathways:PWY3O-697

folate interconversions (S. cerevisiae, SGD YeastPathways)

Lists ADE3/MIS1 (NADP dehydrogenase, cyclohydrolase, formate ligase), MTD1 (NAD dehydrogenase), MET12/MET13 (MTHFR) together with SHM1/SHM2, CDC21, DFR1 and glycine cleavage, which are outside this module.

YeastPathways:PWY-2201

folate transformations I (S. cerevisiae, SGD YeastPathways)

Adds FAU1 (5-formyl-THF cyclo-ligase) and three MetaCyc reactions with no yeast gene (cobalamin-dependent methionine synthase, 10-formyl-THF deformylase, ferredoxin-dependent MTHFR, trimethylsulfonium methyltransferase).

PMID:2836393

Isolation and characterization of the Saccharomyces cerevisiae MIS1 gene encoding mitochondrial C1-tetrahydrofolate synthase.

Yeast has cytoplasmic (ADE3) and mitochondrial (MIS1) trifunctional C1-THF synthases; mis1 deletion has no detectable growth effect.

PMID:3514599

Nucleotide sequence of the Saccharomyces cerevisiae ADE3 gene encoding C1-tetrahydrofolate synthase.

ADE3 encodes the cytoplasmic trifunctional C1-THF synthase.

PMID:8464869

Function of yeast cytoplasmic C1-tetrahydrofolate synthase.

Functional analysis of the ADE3 C1-THF synthase domains.

PMID:8416923

Cloning and characterization of the Saccharomyces cerevisiae gene encoding NAD-dependent 5,10-methylenetetrahydrofolate dehydrogenase.

MTD1 encodes a monofunctional cytoplasmic NAD-dependent dehydrogenase.

PMID:10933503

The X-ray structure of the NAD-dependent 5,10-methylenetetrahydrofolate dehydrogenase from Saccharomyces cerevisiae.

MTD1 shares the MTHFD fold but has lost cyclohydrolase activity.

PMID:8608153

Metabolic role of cytoplasmic isozymes of 5,10-methylenetetrahydrofolate dehydrogenase in Saccharomyces cerevisiae.

MTD1 contributes in the oxidative direction only; ADE3 supplies the NADP-dependent activity.

PMID:10600168

Saccharomyces cerevisiae expresses two genes encoding isozymes of methylenetetrahydrofolate reductase.

MET12 and MET13 both encode MTHFR; only MET13 is required for methionine prototrophy.

PMID:11729203

Metabolic engineering in yeast demonstrates that S-adenosylmethionine controls flux through the methylenetetrahydrofolate reductase reaction in vivo.

MET13 MTHFR is NADPH-dependent and AdoMet-inhibited.

PMID:11923304

Cloning and characterization of methenyltetrahydrofolate synthetase from Saccharomyces cerevisiae.

FAU1 encodes the single yeast 5-formyl-THF cyclo-ligase.

PMID:8852837

In vivo analysis of folate coenzymes and their compartmentation in Saccharomyces cerevisiae.

Yeast cytosolic and mitochondrial one-carbon enzymes run in parallel, with mitochondria exporting formate.

PMID:1916088

Compartmentation of folate-mediated one-carbon metabolism in eukaryotes.

Review of compartmentation of one-carbon metabolism, cited by YeastPathways.

file:interpro/panther/PTHR48099/PTHR48099-entries.csv

PANTHER members for tetrahydrofolate dehydrogenase/cyclohydrolase

The local member table places both KT2440 FolD paralogs in PTHR48099:SF5 and human MTHFD1 in PTHR48099:SF1, despite PANTHER using the same generic cytoplasmic C1-THF synthase label for both subfamilies.

file:interpro/panther/PTHR48099/PTHR48099-paint.tsv

PANTHER PAINT annotations for tetrahydrofolate dehydrogenase/cyclohydrolase

Local PAINT data assign GO:0004477 at PTN000002250, bacterial GO:0004488 at PTN000002429, Euteleostomi GO:0004488 at PTN002878475, and NAD+-specific GO:0004487 at PTN002224686.

file:interpro/panther/PTHR45754/PTHR45754-entries.csv

PANTHER members for methylenetetrahydrofolate reductase

PTHR45754:SF3 contains both the bacterial NADH enzyme P0AEZ1 and human MTHFR P42898, as well as plant NADH-labeled members O80585, Q75HE6, and Q9SE94, despite its NADPH label. It is therefore not used to distinguish cofactor variants or to infer cofactor use from taxon.

file:interpro/panther/PTHR45754/PTHR45754-paint.tsv

PANTHER PAINT annotations for methylenetetrahydrofolate reductase

PANTHER PTHR45754 and PTN000472667 ground the conserved MTHFR family and its broad GO:0004489 activity without forcing a cofactor assignment; the local PAINT row does not support either cofactor-specific child term.

file:interpro/panther/PTHR23407/PTHR23407-paint.tsv

PANTHER PAINT annotations for 5-formyltetrahydrofolate cyclo-ligase

PANTHER PTHR23407 and PTN000601268 ground the conserved 5-formyl-THF salvage activity.

18Nodes

4Parts

3Variant Sets

13Variants

15Annotons

2Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✓ present

folate_one_carbon_interconversion-deep-research-openscientist.md (openscientist)

Leaf nodes lacking representative members

✓ every leaf node grounds to a representative protein.

Template conformance

✓ every declared conforms_to bundle matches its template motif.

Function consistency and core coverage

18 gene-function check(s) reflected in core functions · 0 conflict(s) · 7 evidence or coverage gap(s) (41 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
bacterial_fold_nadp_methylene_methenyl_activity	FolD1 (Pseudomonas putida KT2440) UniProtKB:Q88LI7 Family Representative	methylenetetrahydrofolate dehydrogenase (NADP+) activity GO:0004488	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bacterial_fold_nadp_methylene_methenyl_activity	FolD2 (Pseudomonas putida KT2440) UniProtKB:Q88KM5 Family Representative	methylenetetrahydrofolate dehydrogenase (NADP+) activity GO:0004488	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
bacterial_fold_nadp_methylene_methenyl_activity	FolD (Escherichia coli K-12) UniProtKB:P24186 Family Representative	methylenetetrahydrofolate dehydrogenase (NADP+) activity GO:0004488	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
monofunctional_mtda_nadp_methylene_methenyl_activity	ORTHOLOG_OF Gene	methylenetetrahydrofolate dehydrogenase (NADP+) activity GO:0004488	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
cytosolic_mthfd1_nadp_methylene_methenyl_activity	MTHFD1 (human) UniProtKB:P11586 Family Representative	methylenetetrahydrofolate dehydrogenase (NADP+) activity GO:0004488	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
cytosolic_c1thf_synthase_nadp_activity	ADE3 (Saccharomyces cerevisiae) UniProtKB:P07245 Family Representative	methylenetetrahydrofolate dehydrogenase (NADP+) activity GO:0004488	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
mitochondrial_c1thf_synthase_nadp_activity	MIS1 (Saccharomyces cerevisiae) UniProtKB:P09440 Family Representative	methylenetetrahydrofolate dehydrogenase (NADP+) activity GO:0004488	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
monofunctional_mtd1_nad_activity	MTD1 (Saccharomyces cerevisiae) UniProtKB:Q02046 Family Representative	methylenetetrahydrofolate dehydrogenase (NAD+) activity GO:0004487	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nad_methylene_methenyl_activity	MTHFD2 (human) UniProtKB:P13995 Family Representative	methylenetetrahydrofolate dehydrogenase (NAD+) activity GO:0004487	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fused_fold_mthfd_cyclohydrolase_activity	ADE3 (Saccharomyces cerevisiae) UniProtKB:P07245 Family Representative	methenyltetrahydrofolate cyclohydrolase activity GO:0004477	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fused_fold_mthfd_cyclohydrolase_activity	MIS1 (Saccharomyces cerevisiae) UniProtKB:P09440 Family Representative	methenyltetrahydrofolate cyclohydrolase activity GO:0004477	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fused_fold_mthfd_cyclohydrolase_activity	FolD1 (Pseudomonas putida KT2440) UniProtKB:Q88LI7 Family Representative	methenyltetrahydrofolate cyclohydrolase activity GO:0004477	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fused_fold_mthfd_cyclohydrolase_activity	FolD2 (Pseudomonas putida KT2440) UniProtKB:Q88KM5 Family Representative	methenyltetrahydrofolate cyclohydrolase activity GO:0004477	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fused_fold_mthfd_cyclohydrolase_activity	FolD (Escherichia coli K-12) UniProtKB:P24186 Family Representative	methenyltetrahydrofolate cyclohydrolase activity GO:0004477	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
fused_fold_mthfd_cyclohydrolase_activity	MTHFD1 (human) UniProtKB:P11586 Family Representative	methenyltetrahydrofolate cyclohydrolase activity GO:0004477	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fused_fold_mthfd_cyclohydrolase_activity	MTHFD2 (human) UniProtKB:P13995 Family Representative	methenyltetrahydrofolate cyclohydrolase activity GO:0004477	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
monofunctional_fcha_cyclohydrolase_activity	FchA (Methylorubrum extorquens AM1) UniProtKB:Q49135 Family Representative	methenyltetrahydrofolate cyclohydrolase activity GO:0004477	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
fungal_met13_nadph_mthfr_activity	MET13 (Saccharomyces cerevisiae) UniProtKB:P53128 Family Representative	methylenetetrahydrofolate reductase (NADPH) activity GO:0106313	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fungal_met12_mthfr_activity	MET12 (Saccharomyces cerevisiae) UniProtKB:P46151 Family Representative	methylenetetrahydrofolate reductase [NAD(P)H] activity GO:0004489	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nadh_mthfr_activity	MetF (Pseudomonas putida KT2440) UniProtKB:Q88D51 Family Representative	methylenetetrahydrofolate reductase (NADH) activity GO:0106312	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
nadh_mthfr_activity	MetF (Escherichia coli K-12) UniProtKB:P0AEZ1 Family Representative	methylenetetrahydrofolate reductase (NADH) activity GO:0106312	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
regulatory_nadh_mthfr_activity	ORTHOLOG_OF Gene	methylenetetrahydrofolate reductase (NADH) activity GO:0106312	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
nadph_mthfr_activity	ORTHOLOG_OF Gene	methylenetetrahydrofolate reductase (NADPH) activity GO:0106313	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
formyl_folate_cycloligase_activity	Fau (Pseudomonas putida KT2440) UniProtKB:Q88CH8 Family Representative	5-formyltetrahydrofolate cyclo-ligase activity GO:0030272	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
formyl_folate_cycloligase_activity	FAU1 (Saccharomyces cerevisiae) UniProtKB:P40099 Family Representative	5-formyltetrahydrofolate cyclo-ligase activity GO:0030272	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
formyl_folate_cycloligase_activity	YgfA (Escherichia coli K-12) UniProtKB:P0AC28 Family Representative	5-formyltetrahydrofolate cyclo-ligase activity GO:0030272	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
bacterial_fold_nadp_methylene_methenyl_activity	bifunctional FolD enzymes PANTHER:PTHR48099:SF5 Family	methylenetetrahydrofolate dehydrogenase (NADP+) activity GO:0004488	Family Supported Family review supports GO:0004488 for PANTHER:PTHR48099:SF5. NADP-dependent dehydrogenase, as folate_one_carbon_interconversion selects; accepted by MTHFD1, ADE3, MIS1 and P. putida FolD.
cytosolic_mthfd1_nadp_methylene_methenyl_activity	Euteleostomi cytosolic MTHFD1 enzymes PANTHER:PTHR48099:SF1 Family	methylenetetrahydrofolate dehydrogenase (NADP+) activity GO:0004488	Family Supported Family review supports GO:0004488 for PANTHER:PTHR48099:SF1. NADP-dependent dehydrogenase, as folate_one_carbon_interconversion selects; accepted by MTHFD1, ADE3, MIS1 and P. putida FolD.
cytosolic_c1thf_synthase_nadp_activity	fungal cytosolic trifunctional C1-THF synthases PANTHER:PTHR48099:SF5 Family	methylenetetrahydrofolate dehydrogenase (NADP+) activity GO:0004488	Family Supported Family review supports GO:0004488 for PANTHER:PTHR48099:SF5. NADP-dependent dehydrogenase, as folate_one_carbon_interconversion selects; accepted by MTHFD1, ADE3, MIS1 and P. putida FolD.
mitochondrial_c1thf_synthase_nadp_activity	fungal mitochondrial trifunctional C1-THF synthases PANTHER:PTHR48099:SF26 Family	methylenetetrahydrofolate dehydrogenase (NADP+) activity GO:0004488	Family Supported Family review supports GO:0004488 for PANTHER:PTHR48099:SF26. NADP-dependent dehydrogenase, as folate_one_carbon_interconversion selects; accepted by MTHFD1, ADE3, MIS1 and P. putida FolD.
monofunctional_mtd1_nad_activity	monofunctional NAD-dependent MTD1 enzymes PANTHER:PTHR48099:SF3 Family	methylenetetrahydrofolate dehydrogenase (NAD+) activity GO:0004487	Family Supported Family review supports GO:0004487 for PANTHER:PTHR48099:SF3. NAD-dependent dehydrogenase, as folate_one_carbon_interconversion selects for MTD1 and MTHFD2.
nad_methylene_methenyl_activity	mitochondrial MTHFD2 enzymes PANTHER:PTHR48099:SF15 Family	methylenetetrahydrofolate dehydrogenase (NAD+) activity GO:0004487	Family Supported Family review supports GO:0004487 for PANTHER:PTHR48099:SF15. NAD-dependent dehydrogenase, as folate_one_carbon_interconversion selects for MTD1 and MTHFD2.
fused_fold_mthfd_cyclohydrolase_activity	FolD/MTHFD methenyltetrahydrofolate cyclohydrolases PANTHER:PTHR48099:SF5 Family	methenyltetrahydrofolate cyclohydrolase activity GO:0004477	Family Supported Family review supports GO:0004477 for PANTHER:PTHR48099:SF5. Cyclohydrolase; accepted by MTHFD1, MTHFD2, ADE3, MIS1 and FolD. Not MTD1 or MTHFD1L, which PAINT negates.
fused_fold_mthfd_cyclohydrolase_activity	FolD/MTHFD methenyltetrahydrofolate cyclohydrolases PANTHER:PTHR48099:SF1 Family	methenyltetrahydrofolate cyclohydrolase activity GO:0004477	Family Supported Family review supports GO:0004477 for PANTHER:PTHR48099:SF1. Cyclohydrolase; accepted by MTHFD1, MTHFD2, ADE3, MIS1 and FolD. Not MTD1 or MTHFD1L, which PAINT negates.
fused_fold_mthfd_cyclohydrolase_activity	FolD/MTHFD methenyltetrahydrofolate cyclohydrolases PANTHER:PTHR48099:SF15 Family	methenyltetrahydrofolate cyclohydrolase activity GO:0004477	Family Supported Family review supports GO:0004477 for PANTHER:PTHR48099:SF15. Cyclohydrolase; accepted by MTHFD1, MTHFD2, ADE3, MIS1 and FolD. Not MTD1 or MTHFD1L, which PAINT negates.
fused_fold_mthfd_cyclohydrolase_activity	FolD/MTHFD methenyltetrahydrofolate cyclohydrolases PANTHER:PTHR48099:SF26 Family	methenyltetrahydrofolate cyclohydrolase activity GO:0004477	Family Supported Family review supports GO:0004477 for PANTHER:PTHR48099:SF26. Cyclohydrolase; accepted by MTHFD1, MTHFD2, ADE3, MIS1 and FolD. Not MTD1 or MTHFD1L, which PAINT negates.
monofunctional_fcha_cyclohydrolase_activity	monofunctional FchA cyclohydrolases InterPro:IPR054893 Family	methenyltetrahydrofolate cyclohydrolase activity GO:0004477	Family Review Missing No supported structured family review is available for InterPro:IPR054893.
fungal_met13_nadph_mthfr_activity	MET13-type MTHFR subfamily PANTHER:PTHR45754:SF3 Family	methylenetetrahydrofolate reductase (NADPH) activity GO:0106313	Family Supported Family review supports GO:0106313 for PANTHER:PTHR45754:SF3. NADPH-specific MTHFR (MET13-type), as folate_one_carbon_interconversion selects; accepted by MET13 and by S. pombe met11 (SF1, from the EC mapping). Bacterial MetF in SF3 uses NADH.
fungal_met12_mthfr_activity	MET12-type MTHFR subfamily PANTHER:PTHR45754:SF1 Family	methylenetetrahydrofolate reductase [NAD(P)H] activity GO:0004489	Family Supported Family review supports GO:0004489 FAMILY_WIDE. Asserted by methionine_cycle, homocysteine_metabolism and folate_one_carbon_interconversion; accepted by every reviewed member.
nadh_mthfr_activity	compact bacterial MetF enzymes InterPro:IPR004620 Family	methylenetetrahydrofolate reductase (NADH) activity GO:0106312	Family Review Missing No supported structured family review is available for InterPro:IPR004620.
formyl_folate_cycloligase_activity	Fau/MTHFS 5-formyltetrahydrofolate cyclo-ligases PANTHER:PTHR23407:SF1 Family	5-formyltetrahydrofolate cyclo-ligase activity GO:0030272	Family Supported Family review supports GO:0030272 FAMILY_WIDE. Asserted by folate_one_carbon_interconversion (SF1); accepted by FAU1 and P. putida Fau.

Gene-review completeness (14/19 grounded genes reviewed)

13 complete review(s) · 11 with deep research · 5 missing review · 3 reviewed but lacking deep research

Gene	Review	Complete	Deep research
ADE3 P07245	✓	✓	✓
fau Q88CH8	✓	✓	✓
FAU1 P40099	✓	✓	✓
folD1 Q88LI7	✓	✓	✓
folD2 Q88KM5	✓	✓	✓
MET12 P46151	✓	26/28	✓
MET13 P53128	✓	✓	✓
metF Q88D51	✓	✓	✓
MIS1 P09440	✓	✓	✓
MTD1 Q02046	✓	✓	✓
mtdA P55818	✓	✓	✓
MTHFD1 P11586	✓	✓	✗
MTHFD2 P13995	✓	✓	✗
MTHFR P42898	✓	✓	✗
MTHFR2 (Arabidopsis thaliana) O80585	✗	—	—
YgfA (Escherichia coli K-12) P0AC28	✗	—	—
MetF (Escherichia coli K-12) P0AEZ1	✗	—	—
FolD (Escherichia coli K-12) P24186	✗	—	—
FchA (Methylorubrum extorquens AM1) Q49135	✗	—	—

Tree

Folate one-carbon carrier-state interconversionMetabolic Pathwayfolate_one_carbon_interconversion

Parts
1. Required core 5,10-methylene-THF and 5,10-methenyl-THF redox interconversion
2. 5,10-methylene-THF to 5,10-methenyl-THF redoxReactionmethylene_methenyl_redox
  
  Variants
  1. Pyridine-nucleotide-linked dehydrogenase variants by redox cofactor and enzyme architecture (Exactly One)
    
    NADP-linked bifunctional FolD reactionReactionbacterial_fold_nadp_methylene_methenyl_variant
    
    Annotons
    
    Bacterial FolD NADP-linked dehydrogenase Family: bifunctional FolD enzymes
    
    NADP-linked monofunctional MtdA reactionReactionmonofunctional_mtda_nadp_methylene_methenyl_variant
    
    Annotons
    
    Monofunctional MtdA NADP-linked dehydrogenase Ortholog Of: MtdA (Methylorubrum extorquens AM1)
    
    NADP-linked cytosolic MTHFD1 reactionReactioncytosolic_mthfd1_nadp_methylene_methenyl_variant
    
    Annotons
    
    Cytosolic MTHFD1 NADP-linked dehydrogenase Family: Euteleostomi cytosolic MTHFD1 enzymes
    
    NADP-linked trifunctional C1-THF synthase reaction (fungal cytosolic and mitochondrial isozymes)Reactionfungal_c1thf_synthase_nadp_variant
    
    Annotons
    
    Cytosolic C1-THF synthase NADP-linked dehydrogenase (ADE3) Family: fungal cytosolic trifunctional C1-THF synthases
    
    Mitochondrial C1-THF synthase NADP-linked dehydrogenase (MIS1) Family: fungal mitochondrial trifunctional C1-THF synthases
    
    NAD-linked monofunctional MTD1 reaction (fungal cytosolic)Reactionmonofunctional_mtd1_nad_variant
    
    Annotons
    
    Monofunctional NAD-specific methylenetetrahydrofolate dehydrogenase (MTD1) Family: monofunctional NAD-dependent MTD1 enzymes
    
    NAD-linked MTHFD2 reactionReactionnad_methylene_methenyl_variant
    
    Annotons
    
    NAD-linked methylenetetrahydrofolate dehydrogenase Family: mitochondrial MTHFD2 enzymes
3. Required core 5,10-methenyl-THF and 10-formyl-THF hydrolytic interconversion
4. 5,10-methenyl-THF to 10-formyl-THF hydrolysisReactionmethenyl_formyl_hydrolysis
  
  Variants
  1. Methenyltetrahydrofolate cyclohydrolase architecture variants by fused versus monofunctional enzyme architecture (Exactly One)
    
    Fused FolD/MTHFD cyclohydrolase reactionReactionfused_fold_mthfd_cyclohydrolase_variant
    
    Annotons
    
    Fused FolD/MTHFD methenyltetrahydrofolate cyclohydrolase Family: FolD/MTHFD methenyltetrahydrofolate cyclohydrolases
    
    Monofunctional FchA cyclohydrolase reactionReactionmonofunctional_fcha_cyclohydrolase_variant
    
    Annotons
    
    Monofunctional FchA methenyltetrahydrofolate cyclohydrolase Family: monofunctional FchA cyclohydrolases
5. Optional 5,10-methylene-THF reduction to 5-methyl-THF branch optional
6. 5,10-methylene-THF to 5-methyl-THF reductionReactionmethylene_methyl_reduction
  
  Variants
  1. Methylenetetrahydrofolate reductase cofactor variants by pyridine-nucleotide specificity and enzyme architecture (Exactly One)
    
    NADPH-linked fungal MTHFR reaction (MET13-type)Reactionfungal_met13_nadph_mthfr_variant
    
    Annotons
    
    MET13-type NADPH methylenetetrahydrofolate reductase Family: MET13-type MTHFR subfamily
    
    MET12-type MTHFR isozyme reaction (cofactor unassigned)Reactionfungal_met12_mthfr_variant
    
    Annotons
    
    MET12-type methylenetetrahydrofolate reductase isozyme Family: MET12-type MTHFR subfamily
    
    NADH-linked compact MetF reactionReactionnadh_mthfr_variant
    
    Annotons
    
    NADH-linked methylenetetrahydrofolate reductase Family: compact bacterial MetF enzymes
    
    NADH-linked regulatory MTHFR reactionReactionregulatory_nadh_mthfr_variant
    
    Annotons
    
    Regulatory-architecture NADH methylenetetrahydrofolate reductase Ortholog Of: MTHFR2 (Arabidopsis thaliana)
    
    NADPH-linked regulatory MTHFR reactionReactionnadph_mthfr_variant
    
    Annotons
    
    NADPH-linked methylenetetrahydrofolate reductase Ortholog Of: MTHFR (human)
7. Optional 5-formyl-THF salvage to 5,10-methenyl-THF branch optional
8. 5-formyl-THF salvageReactionformyl_folate_salvage
  
  Annotons
  - 5-Formyltetrahydrofolate cyclo-ligase Family: Fau/MTHFS 5-formyltetrahydrofolate cyclo-ligases

Details

Folate one-carbon carrier-state interconversionMetabolic Pathwayfolate_one_carbon_interconversion

tetrahydrofolate interconversionGO:0035999

The module is organized by carrier-state chemistry rather than by one particular multidomain protein or species. Molecular-function terms are on leaf annotons. PANTHER families and selective UniProt representatives orient enzyme architecture and cofactor variants; exact PTNs are used only where the local canonical PAINT file carries the corresponding IBD assertion. Cofactor variants are defined by verified reaction and architecture rather than by taxonomic kingdom. The core dehydrogenase and cyclohydrolase operations are required, while the MTHFR and Fau branches are independently optional in concrete realizations. Formate ligation/release is treated as one-carbon loading or unloading and is excluded with SHMT and glycine-cleavage input. Purine, thymidylate, and methionine synthesis are consumers and are also outside the module. ALIGN with YeastPathways (2026-10; PWY3O-697, PWY-2201): S. cerevisiae exemplars were added for every in-scope reaction - ADE3 (cytosolic) and MIS1 (mitochondrial) trifunctional C1-THF synthases as a new NADP-linked variant and as fused cyclohydrolase representatives; MTD1 as a new monofunctional NAD-linked, cytosolic variant (the YeastCyc 1.5.1.15-RXN); MET13 as an NADPH MTHFR variant (PMID:11729203) and MET12 as a separate isozyme variant typed only with GO:0004489 because its cofactor preference and physiological role are not established; and FAU1 as a Fau/MTHFS representative. The boundary was not widened. SHM1/SHM2 (GLYOHMETRANS-RXN), suggested in the crosswalk, stay outside because serine hydroxymethyltransferase is one-carbon loading and is modelled in glycine_serine_interconversion; the formate-tetrahydrofolate ligase domains of ADE3/MIS1 (FORMATETHFLIG-RXN), CDC21 thymidylate synthase, DFR1 and the glycine cleavage system are likewise outside (formate ligation currently has no module and is a curation follow-up). The PWY-2201 reactions with no yeast gene (cobalamin-dependent methionine synthase HOMOCYSMETB12-RXN - yeast MET6 is cobalamin-independent -, 10-formyl-THF deformylase, ferredoxin-dependent MTHFR RXN-5061 and trimethylsulfonium methyltransferase 2.1.1.19-RXN) do not apply to S. cerevisiae. Compartments: MIS1 is mitochondrial and ADE3 and MTD1 cytosolic, whereas both GO-CAMs place every activity, including MIS1's, in cytosol/cytoplasm; FAU1 was detected in the mitochondrial proteome but the module does not assert its compartment. GO-CAM disagreements: YeastPathways_PWY-2201 (and FOLSYN-PWY-1) type METHYLENETHFDEHYDROG-NADP-RXN as GO:0004329 rather than GO:0004488; YeastPathways_PWY3O-697 uses GO:0046655 folic acid metabolic process rather than GO:0035999; the glycine cleavage complex is in mitochondrion in PWY3O-697 but cytosol in PWY-2201; and PWY-2201 has an unexplained causal edge from MTD1 to FAU1. YeastPathways writes the MTHFR reaction with NAD(H), but the physiological yeast enzyme MET13 uses NADPH.

Connections

methylene_methenyl_redox -> methenyl_formyl_hydrolysis Provides Input For

5,10-methenyl-THF produced by the dehydrogenase reaction is the cyclohydrolase substrate; the two activities are often fused but are chemically distinct.

formyl_folate_salvage -> methenyl_formyl_hydrolysis Provides Input For

Salvaged 5,10-methenyl-THF rejoins the methenyl/formyl carrier-state interconversion.

Part: Required core 5,10-methylene-THF and 5,10-methenyl-THF redox interconversion

5,10-methylene-THF to 5,10-methenyl-THF redoxReactionmethylene_methenyl_redox

Reversible pyridine-nucleotide-linked oxidation of 5,10-methylene-THF to 5,10-methenyl-THF. Organisms and compartments use NADP+- or NAD+-linked members of the FolD/MTHFD family.

Variant set: Pyridine-nucleotide-linked dehydrogenase variants by redox cofactor and enzyme architecture (Exactly One)

NADP-linked bifunctional FolD reactionReactionbacterial_fold_nadp_methylene_methenyl_variant

Annotons

Bacterial FolD NADP-linked dehydrogenase

bacterial_fold_nadp_methylene_methenyl_activity

Participant: Family: bifunctional FolD enzymes

Family:

bifunctional FolD enzymesPANTHER:PTHR48099:SF5

Representative Members: FolD1 (Pseudomonas putida KT2440)UniProtKB:Q88LI7 FolD2 (Pseudomonas putida KT2440)UniProtKB:Q88KM5 FolD (Escherichia coli K-12)UniProtKB:P24186

Taxon:

bacteriaNCBITaxon:2 PTN000002429 is the bacterial GO:0004488 function node; SF5 members outside bacteria are not selected by this implementation.

Function

methylenetetrahydrofolate dehydrogenase (NADP+) activityGO:0004488

Substrates: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolateCHEBI:15636 NADP+CHEBI:58349

Products: (6R)-5,10-methenyltetrahydrofolateCHEBI:57455 NADPHCHEBI:57783

Bifunctional FolD implements the NADP-linked reaction together with the separately modeled cyclohydrolase activity in the same polypeptide.

NADP-linked monofunctional MtdA reactionReactionmonofunctional_mtda_nadp_methylene_methenyl_variant

Annotons

Monofunctional MtdA NADP-linked dehydrogenase

monofunctional_mtda_nadp_methylene_methenyl_activity

Participant: Ortholog Of: MtdA (Methylorubrum extorquens AM1)

Ortholog Of:

MtdA (Methylorubrum extorquens AM1)UniProtKB:P55818

Orthologs of experimentally characterized P55818 that retain its dual-carrier NADP-dependent dehydrogenase function; its two InterPro records describe domains and are not alternative family selectors.

Function

methylenetetrahydrofolate dehydrogenase (NADP+) activityGO:0004488

Substrates: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolateCHEBI:15636 NADP+CHEBI:58349

Products: (6R)-5,10-methenyltetrahydrofolateCHEBI:57455 NADPHCHEBI:57783

MtdA provides a monofunctional NADP-linked dehydrogenase architecture. It requires a separate cyclohydrolase such as FchA for the coupled core and primarily acts on H4MPT; only its experimentally observed THF reaction is in scope.

NADP-linked cytosolic MTHFD1 reactionReactioncytosolic_mthfd1_nadp_methylene_methenyl_variant

Annotons

Cytosolic MTHFD1 NADP-linked dehydrogenase

cytosolic_mthfd1_nadp_methylene_methenyl_activity

Participant: Family: Euteleostomi cytosolic MTHFD1 enzymes

Family:

Euteleostomi cytosolic MTHFD1 enzymesPANTHER:PTHR48099:SF1

Representative Members: MTHFD1 (human)UniProtKB:P11586

Taxon:

EuteleostomiNCBITaxon:117571 The PTN002878475 GO:0004488 assertion is scoped to this bony-vertebrate clade; broader eukaryotic MTHFD1 coverage is not inferred from this node.

Function

methylenetetrahydrofolate dehydrogenase (NADP+) activityGO:0004488

Substrates: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolateCHEBI:15636 NADP+CHEBI:58349

Products: (6R)-5,10-methenyltetrahydrofolateCHEBI:57455 NADPHCHEBI:57783

Euteleostomi cytosolic MTHFD1 implements the same NADP-linked reaction in a larger multidomain C1-THF synthase.

NADP-linked trifunctional C1-THF synthase reaction (fungal cytosolic and mitochondrial isozymes)Reactionfungal_c1thf_synthase_nadp_variant

Fungi such as S. cerevisiae express two trifunctional C1-tetrahydrofolate synthases (dehydrogenase, cyclohydrolase and formate-tetrahydrofolate ligase domains): cytosolic ADE3 and mitochondrial MIS1 (PMID:2836393). Only the dehydrogenase operation is modelled here; the formate ligase domain is one-carbon loading and outside the module.

Annotons

Cytosolic C1-THF synthase NADP-linked dehydrogenase (ADE3)

cytosolic_c1thf_synthase_nadp_activity

Participant: Family: fungal cytosolic trifunctional C1-THF synthases

Family:

fungal cytosolic trifunctional C1-THF synthasesPANTHER:PTHR48099:SF5

Representative Members: ADE3 (Saccharomyces cerevisiae)UniProtKB:P07245

Function

methylenetetrahydrofolate dehydrogenase (NADP+) activityGO:0004488

Locations

cytosolGO:0005829

Cytosolic NADP-linked dehydrogenase domain; in yeast it works alongside the NAD-specific MTD1.

Mitochondrial C1-THF synthase NADP-linked dehydrogenase (MIS1)

mitochondrial_c1thf_synthase_nadp_activity

Participant: Family: fungal mitochondrial trifunctional C1-THF synthases

Family:

fungal mitochondrial trifunctional C1-THF synthasesPANTHER:PTHR48099:SF26

Representative Members: MIS1 (Saccharomyces cerevisiae)UniProtKB:P09440

Function

methylenetetrahydrofolate dehydrogenase (NADP+) activityGO:0004488

Locations

mitochondrionGO:0005739

Mitochondrial NADP-linked dehydrogenase domain; MIS1 is not required for growth (PMID:2836393).

NAD-linked monofunctional MTD1 reaction (fungal cytosolic)Reactionmonofunctional_mtd1_nad_variant

Annotons

Monofunctional NAD-specific methylenetetrahydrofolate dehydrogenase (MTD1)

monofunctional_mtd1_nad_activity

Participant: Family: monofunctional NAD-dependent MTD1 enzymes

Family:

monofunctional NAD-dependent MTD1 enzymesPANTHER:PTHR48099:SF3

Representative Members: MTD1 (Saccharomyces cerevisiae)UniProtKB:Q02046

Function

methylenetetrahydrofolate dehydrogenase (NAD+) activityGO:0004487

Substrates: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolateCHEBI:15636 NAD+CHEBI:57540

Products: (6R)-5,10-methenyltetrahydrofolateCHEBI:57455 NADHCHEBI:57945

Locations

cytosolGO:0005829

Distantly related member of the MTHFD fold that has lost the cyclohydrolase activity (PMID:10933503); it requires a separate cyclohydrolase (the ADE3 domain) for the coupled core and acts mainly in the oxidative direction.

NAD-linked MTHFD2 reactionReactionnad_methylene_methenyl_variant

Annotons

NAD-linked methylenetetrahydrofolate dehydrogenase

nad_methylene_methenyl_activity

Participant: Family: mitochondrial MTHFD2 enzymes

Family:

mitochondrial MTHFD2 enzymesPANTHER:PTHR48099:SF15

Representative Members: MTHFD2 (human)UniProtKB:P13995

Function

methylenetetrahydrofolate dehydrogenase (NAD+) activityGO:0004487

Substrates: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolateCHEBI:15636 NAD+CHEBI:57540

Products: (6R)-5,10-methenyltetrahydrofolateCHEBI:57455 NADHCHEBI:57945

Locations

mitochondrial matrixGO:0005759

Mitochondrial MTHFD2-family enzymes implement the NAD-linked version in metazoans and related lineages.

Part: Required core 5,10-methenyl-THF and 10-formyl-THF hydrolytic interconversion

5,10-methenyl-THF to 10-formyl-THF hydrolysisReactionmethenyl_formyl_hydrolysis

Reversible hydrolysis of 5,10-methenyl-THF to 10-formyl-THF can be supplied by the cyclohydrolase domain of a fused FolD/MTHFD enzyme or by a separate monofunctional FchA enzyme.

Variant set: Methenyltetrahydrofolate cyclohydrolase architecture variants by fused versus monofunctional enzyme architecture (Exactly One)

Fused FolD/MTHFD cyclohydrolase reactionReactionfused_fold_mthfd_cyclohydrolase_variant

Annotons

Fused FolD/MTHFD methenyltetrahydrofolate cyclohydrolase

fused_fold_mthfd_cyclohydrolase_activity

Participant: Family: FolD/MTHFD methenyltetrahydrofolate cyclohydrolases

Family:

FolD/MTHFD methenyltetrahydrofolate cyclohydrolases

Representative Members: ADE3 (Saccharomyces cerevisiae)UniProtKB:P07245 MIS1 (Saccharomyces cerevisiae)UniProtKB:P09440 FolD1 (Pseudomonas putida KT2440)UniProtKB:Q88LI7 FolD2 (Pseudomonas putida KT2440)UniProtKB:Q88KM5 FolD (Escherichia coli K-12)UniProtKB:P24186 MTHFD1 (human)UniProtKB:P11586 MTHFD2 (human)UniProtKB:P13995

Function

methenyltetrahydrofolate cyclohydrolase activityGO:0004477

Substrates: (6R)-5,10-methenyltetrahydrofolateCHEBI:57455 waterCHEBI:15377

Products: (6R)-10-formyltetrahydrofolateCHEBI:195366 hydronCHEBI:15378

FolD, mitochondrial MTHFD2, and larger MTHFD architectures (including the fungal trifunctional ADE3 and MIS1 C1-THF synthases) fuse this operation to a methylene-THF dehydrogenase.

Monofunctional FchA cyclohydrolase reactionReactionmonofunctional_fcha_cyclohydrolase_variant

Annotons

Monofunctional FchA methenyltetrahydrofolate cyclohydrolase

monofunctional_fcha_cyclohydrolase_activity

Participant: Family: monofunctional FchA cyclohydrolases

Family:

monofunctional FchA cyclohydrolasesInterPro:IPR054893

Representative Members: FchA (Methylorubrum extorquens AM1)UniProtKB:Q49135

Function

methenyltetrahydrofolate cyclohydrolase activityGO:0004477

Substrates: (6R)-5,10-methenyltetrahydrofolateCHEBI:57455 waterCHEBI:15377

Products: (6R)-10-formyltetrahydrofolateCHEBI:195366 hydronCHEBI:15378

FchA supplies this operation as a separate protein, as in the experimentally grounded MtdA/FchA implementation.

Part: Optional 5,10-methylene-THF reduction to 5-methyl-THF branch (optional)

5,10-methylene-THF to 5-methyl-THF reductionReactionmethylene_methyl_reduction

FAD-dependent methylenetetrahydrofolate reductases use different pyridine-nucleotide cofactors in different enzyme architectures. Cofactor specificity is not inferred from organismal kingdom. The carrier-state product is modeled here; methionine synthase consumption of 5-methyl-THF is downstream.

Variant set: Methylenetetrahydrofolate reductase cofactor variants by pyridine-nucleotide specificity and enzyme architecture (Exactly One)

NADPH-linked fungal MTHFR reaction (MET13-type)Reactionfungal_met13_nadph_mthfr_variant

Annotons

MET13-type NADPH methylenetetrahydrofolate reductase

fungal_met13_nadph_mthfr_activity

Participant: Family: MET13-type MTHFR subfamily

Family:

MET13-type MTHFR subfamilyPANTHER:PTHR45754:SF3 The subfamily also contains NADH-dependent enzymes (see the PTHR45754 evidence note), so the cofactor is asserted from the yeast exemplar, not the family.

Representative Members: MET13 (Saccharomyces cerevisiae)UniProtKB:P53128

Function

methylenetetrahydrofolate reductase (NADPH) activityGO:0106313

Cofactors: FADCHEBI:57692

AdoMet-inhibited fungal MTHFR supplying 5-methyl-THF for methionine synthesis.

MET12-type MTHFR isozyme reaction (cofactor unassigned)Reactionfungal_met12_mthfr_variant

Annotons

MET12-type methylenetetrahydrofolate reductase isozyme

fungal_met12_mthfr_activity

Participant: Family: MET12-type MTHFR subfamily

Family:

MET12-type MTHFR subfamilyPANTHER:PTHR45754:SF1

Representative Members: MET12 (Saccharomyces cerevisiae)UniProtKB:P46151

Function

methylenetetrahydrofolate reductase [NAD(P)H] activityGO:0004489

Minor isozyme with uncharacterised cofactor preference and physiological role.

NADH-linked compact MetF reactionReactionnadh_mthfr_variant

Annotons

NADH-linked methylenetetrahydrofolate reductase

nadh_mthfr_activity

Participant: Family: compact bacterial MetF enzymes

Family:

compact bacterial MetF enzymesInterPro:IPR004620

Representative Members: MetF (Pseudomonas putida KT2440)UniProtKB:Q88D51 MetF (Escherichia coli K-12)UniProtKB:P0AEZ1

Function

methylenetetrahydrofolate reductase (NADH) activityGO:0106312

Substrates: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolateCHEBI:15636 NADHCHEBI:57945 hydronCHEBI:15378

Products: (6S)-5-methyl-5,6,7,8-tetrahydrofolateCHEBI:18608 NAD+CHEBI:57540

Cofactors: FADCHEBI:57692

Compact MetF proteins Q88D51 and P0AEZ1 exemplify this verified NADH-linked implementation; taxon alone is not a cofactor selector.

NADH-linked regulatory MTHFR reactionReactionregulatory_nadh_mthfr_variant

Annotons

Regulatory-architecture NADH methylenetetrahydrofolate reductase

regulatory_nadh_mthfr_activity

Participant: Ortholog Of: MTHFR2 (Arabidopsis thaliana)

Ortholog Of:

MTHFR2 (Arabidopsis thaliana)UniProtKB:O80585

Orthologs of experimentally characterized O80585 whose NADH dependence is established independently; the catalytic and SAM-binding InterPro domains specify architecture but not pyridine-nucleotide preference.

Function

methylenetetrahydrofolate reductase (NADH) activityGO:0106312

Substrates: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolateCHEBI:15636 NADHCHEBI:57945 hydronCHEBI:15378

Products: (6S)-5-methyl-5,6,7,8-tetrahydrofolateCHEBI:18608 NAD+CHEBI:57540

Cofactors: FADCHEBI:57692

Arabidopsis O80585 demonstrates that an MTHFR with the eukaryotic catalytic and regulatory architecture can use NADH; neither cofactor nor architecture follows from kingdom alone.

NADPH-linked regulatory MTHFR reactionReactionnadph_mthfr_variant

Annotons

NADPH-linked methylenetetrahydrofolate reductase

nadph_mthfr_activity

Participant: Ortholog Of: MTHFR (human)

Ortholog Of:

MTHFR (human)UniProtKB:P42898

Orthologs of experimentally characterized P42898 whose NADPH dependence is established independently; broad MTHFR family and regulatory-domain records do not select this cofactor specificity.

Function

methylenetetrahydrofolate reductase (NADPH) activityGO:0106313

Substrates: (6R)-5,10-methylene-5,6,7,8-tetrahydrofolateCHEBI:15636 NADPHCHEBI:57783 hydronCHEBI:15378

Products: (6S)-5-methyl-5,6,7,8-tetrahydrofolateCHEBI:18608 NADP+CHEBI:58349

Cofactors: FADCHEBI:57692

Human P42898 exemplifies an NADPH-linked implementation with a regulatory domain; this architecture is not used as a kingdom-wide cofactor rule.

Part: Optional 5-formyl-THF salvage to 5,10-methenyl-THF branch (optional)

5-formyl-THF salvageReactionformyl_folate_salvage

Annotons

5-Formyltetrahydrofolate cyclo-ligase

formyl_folate_cycloligase_activity

Participant: Family: Fau/MTHFS 5-formyltetrahydrofolate cyclo-ligases

Family:

Fau/MTHFS 5-formyltetrahydrofolate cyclo-ligasesPANTHER:PTHR23407:SF1

Representative Members: Fau (Pseudomonas putida KT2440)UniProtKB:Q88CH8 FAU1 (Saccharomyces cerevisiae)UniProtKB:P40099 YgfA (Escherichia coli K-12)UniProtKB:P0AC28

Function

5-formyltetrahydrofolate cyclo-ligase activityGO:0030272

Substrates: (6S)-5-formyl-5,6,7,8-tetrahydrofolateCHEBI:57457 ATPCHEBI:30616

Products: (6R)-5,10-methenyltetrahydrofolateCHEBI:57455 ADPCHEBI:456216 phosphateCHEBI:43474

Fau/MTHFS removes the stable 5-formyl-THF trap by returning its one-carbon unit to the 5,10-methenyl-THF pool.