De novo tetrahydrofolate and folylpolyglutamate biosynthesis

De novo synthesis of tetrahydrofolate (THF) and its polyglutamylated forms, as found in bacteria, fungi, plants and many protists but absent from animals, which must take up preformed folate. The pathway joins two branches. In the pterin branch, GTP cyclohydrolase I opens the GTP imidazole ring to give 7,8-dihydroneopterin triphosphate; the triphosphate is removed (a Nudix-type pyrophosphatase followed by a phosphatase) to give 7,8-dihydroneopterin; dihydroneopterin aldolase releases glycolaldehyde to give 6-hydroxymethyl-7,8-dihydropterin; and 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase activates it as the diphosphate. In the p-aminobenzoate (pABA) branch, chorismate is aminated by glutamine-dependent aminodeoxychorismate synthase and 4-amino-4-deoxychorismate is cleaved by aminodeoxychorismate lyase to pABA and pyruvate. Dihydropteroate synthase condenses the pterin diphosphate with pABA to 7,8-dihydropteroate, dihydrofolate synthase adds the first L-glutamate to give 7,8-dihydrofolate, and dihydrofolate reductase reduces it with NADPH to THF. Folylpolyglutamate synthase then adds further gamma-linked glutamates, which retain folates in cells and organelles and make them preferred cofactors of folate-dependent enzymes. The reaction chain is conserved, but enzyme architecture varies: dihydroneopterin aldolase, pyrophosphokinase and dihydropteroate synthase are separate proteins in many bacteria and a single trifunctional polypeptide in fungi; aminodeoxychorismate synthase is a two-subunit PabA-PabB enzyme in many bacteria and a fused polypeptide in fungi and plants; and dihydrofolate synthase and folylpolyglutamate synthase are one bifunctional FolC protein in many bacteria but separate proteins in fungi and plants. In eukaryotes the steps are split between compartments (for example, the fungal trifunctional pterin enzyme and plant dihydrofolate synthase are mitochondrial). Chorismate supply, folate salvage and transport, and the interconversion and use of one-carbon-substituted THF are outside the module.

MODULE:tetrahydrofolate_biosynthesisDRAFTMetabolic Pathwaymodules/tetrahydrofolate_biosynthesis.yaml

tetrahydrofolate biosynthetic processGO:0046654 tetrahydrofolylpolyglutamate biosynthetic processGO:0046901

YeastPathways:FOLSYN-PWY-1

superpathway of tetrahydrofolate biosynthesis and salvage (S. cerevisiae, SGD YeastPathways)

Superpathway combining de novo THF synthesis with one-carbon interconversion reactions (SHM1/SHM2, ADE3/MIS1, MTD1, MET12/MET13, CDC21, glycine cleavage). Only the biosynthetic reactions are modelled here; the interconversion reactions belong to folate_one_carbon_interconversion and neighbouring modules.

YeastPathways:PWY3O-45

folate biosynthesis II (S. cerevisiae, SGD YeastPathways)

Lists the ten de novo reactions from GTP and chorismate to THF with FOL2, FOL1 (DHNA, HPPK and DHPS), ABZ1, ABZ2, FOL3 and DFR1 as catalysts. The dihydroneopterin triphosphate pyrophosphatase and dihydroneopterin monophosphate phosphatase reactions have no assigned gene.

YeastPathways:PWY-6147

6-hydroxymethyl-dihydropterin diphosphate biosynthesis I (S. cerevisiae, SGD YeastPathways)

Pterin-branch subpathway (FOL2, FOL1; two dephosphorylation steps without genes).

YeastPathways:PWY-6614

tetrahydrofolate biosynthesis (S. cerevisiae, SGD YeastPathways)

Dihydropteroate synthase, dihydrofolate synthase and dihydrofolate reductase (FOL1, FOL3, DFR1).

YeastPathways:PWY-6543

4-aminobenzoate biosynthesis (S. cerevisiae, SGD YeastPathways)

pABA branch (ABZ1, ABZ2).

YeastPathways:PWY3O-1874

p-aminobenzoate biosynthesis (S. cerevisiae, SGD YeastPathways)

Duplicate representation of the pABA branch (ABZ1, ABZ2).

YeastPathways:PWY3O-20

folate polyglutamylation (S. cerevisiae, SGD YeastPathways)

FOL3 adds the first glutamate and MET7 extends the glutamate chain on dihydrofolate, THF, 5,10-methylene-THF, 5-methyl-THF and 10-formyl-THF. The pathway also lists SHM1/SHM2, MET12/MET13, ADE3/MIS1 and DFR1 reactions that are interconversion, not polyglutamylation.

GO:0046654

tetrahydrofolate biosynthetic process

Module-level process term for de novo THF formation.

GO:0046901

tetrahydrofolylpolyglutamate biosynthetic process

Process term for the polyglutamylation part of the module.

GO:0008153

4-aminobenzoate biosynthetic process

Process term for the pABA branch.

PMID:15169867

Characterization of the Saccharomyces cerevisiae Fol1 protein: starvation for C1 carrier induces pseudohyphal growth.

Fol1p catalyses the DHNA, HPPK and DHPS steps, is essential, and is located only in mitochondria.

PMID:15826662

The three-dimensional structure of the bifunctional 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase/dihydropteroate synthase of Saccharomyces cerevisiae.

In fungi DHNA, HPPK and DHPS are one polypeptide whose HPPK and DHPS domains each resemble the monofunctional bacterial enzymes.

PMID:10049741

Complementation of the fol2 deletion in Saccharomyces cerevisiae by human and Escherichia coli genes encoding GTP cyclohydrolase I.

fol2 deletion causes folinic acid auxotrophy, rescued by E. coli folE or human GTP cyclohydrolase I.

PMID:17698004

Structure and function of the E. coli dihydroneopterin triphosphate pyrophosphatase: a Nudix enzyme involved in folate biosynthesis.

E. coli NudB (orf17) removes pyrophosphate from dihydroneopterin triphosphate, and its knockout markedly reduces folate synthesis.

PMID:8346682

Para-aminobenzoate synthase gene of Saccharomyces cerevisiae encodes a bifunctional enzyme.

The yeast PABA synthase gene (ABZ1) encodes one protein similar to both E. coli PabA and PabB.

PMID:17873082

A chemogenomic screening of sulfanilamide-hypersensitive Saccharomyces cerevisiae mutants uncovers ABZ2, the gene encoding a fungal aminodeoxychorismate lyase.

Identifies ABZ2 as the fungal aminodeoxychorismate lyase.

PMID:10799479

Polyglutamylation of folate coenzymes is necessary for methionine biosynthesis and maintenance of intact mitochondrial genome in Saccharomyces cerevisiae.

FOL3 (YMR113w) encodes dihydrofolate synthetase and MET7 encodes folylpolyglutamate synthetase; fol3 mutants require folinic acid.

PMID:10775416

Disruption of cytoplasmic and mitochondrial folylpolyglutamate synthetase activity in Saccharomyces cerevisiae.

MET7 appears to encode both the cytoplasmic and mitochondrial folylpolyglutamate synthetase activities.

PMID:2985605

Folylpoly-gamma-glutamate synthetase-dihydrofolate synthetase. Cloning and high expression of the Escherichia coli folC gene and purification and properties of the gene product.

Both glutamate-adding activities of E. coli are catalysed by the single FolC protein.

PMID:11752472

Tetrahydrofolate biosynthesis in plants: molecular and functional characterization of dihydrofolate synthetase and three isoforms of folylpolyglutamate synthetase in Arabidopsis thaliana.

Plant DHFS is mitochondrial and separate from FPGS, which has mitochondrial, cytosolic and plastid isoforms.

PMID:18804690

Folate-mediated one-carbon metabolism.

Review cited by YeastPathways for the folate pathways.

20Nodes

9Parts

5Variant Sets

10Variants

19Annotons

7Connections

Derived QC

Recommended-field compliance

100.0% recommended fields populated

All recommended fields populated.

Module deep research

✗ none found

No MODULE:tetrahydrofolate_biosynthesis 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.

gtp_cyclohydrolase_step → dihydroneopterin_dephosphorylation_step [NOT_CHECKED]
dihydroneopterin_dephosphorylation_step → pterin_activation_and_condensation_steps [NOT_CHECKED]
pterin_activation_and_condensation_steps → dihydrofolate_synthase_step [NOT_CHECKED]
dihydrofolate_synthase_step → dihydrofolate_reductase_step [NOT_CHECKED]
dihydrofolate_reductase_step → polyglutamylation_step [NOT_CHECKED]

Function consistency and core coverage

18 gene-function check(s) reflected in core functions · 0 conflict(s) · 13 evidence or coverage gap(s) (47 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
gtp_cyclohydrolase_i_activity	FOL2 (Saccharomyces cerevisiae) UniProtKB:P51601 Family Representative	GTP cyclohydrolase I activity GO:0003934	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gtp_cyclohydrolase_i_activity	fol2 (Schizosaccharomyces pombe) UniProtKB:O13774 Family Representative	GTP cyclohydrolase I activity GO:0003934	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
gtp_cyclohydrolase_i_activity	FolE (Escherichia coli K-12) UniProtKB:P0A6T5 Family Representative	GTP cyclohydrolase I activity GO:0003934	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
dhntp_pyrophosphatase_activity	ORTHOLOG_OF Gene	dihydroneopterin triphosphate pyrophosphohydrolase activity GO:0019177	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
dhnmp_phosphatase_activity	ANY_WITH_FUNCTION Gene	dihydroneopterin monophosphate phosphatase activity GO:0019176	Participant Unchecked No direct UniProt participant to compare. Abstract selectors and complex-wide activities cannot be inferred from donor or subunit gene reviews.
folB_dhna_activity	FolB (Escherichia coli K-12) UniProtKB:P0AC16 Family Representative	dihydroneopterin aldolase activity GO:0004150	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
folK_hppk_activity	FolK (Escherichia coli K-12) UniProtKB:P26281 Family Representative	2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase activity GO:0003848	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
folP_dhps_activity	FolP (Escherichia coli K-12) UniProtKB:P0AC13 Family Representative	dihydropteroate synthase activity GO:0004156	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
fol1_dhna_activity	FOL1 (Saccharomyces cerevisiae) UniProtKB:P53848 Family Representative	dihydroneopterin aldolase activity GO:0004150	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fol1_dhna_activity	fol1 (Schizosaccharomyces pombe) UniProtKB:Q4LB35 Family Representative	dihydroneopterin aldolase activity GO:0004150	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fol1_hppk_activity	FOL1 (Saccharomyces cerevisiae) UniProtKB:P53848 Family Representative	2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase activity GO:0003848	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fol1_hppk_activity	fol1 (Schizosaccharomyces pombe) UniProtKB:Q4LB35 Family Representative	2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase activity GO:0003848	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fol1_dhps_activity	FOL1 (Saccharomyces cerevisiae) UniProtKB:P53848 Family Representative	dihydropteroate synthase activity GO:0004156	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fol1_dhps_activity	fol1 (Schizosaccharomyces pombe) UniProtKB:Q4LB35 Family Representative	dihydropteroate synthase activity GO:0004156	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fused_adcs_activity	ABZ1 (Saccharomyces cerevisiae) UniProtKB:P37254 Family Representative	aminodeoxychorismate synthase activity GO:0046820	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fused_adcs_activity	abz1 (Schizosaccharomyces pombe) UniProtKB:O94277 Family Representative	aminodeoxychorismate synthase activity GO:0046820	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pabB_adcs_activity	PabB (Escherichia coli K-12) UniProtKB:P05041 Family Representative	aminodeoxychorismate synthase activity GO:0046820	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
pabA_glutaminase_activity	PabA (Escherichia coli K-12) UniProtKB:P00903 Family Representative	glutaminase activity GO:0004359	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
fungal_adc_lyase_activity	ABZ2 (Saccharomyces cerevisiae) UniProtKB:Q03266 Family Representative	4-amino-4-deoxychorismate lyase activity GO:0008696	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
fungal_adc_lyase_activity	abz2 (Schizosaccharomyces pombe) UniProtKB:O42951 Family Representative	4-amino-4-deoxychorismate lyase activity GO:0008696	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
pabC_adc_lyase_activity	PabC (Escherichia coli K-12) UniProtKB:P28305 Family Representative	4-amino-4-deoxychorismate lyase activity GO:0008696	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
monofunctional_dhfs_activity	FOL3 (Saccharomyces cerevisiae) UniProtKB:Q12676 Family Representative	dihydrofolate synthase activity GO:0008841	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
monofunctional_dhfs_activity	fol3 (Schizosaccharomyces pombe) UniProtKB:Q9UTD0 Family Representative	dihydrofolate synthase activity GO:0008841	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
folC_dhfs_activity	FolC (Escherichia coli K-12) UniProtKB:P08192 Family Representative	dihydrofolate synthase activity GO:0008841	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
dhfr_activity	DFR1 (Saccharomyces cerevisiae) UniProtKB:P07807 Family Representative	dihydrofolate reductase activity GO:0004146	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dhfr_activity	dfr1 (Schizosaccharomyces pombe) UniProtKB:P36591 Family Representative	dihydrofolate reductase activity GO:0004146	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
dhfr_activity	FolA (Escherichia coli K-12) UniProtKB:P0ABQ4 Family Representative	dihydrofolate reductase activity GO:0004146	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
monofunctional_fpgs_activity	MET7 (Saccharomyces cerevisiae) UniProtKB:Q08645 Family Representative	tetrahydrofolylpolyglutamate synthase activity GO:0004326	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
monofunctional_fpgs_activity	met7 (Schizosaccharomyces pombe) UniProtKB:O74742 Family Representative	tetrahydrofolylpolyglutamate synthase activity GO:0004326	Core Supported The GO molecular function is reflected in core_functions (exact term or a reviewed subclass).
folC_fpgs_activity	FolC (Escherichia coli K-12) UniProtKB:P08192 Family Representative	tetrahydrofolylpolyglutamate synthase activity GO:0004326	Review Missing No ai-review exists for this protein; its function and core-function coverage cannot yet be checked.
gtp_cyclohydrolase_i_activity	GTP cyclohydrolase I (FolE type) PANTHER:PTHR11109:SF7 Family	GTP cyclohydrolase I activity GO:0003934	Family Supported Family review supports GO:0003934 FAMILY_WIDE. Asserted by tetrahydrofolate_biosynthesis (SF7) and tetrahydrobiopterin_metabolism (base family); accepted by FOL2, SPAC17A5.13 and GCH1.
folB_dhna_activity	FolB dihydroneopterin aldolases PANTHER:PTHR42844:SF1 Family	dihydroneopterin aldolase activity GO:0004150	Family Supported Family review supports GO:0004150 for PANTHER:PTHR42844:SF1. FolB (SF1), as tetrahydrofolate_biosynthesis selects. No member gene review exists.
folK_hppk_activity	FolK pterin pyrophosphokinases PANTHER:PTHR43071:SF1 Family	2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase activity GO:0003848	Family Supported Family review supports GO:0003848 FAMILY_WIDE. Asserted by tetrahydrofolate_biosynthesis; every Swiss-Prot member is named FolK.
folP_dhps_activity	FolP dihydropteroate synthases PANTHER:PTHR20941:SF1 Family	dihydropteroate synthase activity GO:0004156	Family Supported Family review supports GO:0004156 for PANTHER:PTHR20941:SF1. SF1, as tetrahydrofolate_biosynthesis selects; not inactive FolP2 (SF8).
fol1_dhna_activity	fungal FOL1 trifunctional folate synthesis proteins PANTHER:PTHR20941:SF1 Family	dihydroneopterin aldolase activity GO:0004150	Family Supported Family review supports GO:0004150 for PANTHER:PTHR20941:SF1. Only the fused fungal FOL1 proteins within SF1 carry the aldolase domain; bacterial FolP does not.
fol1_hppk_activity	fungal FOL1 trifunctional folate synthesis proteins PANTHER:PTHR20941:SF1 Family	2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase activity GO:0003848	Family Supported Family review supports GO:0003848 for PANTHER:PTHR20941:SF1. Only the fused fungal FOL1 proteins within SF1 carry the HPPK domain.
fol1_dhps_activity	fungal FOL1 trifunctional folate synthesis proteins PANTHER:PTHR20941:SF1 Family	dihydropteroate synthase activity GO:0004156	Family Supported Family review supports GO:0004156 for PANTHER:PTHR20941:SF1. SF1, as tetrahydrofolate_biosynthesis selects; not inactive FolP2 (SF8).
fused_adcs_activity	fused fungal aminodeoxychorismate synthases PANTHER:PTHR11236:SF18 Family	aminodeoxychorismate synthase activity GO:0046820	Family Supported Family review supports GO:0046820 for PANTHER:PTHR11236:SF18. Aminodeoxychorismate synthases (SF18 fungal ABZ1/abz1; SF50 and SF41 bacterial PabB), as tetrahydrofolate_biosynthesis selects.
pabB_adcs_activity	PabB ADC synthase component 1 PANTHER:PTHR11236:SF50 Family	aminodeoxychorismate synthase activity GO:0046820	Family Supported Family review supports GO:0046820 for PANTHER:PTHR11236:SF50. Aminodeoxychorismate synthases (SF18 fungal ABZ1/abz1; SF50 and SF41 bacterial PabB), as tetrahydrofolate_biosynthesis selects.
pabA_glutaminase_activity	PabA ADC synthase glutamine amidotransferase subunit Family	glutaminase activity GO:0004359	Family Id Missing The family has no identifier linking it to a curated family review.
fungal_adc_lyase_activity	fungal ABZ2-type aminodeoxychorismate lyases PANTHER:PTHR42743:SF11 Family	4-amino-4-deoxychorismate lyase activity GO:0008696	Family Function Unreviewed Family review leaves GO:0008696 UNRESOLVED. Safe for SF2 (gammaproteobacterial PabC) as a whole. In SF11 it holds for the ADC-lyase members (ABZ2, S. pombe SPBC19G7.02, B. subtilis PabC, M. tuberculosis Rv0812) but not for the many IlvE members of the same subfamily (E. coli, Salmonella, P. aeruginosa, archaeal and Rickettsia IlvE); E. coli ADC lyase activity is PabC (SF2), while E. coli IlvE is transaminase B. The tetrahydrofolate module's use of SF11 for the fungal ABZ2 variant is therefore correct only if read as "the ABZ2 members of SF11". Because SF11 is not pure, the scope is left unresolved and per-lineage application is required.
pabC_adc_lyase_activity	PabC aminodeoxychorismate lyases PANTHER:PTHR42743:SF2 Family	4-amino-4-deoxychorismate lyase activity GO:0008696	Family Function Unreviewed Family review leaves GO:0008696 UNRESOLVED. Safe for SF2 (gammaproteobacterial PabC) as a whole. In SF11 it holds for the ADC-lyase members (ABZ2, S. pombe SPBC19G7.02, B. subtilis PabC, M. tuberculosis Rv0812) but not for the many IlvE members of the same subfamily (E. coli, Salmonella, P. aeruginosa, archaeal and Rickettsia IlvE); E. coli ADC lyase activity is PabC (SF2), while E. coli IlvE is transaminase B. The tetrahydrofolate module's use of SF11 for the fungal ABZ2 variant is therefore correct only if read as "the ABZ2 members of SF11". Because SF11 is not pure, the scope is left unresolved and per-lineage application is required.
monofunctional_dhfs_activity	eukaryotic monofunctional dihydrofolate synthases PANTHER:PTHR11136:SF0 Family	dihydrofolate synthase activity GO:0008841	Family Supported Family review supports GO:0008841 for PANTHER:PTHR11136:SF0. SF0 (monofunctional fungal DHFS and bacterial FolC), as tetrahydrofolate_biosynthesis selects.
folC_dhfs_activity	bacterial bifunctional FolC PANTHER:PTHR11136:SF0 Family	dihydrofolate synthase activity GO:0008841	Family Supported Family review supports GO:0008841 for PANTHER:PTHR11136:SF0. SF0 (monofunctional fungal DHFS and bacterial FolC), as tetrahydrofolate_biosynthesis selects.
dhfr_activity	type I dihydrofolate reductases PANTHER:PTHR48069:SF3 Family	dihydrofolate reductase activity GO:0004146	Family Supported Family review supports GO:0004146 FAMILY_WIDE. Asserted by tetrahydrofolate_biosynthesis; accepted by every reviewed member.
monofunctional_fpgs_activity	eukaryotic folylpolyglutamate synthases PANTHER:PTHR11136:SF5 Family	tetrahydrofolylpolyglutamate synthase activity GO:0004326	Family Supported Family review supports GO:0004326 for PANTHER:PTHR11136:SF5. SF5 FPGS (MET7, met7), as tetrahydrofolate_biosynthesis selects, plus bacterial bifunctional FolC in SF0. The monofunctional fungal DHFS in SF0 do not make polyglutamates.
folC_fpgs_activity	bacterial bifunctional FolC PANTHER:PTHR11136:SF0 Family	tetrahydrofolylpolyglutamate synthase activity GO:0004326	Family Supported Family review supports GO:0004326 for PANTHER:PTHR11136:SF0. SF5 FPGS (MET7, met7), as tetrahydrofolate_biosynthesis selects, plus bacterial bifunctional FolC in SF0. The monofunctional fungal DHFS in SF0 do not make polyglutamates.

Gene-review completeness (14/24 grounded genes reviewed)

14 complete review(s) · 7 with deep research · 10 missing review · 7 reviewed but lacking deep research

Gene	Review	Complete	Deep research
ABZ1 P37254	✓	✓	✓
ABZ2 Q03266	✓	✓	✓
DFR1 P07807	✓	✓	✓
dfr1 P36591	✓	✓	✗
FOL1 P53848	✓	✓	✓
fol1 Q4LB35	✓	✓	✗
FOL2 P51601	✓	✓	✓
FOL3 Q12676	✓	✓	✓
fol3 Q9UTD0	✓	✓	✗
met7 O74742	✓	✓	✗
MET7 Q08645	✓	✓	✓
PabA (Escherichia coli K-12) P00903	✗	—	—
PabB (Escherichia coli K-12) P05041	✗	—	—
FolC (Escherichia coli K-12) P08192	✗	—	—
FolE (Escherichia coli K-12) P0A6T5	✗	—	—
FolA (Escherichia coli K-12) P0ABQ4	✗	—	—
FolP (Escherichia coli K-12) P0AC13	✗	—	—
FolB (Escherichia coli K-12) P0AC16	✗	—	—
NudB (Escherichia coli K-12) P0AFC0	✗	—	—
FolK (Escherichia coli K-12) P26281	✗	—	—
PabC (Escherichia coli K-12) P28305	✗	—	—
SPAC17A5.13 O13774	✓	✓	✗
SPBC19G7.02 O42951	✓	✓	✗
SPBP8B7.29 O94277	✓	✓	✗

Tree

De novo tetrahydrofolate and folylpolyglutamate biosynthesisMetabolic Pathwaytetrahydrofolate_biosynthesis

Parts
1. 1. pterin branch committed step
2. GTP to 7,8-dihydroneopterin triphosphateReactiongtp_cyclohydrolase_step
  
  Annotons
  - GTP cyclohydrolase I (FolE/FOL2) Family: GTP cyclohydrolase I (FolE type)
3. 2. removal of the triphosphate from dihydroneopterin triphosphate
4. 7,8-dihydroneopterin triphosphate to 7,8-dihydroneopterinMetabolic Pathwaydihydroneopterin_dephosphorylation_step
  
  Annotons
  - Dihydroneopterin triphosphate pyrophosphatase (FolQ/NudB) Ortholog Of: NudB (Escherichia coli K-12)
  - Dihydroneopterin monophosphate phosphatase Any With Function: dihydroneopterin monophosphate phosphatase activity
5. 3. dihydroneopterin aldolase, pterin pyrophosphokinase and dihydropteroate synthase
6. 7,8-dihydroneopterin to 7,8-dihydropteroateMetabolic Pathwaypterin_activation_and_condensation_steps
  
  Variants
  1. DHNA/HPPK/DHPS architecture variants by enzyme architecture (Exactly One)
    
    Separate monofunctional FolB, FolK and FolP proteinsMetabolic Pathwayseparate_folB_folK_folP_variant
    
    Annotons
    
    Dihydroneopterin aldolase (FolB) Family: FolB dihydroneopterin aldolases
    
    6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (FolK) Family: FolK pterin pyrophosphokinases
    
    Dihydropteroate synthase (FolP) Family: FolP dihydropteroate synthases
    
    Fungal trifunctional FOL1 (DHNA-HPPK-DHPS)Metabolic Pathwayfungal_trifunctional_fol1_variant
    
    Annotons
    
    FOL1 dihydroneopterin aldolase domain Family: fungal FOL1 trifunctional folate synthesis proteins
    
    FOL1 pterin pyrophosphokinase domain Family: fungal FOL1 trifunctional folate synthesis proteins
    
    FOL1 dihydropteroate synthase domain Family: fungal FOL1 trifunctional folate synthesis proteins
7. 4. p-aminobenzoate branch
8. Chorismate to p-aminobenzoateMetabolic Pathwaypaba_branch
  
  Parts
  1. 1. aminodeoxychorismate synthase
  2. Chorismate to 4-amino-4-deoxychorismateReactionadc_synthase_step
    
    Variants
    
    Aminodeoxychorismate synthase architecture variants by enzyme architecture (Exactly One)
    
    Fused PabA-PabB single-chain ADC synthaseReactionfused_adcs_variant
    
    Annotons
    
    Fused aminodeoxychorismate synthase (ABZ1-type) Family: fused fungal aminodeoxychorismate synthases
    
    Two-subunit PabA + PabB ADC synthaseProtein Complexheteromeric_pabA_pabB_variant
    
    Annotons
    
    PabB aminodeoxychorismate synthase component 1 Family: PabB ADC synthase component 1
    
    PabA glutamine amidotransferase component 2 Family: PabA ADC synthase glutamine amidotransferase subunit
  3. 2. aminodeoxychorismate lyase
  4. 4-Amino-4-deoxychorismate to p-aminobenzoateReactionadc_lyase_step
    
    Variants
    
    Aminodeoxychorismate lyase lineage variants by enzyme lineage (distantly related class IV PLP enzymes) (Exactly One)
    
    Fungal ABZ2-type ADC lyaseReactionfungal_abz2_adcl_variant
    
    Annotons
    
    Aminodeoxychorismate lyase (ABZ2) Family: fungal ABZ2-type aminodeoxychorismate lyases
    
    Bacterial PabC ADC lyaseReactionbacterial_pabC_adcl_variant
    
    Annotons
    
    Aminodeoxychorismate lyase (PabC) Family: PabC aminodeoxychorismate lyases
9. 5. first glutamylation
10. 7,8-Dihydropteroate to 7,8-dihydrofolateReactiondihydrofolate_synthase_step
  
  Variants
  1. Dihydrofolate synthase architecture variants by monofunctional DHFS versus bifunctional DHFS/FPGS (Exactly One)
    
    Monofunctional dihydrofolate synthase (FOL3-type)Reactionmonofunctional_dhfs_variant
    
    Annotons
    
    Dihydrofolate synthase (FOL3) Family: eukaryotic monofunctional dihydrofolate synthases
    
    Bifunctional FolC (DHFS activity)Reactionbifunctional_folC_dhfs_variant
    
    Annotons
    
    FolC dihydrofolate synthase activity Family: bacterial bifunctional FolC
11. 6. reduction to tetrahydrofolate
12. 7,8-Dihydrofolate to tetrahydrofolateReactiondihydrofolate_reductase_step
  
  Annotons
  - Dihydrofolate reductase (FolA/DFR1) Family: type I dihydrofolate reductases
13. 7. folate polyglutamylation
14. Folylpolyglutamate formationReactionpolyglutamylation_step
  
  Variants
  1. Folylpolyglutamate synthase architecture variants by monofunctional FPGS versus bifunctional DHFS/FPGS (Exactly One)
    
    Monofunctional folylpolyglutamate synthase (MET7-type)Reactionmonofunctional_fpgs_variant
    
    Annotons
    
    Folylpolyglutamate synthase (MET7) Family: eukaryotic folylpolyglutamate synthases
    
    Bifunctional FolC (FPGS activity)Reactionbifunctional_folC_fpgs_variant
    
    Annotons
    
    FolC folylpolyglutamate synthase activity Family: bacterial bifunctional FolC

Details

De novo tetrahydrofolate and folylpolyglutamate biosynthesisMetabolic Pathwaytetrahydrofolate_biosynthesis

tetrahydrofolate biosynthetic processGO:0046654 tetrahydrofolylpolyglutamate biosynthetic processGO:0046901

NEW module from the YeastPathways crosswalk (FOLSYN-PWY-1, PWY-6147, PWY3O-45, PWY-6614, PWY-6543, PWY3O-1874, PWY3O-20). Reaction assessment: the ten de novo reactions of PWY3O-45 map onto parts 1-6; the two dephosphorylation reactions (H2NEOPTERINP3PYROPHOSPHOHYDRO-RXN, DIHYDRONEOPTERIN-MONO-P-DEPHOS-RXN) have no yeast gene and are grounded only by bacterial NudB plus an ANY_WITH_FUNCTION selector. The YeastCyc catalysts FOL2, FOL1, ABZ1, ABZ2, FOL3, DFR1 and MET7 are all correct; no yeast enzyme was missing. The five MET7 polyglutamylation reactions of PWY3O-20 (one per folate species) are one GO:0004326 annoton. The one-carbon interconversion reactions bundled into FOLSYN-PWY-1 and PWY3O-20 (SHM1/SHM2, ADE3/MIS1, MTD1, MET12/MET13, CDC21 and glycine cleavage) are excluded and belong to folate_one_carbon_interconversion, glycine_serine_interconversion, glycine_cleavage_system and thymidylate_synthesis. Compartment corrections: S. cerevisiae Fol1p is exclusively mitochondrial (PMID:15169867) and MET7 supplies cytosolic and mitochondrial FPGS (PMID:10775416), whereas all YeastPathways models put every activity in cytosol. GO-CAM disagreements: YeastPathways_FOLSYN-PWY-1 annotates the biosynthetic activities as part_of GO:0035999 tetrahydrofolate interconversion rather than a biosynthetic process; YeastPathways_PWY3O-1874 uses only the root term GO:0009058; YeastPathways_PWY3O-20 mixes interconversion enzymes into the polyglutamylation pathway. The PomBase models give S. pombe fol3 both dihydrofolate synthase and folylpolyglutamate synthase activities (UniProt Q9UTD0 describes only probable DHFS) and place fol1 DHPS in both cytosol and mitochondrial envelope; the module keeps fol3 only as a DHFS exemplar. Process terms follow GO:0046654 (THF biosynthesis), GO:0006761 (dihydrofolate biosynthesis) and GO:0046901; the YeastPathways and PomBase use of GO:0046656 folic acid biosynthetic process is not adopted because folic acid itself is not an intermediate. Variants: separate FolB/FolK/FolP versus fungal trifunctional FOL1; fused versus two-subunit ADC synthase; fungal ABZ2-type versus bacterial PabC ADC lyase (distantly related class IV PLP enzymes); monofunctional DHFS + FPGS versus bacterial bifunctional FolC. Lineage-specific alternatives not modelled as variants (no curated exemplar yet) include the type IB GTP cyclohydrolase FolE2, the FolM alternative dihydrofolate reductase, the plant bifunctional HPPK-DHPS and plastid ADC synthase, and archaeal routes. Chorismate synthesis (shikimate pathway), folate salvage and transport are outside the module.

Connections

gtp_cyclohydrolase_step -> dihydroneopterin_dephosphorylation_step Precedes

dihydroneopterin_dephosphorylation_step -> pterin_activation_and_condensation_steps Precedes

paba_branch -> pterin_activation_and_condensation_steps Provides Input For

pABA is the second substrate of dihydropteroate synthase.

pterin_activation_and_condensation_steps -> dihydrofolate_synthase_step Precedes

dihydrofolate_synthase_step -> dihydrofolate_reductase_step Precedes

dihydrofolate_reductase_step -> polyglutamylation_step Precedes

Part 1: pterin branch committed step

GTP to 7,8-dihydroneopterin triphosphateReactiongtp_cyclohydrolase_step

Annotons

GTP cyclohydrolase I (FolE/FOL2)

gtp_cyclohydrolase_i_activity

Participant: Family: GTP cyclohydrolase I (FolE type)

Family:

GTP cyclohydrolase I (FolE type)PANTHER:PTHR11109:SF7

Representative Members: FOL2 (Saccharomyces cerevisiae)UniProtKB:P51601 fol2 (Schizosaccharomyces pombe)UniProtKB:O13774 FolE (Escherichia coli K-12)UniProtKB:P0A6T5

Function

GTP cyclohydrolase I activityGO:0003934

Substrates: GTP water

Products: 7,8-dihydroneopterin 3'-triphosphate formate

First and committed pterin-branch step. The same enzyme also supplies the pterin for tetrahydrobiopterin in animals, which is outside this module.

Part 2: removal of the triphosphate from dihydroneopterin triphosphate

7,8-dihydroneopterin triphosphate to 7,8-dihydroneopterinMetabolic Pathwaydihydroneopterin_dephosphorylation_step

Two hydrolytic steps: a Nudix-family pyrophosphatase releases diphosphate to give dihydroneopterin monophosphate, and a phosphatase removes the last phosphate. Only the pyrophosphatase has a characterised dedicated enzyme (bacterial FolQ/NudB); the monophosphate phosphatase is thought to be non-specific, and neither enzyme has been identified in yeasts.

Annotons

Dihydroneopterin triphosphate pyrophosphatase (FolQ/NudB)

dhntp_pyrophosphatase_activity

Participant: Ortholog Of: NudB (Escherichia coli K-12)

Ortholog Of:

NudB (Escherichia coli K-12)UniProtKB:P0AFC0

Orthologs of the experimentally characterised E. coli Nudix enzyme. The PANTHER subfamily that contains NudB is named for diadenosine tetraphosphatases, so no PANTHER id is asserted.

Function

dihydroneopterin triphosphate pyrophosphohydrolase activityGO:0019177

Substrates: 7,8-dihydroneopterin 3'-triphosphate water

Products: 7,8-dihydroneopterin 3'-phosphate diphosphate

Bacterial implementation of the pyrophosphatase step. The yeast enzyme is unknown (no gene in YeastPathways).

Dihydroneopterin monophosphate phosphatase

dhnmp_phosphatase_activity

Participant: Any With Function: dihydroneopterin monophosphate phosphatase activity

Required Function:

dihydroneopterin monophosphate phosphatase activityGO:0019176

No dedicated enzyme is established in any lineage; the reaction is generally attributed to non-specific phosphatases.

Function

dihydroneopterin monophosphate phosphatase activityGO:0019176

Substrates: 7,8-dihydroneopterin 3'-phosphate water

Products: 7,8-dihydroneopterin phosphate

Completes dephosphorylation; enzyme identity unknown.

Part 3: dihydroneopterin aldolase, pterin pyrophosphokinase and dihydropteroate synthase

7,8-dihydroneopterin to 7,8-dihydropteroateMetabolic Pathwaypterin_activation_and_condensation_steps

Three consecutive reactions: dihydroneopterin aldolase (DHNA) gives 6-hydroxymethyl-7,8-dihydropterin, HPPK pyrophosphorylates it with ATP, and dihydropteroate synthase (DHPS) condenses the pterin diphosphate with pABA to 7,8-dihydropteroate. The chemistry is the same in all lineages; the protein architecture differs.

Variant set: DHNA/HPPK/DHPS architecture variants by enzyme architecture (Exactly One)

Plants use a third arrangement (a separate DHNA and a mitochondrial bifunctional HPPK-DHPS); it is not modelled as a separate variant until a plant exemplar is curated.

Separate monofunctional FolB, FolK and FolP proteinsMetabolic Pathwayseparate_folB_folK_folP_variant

Annotons

Dihydroneopterin aldolase (FolB)

folB_dhna_activity

Participant: Family: FolB dihydroneopterin aldolases

Family:

FolB dihydroneopterin aldolasesPANTHER:PTHR42844:SF1

Representative Members: FolB (Escherichia coli K-12)UniProtKB:P0AC16

Function

dihydroneopterin aldolase activityGO:0004150

Substrates: 7,8-dihydroneopterin

Products: 6-hydroxymethyl-7,8-dihydropterin glycolaldehyde

Standalone bacterial DHNA.

6-Hydroxymethyl-7,8-dihydropterin pyrophosphokinase (FolK)

folK_hppk_activity

Participant: Family: FolK pterin pyrophosphokinases

Family:

FolK pterin pyrophosphokinasesPANTHER:PTHR43071:SF1

Representative Members: FolK (Escherichia coli K-12)UniProtKB:P26281

Function

2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase activityGO:0003848

Substrates: 6-hydroxymethyl-7,8-dihydropterin ATP

Products: (7,8-dihydropterin-6-yl)methyl diphosphate AMP

Standalone bacterial HPPK.

Dihydropteroate synthase (FolP)

folP_dhps_activity

Participant: Family: FolP dihydropteroate synthases

Family:

FolP dihydropteroate synthasesPANTHER:PTHR20941:SF1 PANTHER places the bacterial FolP and the fungal FOL1 fusion in the same subfamily; the variant is defined by architecture, not by this family.

Representative Members: FolP (Escherichia coli K-12)UniProtKB:P0AC13

Function

dihydropteroate synthase activityGO:0004156

Substrates: (7,8-dihydropterin-6-yl)methyl diphosphate 4-aminobenzoate

Products: 7,8-dihydropteroate diphosphate

Standalone bacterial DHPS.

Fungal trifunctional FOL1 (DHNA-HPPK-DHPS)Metabolic Pathwayfungal_trifunctional_fol1_variant

One polypeptide carries all three activities (PMID:15169867, PMID:15826662). In S. cerevisiae Fol1p is located only in mitochondria (PMID:15169867); the YeastPathways models place all three FOL1 activities in cytosol, and the PomBase models place the S. pombe fol1 DHNA and HPPK activities in cytosol and DHPS in both cytosol and mitochondrial envelope.

Annotons

FOL1 dihydroneopterin aldolase domain

fol1_dhna_activity

Participant: Family: fungal FOL1 trifunctional folate synthesis proteins

Family:

fungal FOL1 trifunctional folate synthesis proteinsPANTHER:PTHR20941:SF1

Representative Members: FOL1 (Saccharomyces cerevisiae)UniProtKB:P53848 fol1 (Schizosaccharomyces pombe)UniProtKB:Q4LB35

Function

dihydroneopterin aldolase activityGO:0004150

Substrates: 7,8-dihydroneopterin

Products: 6-hydroxymethyl-7,8-dihydropterin glycolaldehyde

Locations

mitochondrionGO:0005739

N-terminal DHNA domain of the trifunctional protein.

FOL1 pterin pyrophosphokinase domain

fol1_hppk_activity

Participant: Family: fungal FOL1 trifunctional folate synthesis proteins

Family:

fungal FOL1 trifunctional folate synthesis proteinsPANTHER:PTHR20941:SF1

Representative Members: FOL1 (Saccharomyces cerevisiae)UniProtKB:P53848 fol1 (Schizosaccharomyces pombe)UniProtKB:Q4LB35

Function

2-amino-4-hydroxy-6-hydroxymethyldihydropteridine diphosphokinase activityGO:0003848

Substrates: 6-hydroxymethyl-7,8-dihydropterin ATP

Products: (7,8-dihydropterin-6-yl)methyl diphosphate AMP

Locations

mitochondrionGO:0005739

Central HPPK domain of the trifunctional protein.

FOL1 dihydropteroate synthase domain

fol1_dhps_activity

Participant: Family: fungal FOL1 trifunctional folate synthesis proteins

Family:

fungal FOL1 trifunctional folate synthesis proteinsPANTHER:PTHR20941:SF1

Representative Members: FOL1 (Saccharomyces cerevisiae)UniProtKB:P53848 fol1 (Schizosaccharomyces pombe)UniProtKB:Q4LB35

Function

dihydropteroate synthase activityGO:0004156

Substrates: (7,8-dihydropterin-6-yl)methyl diphosphate 4-aminobenzoate

Products: 7,8-dihydropteroate diphosphate

Locations

mitochondrionGO:0005739

C-terminal DHPS domain; the sulfonamide target.

Part 4: p-aminobenzoate branch

Chorismate to p-aminobenzoateMetabolic Pathwaypaba_branch

Glutamine-dependent amination of chorismate to 4-amino-4-deoxychorismate (ADC) followed by PLP-dependent elimination of pyruvate to give pABA. Chorismate itself comes from the shikimate pathway, which is a separate module.

4-aminobenzoate biosynthetic processGO:0008153

Connections

adc_synthase_step -> adc_lyase_step Precedes

Part 1: aminodeoxychorismate synthase

Chorismate to 4-amino-4-deoxychorismateReactionadc_synthase_step

Variant set: Aminodeoxychorismate synthase architecture variants by enzyme architecture (Exactly One)

Fused PabA-PabB single-chain ADC synthaseReactionfused_adcs_variant

Annotons

Fused aminodeoxychorismate synthase (ABZ1-type)

fused_adcs_activity

Participant: Family: fused fungal aminodeoxychorismate synthases

Family:

fused fungal aminodeoxychorismate synthasesPANTHER:PTHR11236:SF18

Representative Members: ABZ1 (Saccharomyces cerevisiae)UniProtKB:P37254 abz1 (Schizosaccharomyces pombe)UniProtKB:O94277

Function

aminodeoxychorismate synthase activityGO:0046820

Substrates: chorismate L-glutamine

Products: 4-amino-4-deoxychorismate L-glutamate

Glutamine amidotransferase and chorismate-binding domains in one chain, as in fungi and plants.

Two-subunit PabA + PabB ADC synthaseProtein Complexheteromeric_pabA_pabB_variant

Annotons

PabB aminodeoxychorismate synthase component 1

pabB_adcs_activity

Participant: Family: PabB ADC synthase component 1

Family:

PabB ADC synthase component 1PANTHER:PTHR11236:SF50

Representative Members: PabB (Escherichia coli K-12)UniProtKB:P05041

Function

aminodeoxychorismate synthase activityGO:0046820

Substrates: chorismate ammonia (from PabA)

Products: 4-amino-4-deoxychorismate

Chorismate-aminating subunit.

PabA glutamine amidotransferase component 2

pabA_glutaminase_activity

Participant: Family: PabA ADC synthase glutamine amidotransferase subunit

Family:

PabA ADC synthase glutamine amidotransferase subunit The PANTHER subfamily for E. coli PabA is named for multifunctional tryptophan-biosynthesis proteins, so no PANTHER id is asserted.

Representative Members: PabA (Escherichia coli K-12)UniProtKB:P00903

Function

glutaminase activityGO:0004359 Hydrolyses L-glutamine within the PabA-PabB complex and channels the ammonia to PabB.

Substrates: L-glutamine water

Products: L-glutamate ammonia

Glutaminase subunit that supplies ammonia to PabB.

Part 2: aminodeoxychorismate lyase

4-Amino-4-deoxychorismate to p-aminobenzoateReactionadc_lyase_step

PLP-dependent elimination of pyruvate from ADC. Fungal ADC lyases (ABZ2 group) share only the class IV aminotransferase fold with bacterial PabC and plant ADC lyases and have no significant sequence similarity to them (PMID:17873082), so the two groups are modelled as separate implementations.

Variant set: Aminodeoxychorismate lyase lineage variants by enzyme lineage (distantly related class IV PLP enzymes) (Exactly One)

Fungal ABZ2-type ADC lyaseReactionfungal_abz2_adcl_variant

Annotons

Aminodeoxychorismate lyase (ABZ2)

fungal_adc_lyase_activity

Participant: Family: fungal ABZ2-type aminodeoxychorismate lyases

Family:

fungal ABZ2-type aminodeoxychorismate lyasesPANTHER:PTHR42743:SF11

Representative Members: ABZ2 (Saccharomyces cerevisiae)UniProtKB:Q03266 abz2 (Schizosaccharomyces pombe)UniProtKB:O42951

Function

4-amino-4-deoxychorismate lyase activityGO:0008696

Substrates: 4-amino-4-deoxychorismate

Products: 4-aminobenzoate pyruvate

Cofactors: pyridoxal 5'-phosphate

Cytosolic fungal ADC lyase; complements an E. coli pabC mutant despite low sequence similarity.

Bacterial PabC ADC lyaseReactionbacterial_pabC_adcl_variant

Annotons

Aminodeoxychorismate lyase (PabC)

pabC_adc_lyase_activity

Participant: Family: PabC aminodeoxychorismate lyases

Family:

PabC aminodeoxychorismate lyasesPANTHER:PTHR42743:SF2

Representative Members: PabC (Escherichia coli K-12)UniProtKB:P28305

Function

4-amino-4-deoxychorismate lyase activityGO:0008696

Substrates: 4-amino-4-deoxychorismate

Products: 4-aminobenzoate pyruvate

Cofactors: pyridoxal 5'-phosphate

Bacterial ADC lyase.

Part 5: first glutamylation

7,8-Dihydropteroate to 7,8-dihydrofolateReactiondihydrofolate_synthase_step

dihydrofolate biosynthetic processGO:0006761

Variant set: Dihydrofolate synthase architecture variants by monofunctional DHFS versus bifunctional DHFS/FPGS (Exactly One)

Monofunctional dihydrofolate synthase (FOL3-type)Reactionmonofunctional_dhfs_variant

Annotons

Dihydrofolate synthase (FOL3)

monofunctional_dhfs_activity

Participant: Family: eukaryotic monofunctional dihydrofolate synthases

Family:

eukaryotic monofunctional dihydrofolate synthasesPANTHER:PTHR11136:SF0 PANTHER SF0 also contains bacterial bifunctional FolC, so the family does not by itself select the monofunctional architecture.

Representative Members: FOL3 (Saccharomyces cerevisiae)UniProtKB:Q12676 fol3 (Schizosaccharomyces pombe)UniProtKB:Q9UTD0

Function

dihydrofolate synthase activityGO:0008841

Substrates: 7,8-dihydropteroate L-glutamate ATP

Products: 7,8-dihydrofolate (monoglutamate) ADP phosphate

Adds the first glutamate only; chain extension is by a separate FPGS. Plant DHFS is mitochondrial (PMID:11752472).

Bifunctional FolC (DHFS activity)Reactionbifunctional_folC_dhfs_variant

Annotons

FolC dihydrofolate synthase activity

folC_dhfs_activity

Participant: Family: bacterial bifunctional FolC

Family:

bacterial bifunctional FolCPANTHER:PTHR11136:SF0

Representative Members: FolC (Escherichia coli K-12)UniProtKB:P08192

Function

dihydrofolate synthase activityGO:0008841

Substrates: 7,8-dihydropteroate L-glutamate ATP

Products: 7,8-dihydrofolate (monoglutamate) ADP phosphate

The same FolC polypeptide also performs the polyglutamylation step (folC_fpgs_activity).

Part 6: reduction to tetrahydrofolate

7,8-Dihydrofolate to tetrahydrofolateReactiondihydrofolate_reductase_step

Annotons

Dihydrofolate reductase (FolA/DFR1)

dhfr_activity

Participant: Family: type I dihydrofolate reductases

Family:

type I dihydrofolate reductasesPANTHER:PTHR48069:SF3

Representative Members: DFR1 (Saccharomyces cerevisiae)UniProtKB:P07807 dfr1 (Schizosaccharomyces pombe)UniProtKB:P36591 FolA (Escherichia coli K-12)UniProtKB:P0ABQ4

Function

dihydrofolate reductase activityGO:0004146

Substrates: 7,8-dihydrofolate NADPH

Products: (6S)-5,6,7,8-tetrahydrofolate NADP+

Final de novo step. The same enzyme regenerates THF from the dihydrofolate released by thymidylate synthase, a recycling role outside this module.

Part 7: folate polyglutamylation

Folylpolyglutamate formationReactionpolyglutamylation_step

ATP-dependent addition of further gamma-linked L-glutamates to dihydrofolate, THF and one-carbon-substituted THF monoglutamates.

tetrahydrofolylpolyglutamate biosynthetic processGO:0046901

Variant set: Folylpolyglutamate synthase architecture variants by monofunctional FPGS versus bifunctional DHFS/FPGS (Exactly One)

Monofunctional folylpolyglutamate synthase (MET7-type)Reactionmonofunctional_fpgs_variant

Annotons

Folylpolyglutamate synthase (MET7)

monofunctional_fpgs_activity

Participant: Family: eukaryotic folylpolyglutamate synthases

Family:

eukaryotic folylpolyglutamate synthasesPANTHER:PTHR11136:SF5

Representative Members: MET7 (Saccharomyces cerevisiae)UniProtKB:Q08645 met7 (Schizosaccharomyces pombe)UniProtKB:O74742

Function

tetrahydrofolylpolyglutamate synthase activityGO:0004326

Substrates: tetrahydropteroyl-[gamma-Glu](n) L-glutamate ATP

Products: tetrahydropteroyl-[gamma-Glu](n+1) ADP phosphate

Locations

cytosolGO:0005829 mitochondrionGO:0005739

Single fungal FPGS serving both compartments; plants instead have separate mitochondrial, cytosolic and plastid FPGS genes (PMID:11752472).

Bifunctional FolC (FPGS activity)Reactionbifunctional_folC_fpgs_variant

Annotons

FolC folylpolyglutamate synthase activity

folC_fpgs_activity

Participant: Family: bacterial bifunctional FolC

Family:

bacterial bifunctional FolCPANTHER:PTHR11136:SF0

Representative Members: FolC (Escherichia coli K-12)UniProtKB:P08192

Function

tetrahydrofolylpolyglutamate synthase activityGO:0004326

Substrates: tetrahydropteroyl-[gamma-Glu](n) L-glutamate ATP

Products: tetrahydropteroyl-[gamma-Glu](n+1) ADP phosphate

Second activity of the bifunctional FolC protein.