MET7 (MET23, YOR241W) encodes folylpolyglutamate synthetase (FPGS, EC 6.3.2.17), the ATP-dependent Mur-ligase-family enzyme that adds successive gamma-linked glutamate residues to tetrahydrofolate coenzymes. Polyglutamylation retains folates in the cell and organelles and makes them preferred substrates of folate-dependent one-carbon enzymes. A separate enzyme, FOL3, adds the first glutamate (dihydrofolate synthetase). MET7-dependent FPGS activity is found in both the cytoplasm and mitochondria. Cytosolic FPGS is required for methionine synthesis, because cobalamin-independent methionine synthase (Met6) uses polyglutamylated 5-methyl-tetrahydrofolate, so met7 mutants are methionine auxotrophs. met7 mutants also lose mitochondrial DNA (petite) because they are deficient in dTMP synthesis, and they show synthetic phenotypes with mutations in glycine/serine one-carbon interconversion (gly1, ser1, shm2).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0000097 sulfur amino acid biosynthetic process | RCA GO_REF:0000123 | MARK AS OVER ANNOTATED | Summary: Inherited from the YeastPathways superpathway of sulfur amino acid biosynthesis (PWY-821-1), which includes MET7 only because polyglutamylated 5-methyl-tetrahydrofolate is the methyl donor for Met6 methionine synthase. MET7 does not catalyse any step of sulfate assimilation, homocysteine or cysteine synthesis; its connection is cofactor supply to the final methylation step. Reason: Superpathway-level inflation; the more specific methionine-biosynthesis rows already capture the genuine (indirect, cofactor-supplying) link, so this broader term adds nothing. Supporting Evidence: PMID:10775416 disrupted the met7 gene and determined that the strain is a methionine auxotroph PMID:10799479 Folylpolyglutamate synthetase activity is required for methionine synthesis and for maintenance of mitochondrial DNA |
| GO:0004326 tetrahydrofolylpolyglutamate synthase activity | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA for folylpolyglutamate synthase activity, seeded by Arabidopsis FPGS1-3, mouse Fpgs, human FPGS and MET7 itself (SGD:S000005767), which carries its own experimental annotation. MET7 sits squarely in the FPGS clade and the activity is directly demonstrated for the yeast enzyme. Supporting Evidence: PMID:10799479 folylpolyglutamate synthetase, which catalyzes the extension of the glutamate chains of the folate coenzymes, is encoded by the MET7 gene file:yeast/MET7/MET7-uniprot.txt Belongs to the folylpolyglutamate synthase family. |
| GO:0004326 tetrahydrofolylpolyglutamate synthase activity | IDA PMID:10775416 Disruption of cytoplasmic and mitochondrial folylpolyglutama... | ACCEPT | Summary: DeSouza et al. measured FPGS activity in cytoplasmic and mitochondrial fractions and showed it is lost on met7 disruption and restored by MET7 constructs. Independently confirmed by Cherest et al. (2000). This is the core catalytic activity of Met7p (EC 6.3.2.17). Supporting Evidence: PMID:10775416 have folylpolyglutamate synthetase activity in both compartments PMID:10775416 The gene encoding folylpolyglutamate synthetase is MET7 PMID:10799479 folylpolyglutamate synthetase, which catalyzes the extension of the glutamate chains of the folate coenzymes, is encoded by the MET7 gene |
| GO:0004326 tetrahydrofolylpolyglutamate synthase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Combined IEA from the FPGS InterPro signatures (IPR001645, IPR018109 FPGS conserved site), ARBA rule and the EC 6.3.2.17 / RHEA:10580 mapping on the UniProt entry. Correct for this protein: the EC assignment rests on direct enzyme assays. Supporting Evidence: file:yeast/MET7/MET7-uniprot.txt Catalyzes conversion of folates to polyglutamate derivatives PMID:10799479 folylpolyglutamate synthetase, which catalyzes the extension of the glutamate chains of the folate coenzymes, is encoded by the MET7 gene |
| GO:0004326 tetrahydrofolylpolyglutamate synthase activity | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways reaction-to-GO conversion from the superpathway of threonine and methionine biosynthesis (P4-PWY-1). The pathway membership is superpathway-driven, but the MF itself (the FPGS reaction) is correct for Met7p regardless of which pathway diagram it was harvested from. Supporting Evidence: PMID:10799479 folylpolyglutamate synthetase, which catalyzes the extension of the glutamate chains of the folate coenzymes, is encoded by the MET7 gene |
| GO:0004326 tetrahydrofolylpolyglutamate synthase activity | RCA GO_REF:0000123 | ACCEPT | Summary: Same FPGS reaction harvested from the YeastPathways sulfur amino acid superpathway (PWY-821-1). The MF is correct for Met7p; the pathway context is only indirectly relevant (cofactor supply to Met6). Supporting Evidence: PMID:10799479 folylpolyglutamate synthetase, which catalyzes the extension of the glutamate chains of the folate coenzymes, is encoded by the MET7 gene |
| GO:0004326 tetrahydrofolylpolyglutamate synthase activity | RCA GO_REF:0000123 | ACCEPT | Summary: Harvested from the YeastPathways 'folate polyglutamylation' pathway (PWY3O-20), the pathway that most directly describes Met7p's role (extension of the glutamate tail of tetrahydrofolate coenzymes). Correct. Supporting Evidence: PMID:10799479 folylpolyglutamate synthetase, which catalyzes the extension of the glutamate chains of the folate coenzymes, is encoded by the MET7 gene file:yeast/MET7/MET7-uniprot.txt Catalyzes conversion of folates to polyglutamate derivatives |
| GO:0004326 tetrahydrofolylpolyglutamate synthase activity | RCA GO_REF:0000123 | ACCEPT | Summary: Harvested from the YeastPathways 'methionine biosynthesis' pathway (PWY3O-238), which pairs MET7 with MET6 because Met6 uses polyglutamylated 5-methyl-THF. MF is correct for Met7p. Supporting Evidence: PMID:10799479 folylpolyglutamate synthetase, which catalyzes the extension of the glutamate chains of the folate coenzymes, is encoded by the MET7 gene PMID:10799479 Folylpolyglutamate synthetase activity is required for methionine synthesis and for maintenance of mitochondrial DNA |
| GO:0004326 tetrahydrofolylpolyglutamate synthase activity | RCA GO_REF:0000123 | ACCEPT | Summary: Harvested from the YeastPathways superpathway of methionine biosynthesis (PWY3O-954). MF is correct for Met7p (FPGS reaction), independent of the superpathway context. Supporting Evidence: PMID:10799479 folylpolyglutamate synthetase, which catalyzes the extension of the glutamate chains of the folate coenzymes, is encoded by the MET7 gene |
| GO:0005524 ATP binding | IEA GO_REF:0000002 | KEEP AS NON CORE | Summary: InterPro2GO mapping from FPGS family/Mur-ligase domain signatures. ATP is a substrate of the FPGS ligation (ATP + glutamate + THF-Glu(n) -> ADP + Pi + THF-Glu(n+1)), so ATP binding is true but is a component of the catalytic activity rather than an independent function. Reason: True but subsumed by the specific ligase activity. Supporting Evidence: file:yeast/MET7/MET7-uniprot.txt Catalyzes conversion of folates to polyglutamate derivatives |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA (is_active_in cytoplasm) across plant, mammalian and fungal FPGS. Consistent with direct yeast evidence: cytoplasmic FPGS activity is lost in met7 mutants, and cytoplasm-only MET7 complements the methionine auxotrophy. Supporting Evidence: PMID:10775416 have folylpolyglutamate synthetase activity in both compartments PMID:10775416 All the genes providing cytoplasmic folylpolyglutamate synthetase complemented the methionine auxotrophy |
| GO:0005737 cytoplasm | IDA PMID:10775416 Disruption of cytoplasmic and mitochondrial folylpolyglutama... | ACCEPT | Summary: DeSouza et al. fractionated cells and found FPGS activity in the cytoplasm that depends on MET7; the cytoplasmic pool is the one required for methionine synthesis. Supporting Evidence: PMID:10775416 have folylpolyglutamate synthetase activity in both compartments PMID:10775416 All the genes providing cytoplasmic folylpolyglutamate synthetase complemented the methionine auxotrophy |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: UniProt SubCell (SL-0086 Cytoplasm) mapping; the UniProt statement is itself backed by PMID:10775416. Correct. Supporting Evidence: PMID:10775416 have folylpolyglutamate synthetase activity in both compartments |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA from Arabidopsis FPGS1, mouse Fpgs and human FPGS (all with mitochondrial isoforms) plus MET7. Yeast has mitochondrial FPGS activity attributed to MET7 by DeSouza et al., although the physiological importance of the mitochondrial pool is debated (Cherest et al.). Supporting Evidence: PMID:10775416 have folylpolyglutamate synthetase activity in both compartments PMID:10775416 retained the function of the mitochondrial folate-dependent enzymes to produce formate, serine, and glycine |
| GO:0005739 mitochondrion | IDA PMID:10775416 Disruption of cytoplasmic and mitochondrial folylpolyglutama... | ACCEPT | Summary: DeSouza et al. detected MET7-dependent FPGS activity in mitochondrial fractions and generated a MET7 allele lacking the mitochondrial leader. The curator's IDA is consistent with the abstract. Cherest et al. argue the met7 mitochondrial (petite) phenotype is not due to loss of a mitochondrial FPGS, which questions its physiological relevance but not its existence. Supporting Evidence: PMID:10775416 have folylpolyglutamate synthetase activity in both compartments PMID:10775416 retained the function of the mitochondrial folate-dependent enzymes to produce formate, serine, and glycine PMID:10799479 Our results show that the loss of mitochondrial functions in met7 mutant cells is not because of the absence of a mitochondrial folylpolyglutamate synthetase |
| GO:0005739 mitochondrion | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt SubCell (SL-0173) mapping; the UniProt mitochondrion statement carries experimental evidence from PMID:10775416. Supporting Evidence: PMID:10775416 have folylpolyglutamate synthetase activity in both compartments |
| GO:0005743 mitochondrial inner membrane | IEA GO_REF:0000044 | MARK AS OVER ANNOTATED | Summary: UniProt SubCell mapping (SL-0168), but the UniProt inner-membrane statement is by similarity (ECO:0000250) to mammalian FPGS, with no yeast data. Met7p has no predicted transmembrane segment and acts on soluble folate substrates; membrane association has not been shown in yeast. Reason: Similarity-only sublocalization not supported by yeast evidence. Supporting Evidence: file:yeast/MET7/MET7-uniprot.txt Mitochondrion inner membrane {ECO:0000250}. Mitochondrion matrix |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: UniProt SubCell mapping (SL-0170), by similarity (ECO:0000250). A soluble mitochondrial FPGS acting on matrix folate pools is biochemically plausible and consistent with mitochondrial FPGS activity in yeast, but the matrix assignment itself has not been tested in yeast. Reason: Plausible refinement of the experimentally supported mitochondrion annotation; not directly tested. Supporting Evidence: file:yeast/MET7/MET7-uniprot.txt Mitochondrion inner membrane {ECO:0000250}. Mitochondrion matrix PMID:10775416 have folylpolyglutamate synthetase activity in both compartments |
| GO:0005783 endoplasmic reticulum | HDA PMID:26928762 One library to make them all: streamlining the creation of y... | MARK AS OVER ANNOTATED | Summary: High-throughput localization from the N-terminal SWAT-GFP library (Weill et al. 2016). An N-terminal GFP tag masks MET7's mitochondrial presequence, and the authors themselves caution that terminal tags can mask targeting signals. No biochemical or functional evidence places FPGS in the ER. Reason: Likely tag-induced mislocalization; not consistent with fractionation data showing cytoplasmic and mitochondrial activity. Supporting Evidence: PMID:26928762 tagged with an amino terminal (N′) SWAT acceptor module PMID:26928762 Tagging proteins at either terminus can mask targeting sequences as well as regulatory sequences. |
| GO:0005829 cytosol | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA (is_active_in cytosol) from Arabidopsis FPGS3, mouse/human FPGS. Cytosolic FPGS is the pool required for methionine biosynthesis in yeast. Supporting Evidence: PMID:10775416 All the genes providing cytoplasmic folylpolyglutamate synthetase complemented the methionine auxotrophy |
| GO:0005829 cytosol | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways (P4-PWY-1) places the FPGS reaction in the cytosol. Consistent with experimental cytoplasmic FPGS activity. Supporting Evidence: PMID:10775416 All the genes providing cytoplasmic folylpolyglutamate synthetase complemented the methionine auxotrophy |
| GO:0005829 cytosol | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways (PWY-821-1) cytosolic placement of the FPGS reaction; consistent with fractionation data. Supporting Evidence: PMID:10775416 All the genes providing cytoplasmic folylpolyglutamate synthetase complemented the methionine auxotrophy |
| GO:0005829 cytosol | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways folate polyglutamylation (PWY3O-20) places the reaction in the cytosol; correct for the main Met7p pool. Supporting Evidence: PMID:10775416 All the genes providing cytoplasmic folylpolyglutamate synthetase complemented the methionine auxotrophy |
| GO:0005829 cytosol | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways methionine biosynthesis (PWY3O-238) cytosolic placement; correct, as the cytosolic FPGS supplies Met6. Supporting Evidence: PMID:10775416 All the genes providing cytoplasmic folylpolyglutamate synthetase complemented the methionine auxotrophy |
| GO:0005829 cytosol | RCA GO_REF:0000123 | ACCEPT | Summary: YeastPathways methionine superpathway (PWY3O-954) cytosolic placement; correct. Supporting Evidence: PMID:10775416 All the genes providing cytoplasmic folylpolyglutamate synthetase complemented the methionine auxotrophy |
| GO:0006566 L-threonine metabolic process | RCA GO_REF:0000123 | REMOVE | Summary: Inherited from the YeastPathways superpathway of threonine and methionine biosynthesis (P4-PWY-1). MET7 is in that superpathway only via the methionine branch (Met6 cofactor). Met7p has no role in threonine synthesis or degradation, and met7 mutants are methionine (not threonine) auxotrophs. Reason: Superpathway inflation; no biological connection between FPGS and threonine metabolism. Supporting Evidence: PMID:10775416 disrupted the met7 gene and determined that the strain is a methionine auxotroph |
| GO:0006730 one-carbon metabolic process | IMP PMID:10775416 Disruption of cytoplasmic and mitochondrial folylpolyglutama... | ACCEPT | Summary: met7 disruption causes methionine auxotrophy, adenine/thymidine auxotrophy under sulfanilamide, and synthetic phenotypes with gly1/ser1/shm2 (glycine/serine one-carbon interconversion), showing that polyglutamylation by Met7p is needed for folate-dependent one-carbon metabolism. Supporting Evidence: PMID:10775416 disrupted the met7 gene and determined that the strain is a methionine auxotroph PMID:10799479 One-carbon metabolism is essential to provide activated one-carbon units in the biosynthesis of methionine, purines, and thymidylate PMID:10775416 A met7 shm2 strain is nonviable |
| GO:0009396 folic acid-containing compound biosynthetic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO mapping from FPGS signatures. Correct parent of tetrahydrofolylpolyglutamate biosynthetic process; FPGS synthesizes polyglutamyl folate coenzymes. Supporting Evidence: PMID:10799479 folylpolyglutamate synthetase, which catalyzes the extension of the glutamate chains of the folate coenzymes, is encoded by the MET7 gene |
| GO:0016881 acid-amino acid ligase activity | IEA GO_REF:0000002 | MODIFY | Summary: InterPro2GO from the Mur-ligase C-terminal domain superfamily (IPR036615). True but generic; the precise activity, tetrahydrofolylpolyglutamate synthase activity, is experimentally established. Reason: Over-general parent; replace with the specific FPGS activity. Proposed replacements: tetrahydrofolylpolyglutamate synthase activity Supporting Evidence: PMID:10799479 folylpolyglutamate synthetase, which catalyzes the extension of the glutamate chains of the folate coenzymes, is encoded by the MET7 gene |
| GO:0046655 folic acid metabolic process | RCA GO_REF:0000123 | MODIFY | Summary: From YeastPathways folate polyglutamylation (PWY3O-20). GO 'folic acid metabolic process' refers to folic acid (pteroylmonoglutamate) itself; Met7p extends the glutamate chain of reduced (tetrahydro) folate coenzymes, which is captured precisely by tetrahydrofolylpolyglutamate biosynthetic process. Reason: Imprecise mapping of the polyglutamylation pathway; use the specific process term. Proposed replacements: tetrahydrofolylpolyglutamate biosynthetic process Supporting Evidence: PMID:10799479 folylpolyglutamate synthetase, which catalyzes the extension of the glutamate chains of the folate coenzymes, is encoded by the MET7 gene |
| GO:0046901 tetrahydrofolylpolyglutamate biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: PAINT IBA from Arabidopsis FPGS1, mouse Fpgs, human FPGS. Directly describes what Met7p does. Supporting Evidence: PMID:10799479 folylpolyglutamate synthetase, which catalyzes the extension of the glutamate chains of the folate coenzymes, is encoded by the MET7 gene |
| GO:0046901 tetrahydrofolylpolyglutamate biosynthetic process | IEA GO_REF:0000041 | ACCEPT | Summary: UniPathway UPA00850 (tetrahydrofolylpolyglutamate biosynthesis) mapping from the UniProt PATHWAY line. Correct. Supporting Evidence: file:yeast/MET7/MET7-uniprot.txt Catalyzes conversion of folates to polyglutamate derivatives |
| GO:0071265 L-methionine biosynthetic process | RCA GO_REF:0000123 | KEEP AS NON CORE | Summary: YeastPathways 'methionine biosynthesis' (PWY3O-238) groups MET7 with MET6 because cobalamin-independent methionine synthase uses polyglutamylated 5-methyl-THF as methyl donor. met7 mutants are methionine auxotrophs and cytoplasmic FPGS alone rescues this. Met7p supplies the co-substrate rather than catalysing a methionine-forming step, so the link is real but indirect. Reason: Genuine physiological requirement via cofactor/co-substrate supply; not the core function. Supporting Evidence: PMID:10775416 disrupted the met7 gene and determined that the strain is a methionine auxotroph PMID:10799479 Folylpolyglutamate synthetase activity is required for methionine synthesis and for maintenance of mitochondrial DNA PMID:10775416 All the genes providing cytoplasmic folylpolyglutamate synthetase complemented the methionine auxotrophy |
| GO:0071265 L-methionine biosynthetic process | RCA GO_REF:0000123 | KEEP AS NON CORE | Summary: Same term from the YeastPathways superpathway of methionine biosynthesis (PWY3O-954). As above, Met7p contributes by polyglutamylating the folate methyl donor used by Met6; methionine auxotrophy of met7 mutants confirms the requirement. Reason: Indirect (co-substrate supply) contribution; keep as non-core. Supporting Evidence: PMID:10775416 disrupted the met7 gene and determined that the strain is a methionine auxotroph PMID:10799479 Folylpolyglutamate synthetase activity is required for methionine synthesis and for maintenance of mitochondrial DNA |
Loading supporting content…
Download this section (compressed HTML)Q: Is the mitochondrial FPGS pool encoded by MET7 physiologically important? DeSouza et al. (2000) and Cherest et al. (2000) disagree on whether the met7 petite phenotype reflects loss of mitochondrial FPGS or cytosolic dTMP deficiency.
Q: Should folate polyglutamylation enzymes carry L-methionine biosynthetic process (via the Met6 polyglutamyl-methyl-THF requirement), or should that link be expressed through has_input on MET6?
Experiment: Use a C-terminally tagged MET7 at the endogenous locus, or immunogold labelling, to test the ER localization reported from the N-terminal SWAT-GFP screen and to resolve the mitochondrial sub-compartment (matrix vs inner membrane).
Folylpolyglutamate synthetase; catalyzes extension of the glutamate chains of the folate coenzymes, required for methionine synthesis and for maintenance of mitochondrial DNA; protein abundance increases in response to DNA replication stress
Loading supporting content…
Download this section (compressed HTML)Loading supporting content…
Download this section (compressed HTML)