SHMT1

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0004372 glycine hydroxymethyltransferase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic (PAN-GO/IBA) assignment of the core serine hydroxymethyltransferase activity. This is the evolved molecular function of SHMT1 and is strongly corroborated by multiple IDA annotations and by the UniProt catalytic activity (EC 2.1.2.1). Reason: Correct core catalytic function of the SHMT family, confirmed experimentally for the human cytosolic enzyme. Supporting Evidence: file:human/SHMT1/SHMT1-uniprot.txt reversible conversion of serine and tetrahydrofolate (THF) to glycine
GO:0006545 glycine biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: SHMT1 produces glycine from L-serine as one direction of its reversible reaction. Glycine biosynthesis is a genuine biological role and a natural summary of the core reaction. Reason: Phylogenetic assignment consistent with the enzyme's catalytic output; core process.
GO:0005634 nucleus	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Nuclear localization is real for SHMT1 (SUMO/RAN-dependent import during S/G2-M for the de novo thymidylate complex), but it is a conditional, cell-cycle- and proliferation-restricted deployment rather than the primary cytosolic function. Reason: Experimentally supported nuclear role (PMID:22235121, PMID:17446168, PMID:30035852), but represents a specialized secondary localization; the core enzyme acts in the cytosol.
GO:0030170 pyridoxal phosphate binding	IBA GO_REF:0000033	ACCEPT	Summary: SHMT1 is a PLP-dependent enzyme; PLP is bound via a Schiff base to Lys-257. Core cofactor-binding molecular function, confirmed by crystallography and IDA. Reason: Essential cofactor binding for the core catalytic activity; independently supported by structural and biochemical evidence. Supporting Evidence: file:human/SHMT1/SHMT1-uniprot.txt Name=pyridoxal 5'-phosphate; Xref=ChEBI:CHEBI:597326;
GO:0046653 tetrahydrofolate metabolic process	IBA GO_REF:0000033	ACCEPT	Summary: SHMT1 consumes/produces tetrahydrofolate and 5,10-methylene-THF, participating in THF metabolism. Core biological process. Reason: Directly reflects the folate cofactor turnover of the core reaction; well supported.
GO:0005739 mitochondrion	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: SHMT1 is the CYTOSOLIC isozyme; the mitochondrial activity in the SHMT family is carried out by the separate paralog SHMT2 (P34897). This IBA is a mis-propagation from mitochondrial orthologs across the family tree (the with/from list mixes cytosolic and mitochondrial SHMTs and plant/fungal mitochondrial orthologs). Reason: SHMT1 is not a mitochondrial protein; UniProt localizes it to cytoplasm and nucleus only. The mitochondrion call is a phylogenetic branch artifact from SHMT2-type orthologs and should not be treated as a real localization. Propagation Review Root cause: PROPAGATION BAD Failure modes: COMPARTMENT OR COMPLEX MISMATCH
GO:0004372 glycine hydroxymethyltransferase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (multi-method) assignment of the core catalytic activity; redundant with the IBA and IDA annotations of the same term. Reason: Correct core function, consistent with experimental evidence.
GO:0004793 threonine aldolase activity	IEA GO_REF:0000116	KEEP AS NON CORE	Summary: Rhea-based electronic annotation of L-threonine aldolase side activity. SHMT1 cleaves L-threonine to glycine + acetaldehyde by retro-aldol; this is a genuine but promiscuous, low-efficiency activity sharing the same active site (also supported by IDA, PMID:38615009). Reason: Real promiscuous aldolase activity, not the evolved core hydroxymethyltransferase function.
GO:0005634 nucleus	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic nucleus localization, consistent with the experimentally supported conditional nuclear pool. Non-core. Reason: Duplicates the IBA/IDA nucleus annotations; real but secondary localization.
GO:0005737 cytoplasm	IEA GO_REF:0000044	MARK AS OVER ANNOTATED	Summary: "Cytoplasm" is a correct but broad parent of the specific and better-supported "cytosol" localization (GO:0005829, IDA/TAS). Reason: Superseded by the more precise cytosol annotation; uninformative at this granularity. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH
GO:0006544 glycine metabolic process	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic annotation. SHMT1 produces/consumes glycine; glycine metabolic process is a correct core process (also IDA-supported). Reason: Directly reflects the enzyme's substrate/product; core process.
GO:0006545 glycine biosynthetic process	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic assignment of glycine biosynthesis; duplicates the IBA annotation of the same term. Reason: Correct core biological process.
GO:0006563 L-serine metabolic process	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic annotation. L-serine is the primary substrate; L-serine metabolic process is a core process (also IDA-supported). Reason: Directly reflects the core reaction substrate.
GO:0006730 one-carbon metabolic process	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic annotation of one-carbon metabolism, the defining pathway context of SHMT1 (it generates the methylene-THF one-carbon donor). Core process, also IDA-supported. Reason: Central and defining biological process for the enzyme.
GO:0008732 L-allo-threonine aldolase activity	IEA GO_REF:0000116	KEEP AS NON CORE	Summary: Rhea-based electronic annotation of L-allo-threonine aldolase side activity; SHMT1 cleaves L-allo-threonine (erythro configuration) more efficiently than L-threonine. Genuine promiscuous activity (also EXP, PMID:38615009). Reason: Promiscuous aldolase activity of the same active site, not the core function.
GO:0030170 pyridoxal phosphate binding	IEA GO_REF:0000120	ACCEPT	Summary: Electronic PLP-binding annotation; duplicates the IBA/IDA PLP-binding annotations. Core cofactor binding. Reason: Correct essential cofactor binding.
GO:0035999 tetrahydrofolate interconversion	IEA GO_REF:0000120	ACCEPT	Summary: Electronic annotation matching UniProt PATHWAY "One-carbon metabolism; tetrahydrofolate interconversion". SHMT1 interconverts THF and 5,10-methylene-THF as part of the folate cycle. Core process (also IDA, PMID:24698160). Reason: Precise and accurate pathway assignment for the core reaction. Supporting Evidence: file:human/SHMT1/SHMT1-uniprot.txt One-carbon metabolism; tetrahydrofolate interconversion.
GO:0046653 tetrahydrofolate metabolic process	IEA GO_REF:0000117	ACCEPT	Summary: ARBA electronic annotation; duplicates the IBA/IDA THF metabolic process annotations. Core process. Reason: Correct; reflects folate cofactor turnover.
GO:0050179 phenylserine aldolase activity	IEA GO_REF:0000116	KEEP AS NON CORE	Summary: Rhea-based electronic annotation of 3-phenylserine aldolase side activity (by similarity to P35623 in UniProt). Genuine promiscuous retro-aldol activity of the same active site. Reason: Promiscuous aldolase activity, not the core hydroxymethyltransferase function.
GO:0120567 hydroxytrimethyllysine aldolase activity	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic annotation of HTMLA activity (the second step of carnitine biosynthesis). Experimentally demonstrated for human SHMT1 (PMID:38615009), but a low-efficiency backup activity; humans have lost the dedicated Tha1 enzyme. Reason: Real but low-efficiency moonlighting activity that partially compensates for a lost gene; not the evolved core function.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a high-throughput interactome study (with MAPK9/SULT1A4). Uninformative as a molecular function. Reason: Generic protein-binding IPI; provides no specific functional information. Per policy, IPI annotations are marked over-annotated rather than removed.
GO:0005515 protein binding	IPI PMID:30613765 IDH3α regulates one-carbon metabolism in glioblastoma.	MARK AS OVER ANNOTATED	Summary: "Protein binding" supported by the IDH3A(IDH3alpha)-cSHMT interaction that regulates one-carbon metabolism in glioblastoma. Real interaction but the bare term is uninformative as a molecular function. Reason: Underlying interaction is genuine (PMID:30613765) but "protein binding" conveys no specific function; not removed per IPI policy. Supporting Evidence: PMID:30613765 interacting with cytosolic serine
GO:0005515 protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a systematic interaction-perturbation study (with MAPK9). Uninformative molecular function. Reason: Generic protein-binding IPI; no specific functional content.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a binary interactome reference map (DDX6, GORASP2, MDFI). Uninformative molecular function. Reason: Generic protein-binding IPI; no specific functional content.
GO:0042802 identical protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Self-interaction (SHMT1-SHMT1) detected in an interactome study, reflecting the obligate homotetramer. Corroborates GO:0051289 (protein homotetramerization). Reason: Consistent with the tetrameric quaternary structure; captures self-association rather than the catalytic function.
GO:0042802 identical protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	KEEP AS NON CORE	Summary: Self-interaction detected in a binary interactome map, reflecting the homotetramer. Corroborates GO:0051289. Reason: Reflects obligate self-association; supportive of oligomeric assembly, not core MF.
GO:0045329 carnitine biosynthetic process	IDA PMID:38615009 One substrate many enzymes virtual screening uncovers missin...	KEEP AS NON CORE	Summary: SHMT1 catalyzes the HTMLA (second) step of carnitine biosynthesis, demonstrated biochemically. However the catalytic efficiency is very low (~10^1 s^-1 M^-1) and the authors present this as partial compensation for a lost dedicated gene (Tha1). A real but minor/backup contribution. Reason: Experimentally supported (do not remove), but a low-efficiency moonlighting role, not a core dedicated function. Supporting Evidence: PMID:38615009 were found to be able to catalyze the HTMLA reaction PMID:38615009 HTMLA activity of SHMT
GO:0006231 dTMP biosynthetic process	IEA GO_REF:0000107	KEEP AS NON CORE	Summary: Electronic (Ensembl orthology) annotation of dTMP biosynthesis, matching the experimentally established nuclear de novo thymidylate role. Non-core. Reason: Real but specialized nuclear/proliferation-context function (also IDA, PMID:22235121).
GO:0051289 protein homotetramerization	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic annotation of homotetramerization. SHMT1 is an obligate homotetramer (dimer of dimers); this is a genuine structural property (also IDA-supported). Reason: Correct quaternary-structure property underpinning the active enzyme; supportive rather than a standalone core function.
GO:0045329 carnitine biosynthetic process	TAS Reactome:R-HSA-71262	KEEP AS NON CORE	Summary: Reactome (Carnitine synthesis) TAS annotation, consistent with SHMT1's HTMLA backup role in carnitine biosynthesis. Non-core. Reason: Same low-efficiency moonlighting HTMLA activity captured by Reactome; not a core dedicated function.
GO:0046655 folic acid metabolic process	TAS Reactome:R-HSA-196757	ACCEPT	Summary: Reactome (Metabolism of folate and pterines) TAS annotation. SHMT1 participates in folate metabolism; this is a broad parent of the more specific THF interconversion term but a correct pathway context. Reason: Accurate high-level pathway assignment consistent with the enzyme's folate-dependent core reaction.
GO:0005829 cytosol	IDA GO_REF:0000052	ACCEPT	Summary: HPA immunofluorescence localization to the cytosol. This is the primary compartment where SHMT1 acts. Core localization. Reason: Correct and specific primary localization, consistent with UniProt and Reactome.
GO:0008732 L-allo-threonine aldolase activity	EXP PMID:38615009 One substrate many enzymes virtual screening uncovers missin...	KEEP AS NON CORE	Summary: Experimentally measured L-allo-threonine aldolase activity of human SHMT1 (erythro configuration preferred). Genuine promiscuous retro-aldol activity of the active site. Reason: Real experimental promiscuous aldolase activity, not the core hydroxymethyltransferase function.
GO:0050179 phenylserine aldolase activity	ISS GO_REF:0000024	KEEP AS NON CORE	Summary: ISS transfer of 3-phenylserine aldolase activity (from UniProtKB:P35623). A promiscuous retro-aldol activity of the SHMT active site. Reason: Promiscuous side activity inferred by similarity; not core.
GO:0006207 'de novo' pyrimidine nucleobase biosynthetic process	IDA PMID:22235121 Serine hydroxymethyltransferase anchors de novo thymidylate ...	KEEP AS NON CORE	Summary: SHMT1 supplies methylene-THF for de novo thymidylate (dTMP, a pyrimidine deoxyribonucleotide) synthesis in the nuclear thymidylate complex. The more precise term dTMP biosynthetic process (GO:0006231) is also annotated; this broader pyrimidine term is defensible but less specific. Reason: Experimentally supported nuclear thymidylate role; specialized/proliferation-context function rather than the core cytosolic activity. Supporting Evidence: PMID:22235121 de novo thymidylate biosynthesis occurs at replication forks
GO:0006207 'de novo' pyrimidine nucleobase biosynthetic process	IDA PMID:30035852 The catalytic activity of serine hydroxymethyltransferase is...	KEEP AS NON CORE	Summary: Catalytically active SHMT1 is required for de novo nuclear dTMP synthesis in lung cancer cells, supplying the one-carbon unit for thymidylate. Duplicates the pyrimidine biosynthesis annotation from a second study. Reason: Real but specialized nuclear thymidylate function (proliferation context). Supporting Evidence: PMID:30035852 de novo thymidylate synthesis requires SHMT1 to be
GO:0006260 DNA replication	IDA PMID:22235121 Serine hydroxymethyltransferase anchors de novo thymidylate ...	KEEP AS NON CORE	Summary: SHMT1 anchors the de novo thymidylate complex to replication forks and thereby supports DNA replication by supplying dTMP precursors. This is an indirect, supportive role; "DNA replication" is a broad process for a metabolic enzyme. Reason: Experimentally supported association with replication (do not remove), but SHMT1 is a metabolic scaffold/enzyme, not a component of the replication machinery; a downstream contributory role. Supporting Evidence: PMID:22235121 de novo thymidylate biosynthesis occurs at replication forks
GO:0005657 replication fork	IDA PMID:22235121 Serine hydroxymethyltransferase anchors de novo thymidylate ...	KEEP AS NON CORE	Summary: As part of the nuclear de novo thymidylate synthesis complex, SHMT1 localizes to sites of DNA replication initiation (replication forks). Real but specialized nuclear localization. Reason: Experimentally supported conditional localization tied to the thymidylate complex; not the primary compartment. Supporting Evidence: PMID:22235121 The metabolic complex
GO:0005634 nucleus	IDA PMID:22235121 Serine hydroxymethyltransferase anchors de novo thymidylate ...	KEEP AS NON CORE	Summary: Experimentally demonstrated nuclear localization as scaffold of the de novo thymidylate complex. Real but conditional (S/G2-M, proliferation) secondary localization. Reason: Well-supported nuclear pool; the core enzyme acts in the cytosol. Supporting Evidence: PMID:22235121 scaffold protein that is essential for complex formation
GO:0030170 pyridoxal phosphate binding	IDA PMID:9753690 The crystal structure of human cytosolic serine hydroxymethy...	ACCEPT	Summary: Crystal structure of human cytosolic SHMT with PLP; the fold is typical for alpha-class PLP-dependent enzymes and PLP is bound at the active site. Core cofactor binding. Reason: Direct structural evidence for the essential PLP cofactor of the core reaction. Supporting Evidence: PMID:9753690 typical for alpha class pyridoxal 5'-phosphate (PLP) dependent enzymes
GO:0005634 nucleus	IDA PMID:17446168 Evidence for small ubiquitin-like modifier-dependent nuclear...	KEEP AS NON CORE	Summary: SUMO-dependent nuclear import: SUMOylated cSHMT localizes to the nucleus and nuclear periphery during S and G2/M phases. Real conditional secondary localization. Reason: Experimentally supported cell-cycle-restricted nuclear localization; core function is cytosolic. Supporting Evidence: PMID:17446168 cSHMT was shown to localize to the nucleus and
GO:0005737 cytoplasm	IDA PMID:17446168 Evidence for small ubiquitin-like modifier-dependent nuclear...	MARK AS OVER ANNOTATED	Summary: Cytoplasmic localization (IDA). Correct but a broad parent of the more precise cytosol annotation (GO:0005829). Reason: Superseded by the specific cytosol localization; uninformative at this granularity. Propagation Review Root cause: NO FAILURE NON CORE Failure modes: GRANULARITY MISMATCH
GO:0005515 protein binding	IPI PMID:22235121 Serine hydroxymethyltransferase anchors de novo thymidylate ...	MARK AS OVER ANNOTATED	Summary: "Protein binding" supported by the DNA-dependent interaction of SHMT1 with DHFR and TYMS in the de novo thymidylate complex (with/from P00374 DHFR, P04818 TYMS). Real interaction but the bare term is uninformative. Reason: Underlying interactions are genuine and functionally meaningful (scaffolding), but "protein binding" itself conveys no specific function; not removed per IPI policy. Supporting Evidence: PMID:22235121 SHMT serves as
GO:0005521 lamin binding	IDA PMID:22235121 Serine hydroxymethyltransferase anchors de novo thymidylate ...	KEEP AS NON CORE	Summary: SHMT1 binds the nuclear lamina (LMNB1), anchoring the de novo thymidylate complex to the nuclear periphery. A specific, informative moonlighting interaction supporting the nuclear scaffold role. Reason: Experimentally supported specific binding function underlying the nuclear scaffold role; secondary to the core catalytic function. Supporting Evidence: PMID:22235121 associated with the nuclear lamina
GO:0006231 dTMP biosynthetic process	IDA PMID:22235121 Serine hydroxymethyltransferase anchors de novo thymidylate ...	KEEP AS NON CORE	Summary: SHMT1 is essential for de novo thymidylate (dTMP) biosynthesis, both as a scaffold and by supplying the one-carbon unit; the pathway is rate-limited by SHMT expression. This is the specific and accurate term for the nuclear thymidylate role. Reason: Experimentally supported, specialized nuclear/proliferation-context function; not the core cytosolic activity but the best-supported nuclear role. Supporting Evidence: PMID:22235121 SHMT expression is rate-limiting for de novo thymidylate synthesis
GO:0004372 glycine hydroxymethyltransferase activity	IDA PMID:38996576 Structure-based mechanism of riboregulation of the metabolic...	ACCEPT	Summary: Structural/biochemical characterization of human SHMT1 catalyzing the serine/glycine interconversion; the core hydroxymethyltransferase activity (EC 2.1.2.1) confirmed with kinetic parameters. Reason: Direct experimental evidence for the core catalytic function. Supporting Evidence: PMID:38996576 interconverting serine and glycine in one-carbon metabolism
GO:0004793 threonine aldolase activity	IDA PMID:38615009 One substrate many enzymes virtual screening uncovers missin...	KEEP AS NON CORE	Summary: Experimentally measured L-threonine aldolase activity of SHMT1 (retro-aldol cleavage to glycine + acetaldehyde). Genuine promiscuous side activity. Reason: Real promiscuous aldolase activity of the active site; not the core function. Supporting Evidence: file:human/SHMT1/SHMT1-uniprot.txt cleavage of various 3-hydroxy amino acids, such as L-allo-threonine, L-
GO:0006544 glycine metabolic process	IDA PMID:38996576 Structure-based mechanism of riboregulation of the metabolic...	ACCEPT	Summary: Experimentally supported role in glycine metabolism via the reversible serine/glycine interconversion. Core process. Reason: Directly reflects the enzyme's substrate/product.
GO:0006563 L-serine metabolic process	IDA PMID:38996576 Structure-based mechanism of riboregulation of the metabolic...	ACCEPT	Summary: Experimentally supported role in L-serine metabolism; L-serine is the primary substrate. Core process. Reason: Directly reflects the core reaction substrate.
GO:0006730 one-carbon metabolic process	IDA PMID:38996576 Structure-based mechanism of riboregulation of the metabolic...	ACCEPT	Summary: SHMT1 generates the methylene-THF one-carbon donor; riboregulation tunes cytosolic vs mitochondrial one-carbon flux. Core defining process. Reason: Central biological process for the enzyme, experimentally supported. Supporting Evidence: PMID:38996576 one-carbon metabolism
GO:0046653 tetrahydrofolate metabolic process	IDA PMID:38996576 Structure-based mechanism of riboregulation of the metabolic...	ACCEPT	Summary: Experimentally supported role in THF metabolism (THF/5,10-methylene-THF interconversion, folate competition with RNA). Core process. Reason: Reflects the folate cofactor turnover of the core reaction.
GO:0051289 protein homotetramerization	IDA PMID:38996576 Structure-based mechanism of riboregulation of the metabolic...	KEEP AS NON CORE	Summary: SHMT1 assembles into a homotetramer, a structural element required for RNA binding and the active enzyme. Experimentally supported quaternary structure. Reason: Genuine oligomeric assembly property underpinning the active enzyme; supportive of, but distinct from, the catalytic core function. Supporting Evidence: PMID:38996576 we identify the tetrameric
GO:0004372 glycine hydroxymethyltransferase activity	IDA PMID:30035852 The catalytic activity of serine hydroxymethyltransferase is...	ACCEPT	Summary: SHMT1 catalytic activity characterized (with active-site mutants) and shown essential for de novo nuclear dTMP synthesis. Confirms the core catalytic function. Reason: Direct experimental evidence for the core molecular function.
GO:0005634 nucleus	IDA PMID:30035852 The catalytic activity of serine hydroxymethyltransferase is...	KEEP AS NON CORE	Summary: Nuclear localization demonstrated; nuclear translocation is RAN-dependent and independent of oligomeric state and catalytic activity. Real conditional secondary localization. Reason: Experimentally supported nuclear pool; core function is cytosolic.
GO:0006544 glycine metabolic process	IDA PMID:30035852 The catalytic activity of serine hydroxymethyltransferase is...	ACCEPT	Summary: Experimentally supported glycine metabolic role via the core reaction. Duplicates the glycine metabolic process annotation. Reason: Correct core process.
GO:0006563 L-serine metabolic process	IDA PMID:30035852 The catalytic activity of serine hydroxymethyltransferase is...	ACCEPT	Summary: Experimentally supported L-serine metabolic role via the core reaction. Reason: Correct core process.
GO:0046653 tetrahydrofolate metabolic process	IDA PMID:30035852 The catalytic activity of serine hydroxymethyltransferase is...	ACCEPT	Summary: Experimentally supported THF metabolic role via the core reaction. Reason: Correct core process.
GO:0051289 protein homotetramerization	IDA PMID:30035852 The catalytic activity of serine hydroxymethyltransferase is...	KEEP AS NON CORE	Summary: Homotetramerization characterized via oligomer-uncoupling mutants. Genuine quaternary structure property. Reason: Structural assembly property supporting the active enzyme.
GO:0120567 hydroxytrimethyllysine aldolase activity	IDA PMID:38615009 One substrate many enzymes virtual screening uncovers missin...	KEEP AS NON CORE	Summary: Experimentally measured HTMLA activity of human SHMT1 (~10^1 s^-1 M^-1), the second step of carnitine biosynthesis. A low-efficiency backup activity for a lost dedicated enzyme. Reason: Real experimental moonlighting activity; not the evolved core function. Supporting Evidence: PMID:38615009 were found to be able to catalyze the HTMLA reaction
GO:0016832 aldehyde-lyase activity	EXP PMID:11802770 Carnitine biosynthesis in mammals.	KEEP AS NON CORE	Summary: Aldehyde-lyase (C-C lyase) activity is the parent class capturing SHMT1's retro-aldol cleavage reactions (serine cleavage and the 3-hydroxy-amino-acid aldolase side activities). This Reactome-sourced EXP annotation (from a carnitine biosynthesis review) is a broad parent of the specific HTMLA/threonine-aldolase terms. Reason: Correct but broad activity class; the specific glycine hydroxymethyltransferase and aldolase terms are more informative.
GO:0016832 aldehyde-lyase activity	EXP PMID:3110140 Affinity purification and characterization of serine hydroxy...	KEEP AS NON CORE	Summary: Broad aldehyde-lyase class annotation supported by biochemical characterization of purified rat-liver cytosolic SHMT (tetrameric, 4 PLP/enzyme; reactive toward L-allothreonine). Parent of the specific aldolase activities. Reason: Correct but general activity class; superseded by specific MF terms.
GO:0016832 aldehyde-lyase activity	EXP PMID:6795186 Purification and characterization of cytosolic and mitochond...	KEEP AS NON CORE	Summary: Broad aldehyde-lyase class annotation supported by biochemical characterization of purified rat-liver cytosolic and mitochondrial SHMT isozymes (tetrameric, 4 PLP/mol; differing reactivity toward L-allothreonine). Parent of the specific aldolase activities. Reason: Correct but general activity class; superseded by specific MF terms.
GO:0036094 small molecule binding	IPI PMID:24698160 Distinct biochemical properties of human serine hydroxymethy...	MARK AS OVER ANNOTATED	Summary: Very generic "small molecule binding" (with/from CHEBI:67016 = (6S)-5-formyl-THF, a folate ligand). SHMT1 binds folate substrates, but this term is far too broad; the specific PLP-binding and serine-binding annotations are informative. Reason: Uninformative parent term; the specific ligand-binding functions (PLP, serine, folate) are better captured by dedicated terms.
GO:0000900 mRNA regulatory element binding translation repressor activity	IDA PMID:10995219 Human cytoplasmic serine hydroxymethyltransferase is an mRNA...	KEEP AS NON CORE	Summary: SHMT1 binds its own mRNA 5'-UTR and represses translation of 5'-UTR-luciferase fusions by >90% in vitro, independent of amino acid/folate binding. A genuine moonlighting RNA-binding/translation-repressor activity. Reason: Well-supported moonlighting regulatory activity distinct from the catalytic core function. Supporting Evidence: PMID:10995219 inhibits in vitro translation of cSHMT 5'
GO:0004372 glycine hydroxymethyltransferase activity	IDA PMID:10995219 Human cytoplasmic serine hydroxymethyltransferase is an mRNA...	ACCEPT	Summary: The cSHMT enzyme characterized in this study is the catalytically active hydroxymethyltransferase (assayed via allothreonine cleavage); confirms the core activity. Reason: Consistent with the core molecular function.
GO:0017148 negative regulation of translation	IDA PMID:10995219 Human cytoplasmic serine hydroxymethyltransferase is an mRNA...	KEEP AS NON CORE	Summary: SHMT1 represses translation of its own mRNA (and of 5'-UTR fusion reporters). Genuine moonlighting regulatory role in the one-carbon-metabolism riboregulation axis. Reason: Well-supported moonlighting function, secondary to the catalytic core. Supporting Evidence: PMID:10995219 inhibits in vitro translation of cSHMT 5'
GO:0048027 mRNA 5'-UTR binding	IDA PMID:10995219 Human cytoplasmic serine hydroxymethyltransferase is an mRNA...	KEEP AS NON CORE	Summary: SHMT1 binds the 5'-UTR of its own mRNA with increased affinity, mediating translational autoregulation. Specific, informative RNA-binding moonlighting activity (structurally characterized in PMID:38996576). Reason: Well-supported specific RNA-binding function; secondary to the catalytic core. Supporting Evidence: PMID:10995219 displays increased affinity for the 5' untranslated region of its
GO:0004372 glycine hydroxymethyltransferase activity	IDA PMID:24698160 Distinct biochemical properties of human serine hydroxymethy...	ACCEPT	Summary: Biochemical characterization of human cytosolic SHMT catalyzing serine -> glycine + 5,10-methylene-THF, with kinetics and PLP/serine binding. Confirms the core activity. Reason: Direct experimental evidence for the core molecular function. Supporting Evidence: PMID:24698160 catalyzes the transfer of a hydroxymethyl
GO:0006544 glycine metabolic process	IDA PMID:24698160 Distinct biochemical properties of human serine hydroxymethy...	ACCEPT	Summary: Experimentally supported glycine metabolic role via the characterized core reaction. Reason: Correct core process.
GO:0006563 L-serine metabolic process	IDA PMID:24698160 Distinct biochemical properties of human serine hydroxymethy...	ACCEPT	Summary: Experimentally supported L-serine metabolic role; kinetics on L-serine (and D-serine) characterized. Reason: Correct core process, directly reflecting the substrate.
GO:0046653 tetrahydrofolate metabolic process	IDA PMID:24698160 Distinct biochemical properties of human serine hydroxymethy...	ACCEPT	Summary: Experimentally supported THF metabolic role; substrate inhibition by THF (>40 uM) characterized. Reason: Correct core process.
GO:0051289 protein homotetramerization	IDA PMID:24698160 Distinct biochemical properties of human serine hydroxymethy...	KEEP AS NON CORE	Summary: Homotetrameric quaternary structure (subunit analysis). Genuine structural property. Reason: Structural assembly property supporting the active enzyme.
GO:0035999 tetrahydrofolate interconversion	IDA PMID:24698160 Distinct biochemical properties of human serine hydroxymethy...	ACCEPT	Summary: Experimentally supported THF/5,10-methylene-THF interconversion, matching UniProt PATHWAY. Core process. Reason: Precise and accurate pathway assignment for the core reaction.
GO:1904482 cellular response to tetrahydrofolate	IDA PMID:24698160 Distinct biochemical properties of human serine hydroxymethy...	MARK AS OVER ANNOTATED	Summary: Derived from the observation that SHMT1 activity is inhibited by high THF (substrate inhibition above 40 uM). This is an enzyme-kinetics property rather than a genuine cellular signaling "response to" THF; the term over-interprets the data. Reason: The evidence is substrate inhibition (a biochemical property), not a cellular response pathway; the term is an over-interpretation. IDA, so not removed.
GO:0030170 pyridoxal phosphate binding	IDA PMID:24698160 Distinct biochemical properties of human serine hydroxymethy...	ACCEPT	Summary: Experimentally characterized PLP binding (spectral properties of hcSHMT-bound PLP). Core cofactor binding. Reason: Direct evidence for the essential cofactor of the core reaction.
GO:0070905 serine binding	IDA PMID:24698160 Distinct biochemical properties of human serine hydroxymethy...	KEEP AS NON CORE	Summary: Experimentally characterized L-serine (and D-serine) binding at the active site. Specific, informative substrate-binding function underpinning the core reaction. Reason: Genuine specific substrate binding; a molecular detail of the core catalytic activity rather than a standalone core function.
GO:0070062 extracellular exosome	HDA PMID:23533145 In-depth proteomic analyses of exosomes isolated from expres...	MARK AS OVER ANNOTATED	Summary: Detection of SHMT1 in prostatic-secretion/urinary exosome proteomes by high-throughput MS. A common finding for abundant cytosolic enzymes; not indicative of a dedicated extracellular function. Reason: High-throughput proteomic catch-all localization; abundant cytosolic enzyme detected in secreted vesicles, not a functional extracellular localization.
GO:0070062 extracellular exosome	HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos...	MARK AS OVER ANNOTATED	Summary: Detection of SHMT1 in urinary exosome proteomes by large-scale MS. As above, a high-throughput contaminant/secretion catch-all. Reason: Proteomic detection in exosomes; not a dedicated extracellular localization for this cytosolic enzyme.
GO:0005829 cytosol	TAS Reactome:R-HSA-200651	ACCEPT	Summary: Reactome TAS cytosol localization (5,10-methylene-THF + glycine <=> THF + serine reaction). Core primary localization. Reason: Correct primary compartment for the core reaction.
GO:0005829 cytosol	TAS Reactome:R-HSA-200735	ACCEPT	Summary: Reactome TAS cytosol localization (SHMT1 tetramer transfers hydroxymethyl to THFPG). Core primary localization. Reason: Correct primary compartment.
GO:0005829 cytosol	TAS Reactome:R-HSA-71249	ACCEPT	Summary: Reactome TAS cytosol localization (SHMT1 tetramer cleaves HTMLYS to yield TEABL and Gly, the carnitine-pathway step). Core primary localization. Reason: Correct primary compartment.
GO:0004372 glycine hydroxymethyltransferase activity	IDA PMID:17482557 Effect of vitamin B6 availability on serine hydroxymethyltra...	ACCEPT	Summary: SHMT activity assayed in MCF-7 cells under varying vitamin B6 availability; the cytosolic isozyme activity depends on PLP. Confirms the core catalytic function. Reason: Consistent with the core molecular function.
GO:0004372 glycine hydroxymethyltransferase activity	IDA PMID:8505317 Cloning of human cDNAs encoding mitochondrial and cytosolic ...	ACCEPT	Summary: The human cytosolic SHMT cDNA was cloned by functional complementation of an E. coli glyA (SHMT-deficient) mutant, demonstrating the encoded protein has SHMT activity. Reason: Functional complementation directly establishes the core activity of the cloned human cSHMT. Supporting Evidence: PMID:8505317 cloned by functional complementation of an Escherichia coli glyA
GO:0005829 cytosol	IDA PMID:17482557 Effect of vitamin B6 availability on serine hydroxymethyltra...	ACCEPT	Summary: Cytosolic isozyme localization (MCF-7). Core primary localization. Reason: Correct primary compartment.
GO:0006565 L-serine catabolic process	IDA PMID:17482557 Effect of vitamin B6 availability on serine hydroxymethyltra...	MARK AS OVER ANNOTATED	Summary: Frames the serine -> glycine cleavage as serine catabolism. The reaction is reversible, so "catabolic" is a directional over-specification; the more accurate parent is L-serine metabolic process (GO:0006563, also annotated). Reason: Directionally over-specific for a reversible reaction; L-serine metabolic process is the appropriate term. IDA, so not removed.
GO:0009113 purine nucleobase biosynthetic process	IDA PMID:11516159 The role of serine hydroxymethyltransferase isozymes in one-...	MARK AS OVER ANNOTATED	Summary: This 13C-NMR study of one-carbon metabolism in MCF-7 cells actually concludes that cleavage of serine by cytosolic SHMT is NOT a major source of one-carbon groups for purine (or thymidylate) biosynthesis (formate/mitochondrial serine dominate). The annotation over-states cytosolic SHMT1's role in purine biosynthesis. Reason: The cited paper argues against a major purine-biosynthesis role for cytosolic SHMT; the contribution is minor. IDA, so not removed, but flagged as over-annotation. Supporting Evidence: PMID:11516159 does not appear to be a major source of
GO:0030170 pyridoxal phosphate binding	IDA PMID:17482557 Effect of vitamin B6 availability on serine hydroxymethyltra...	ACCEPT	Summary: PLP binding to cytoplasmic SHMT characterized (Kd = 850 nM). Core cofactor binding. Reason: Direct evidence for the essential cofactor. Supporting Evidence: PMID:17482557 PLP bound to cytoplasmic SHMT with a K(d)=850 nM
GO:0042803 protein homodimerization activity	IDA PMID:9753690 The crystal structure of human cytosolic serine hydroxymethy...	KEEP AS NON CORE	Summary: From the crystal structure, SHMT1 forms tight dimers (the active unit; the tetramer is a "dimer of dimers" with the active site at the dimer interface). Homodimerization is a genuine structural property, complementary to the homotetramerization annotation. Reason: Real quaternary-structure property (the obligate tight dimer forms the active site); supportive of, not the same as, the catalytic core function. Supporting Evidence: PMID:9753690 dimer of dimers
GO:0046655 folic acid metabolic process	IDA PMID:11278996 Heavy chain ferritin enhances serine hydroxymethyltransferas...	ACCEPT	Summary: cSHMT expression/activity modulates folate-dependent one-carbon (de novo thymidylate) metabolism (shown via heavy-chain ferritin induction of cSHMT). Consistent with folate metabolism involvement, a broad but correct process. Reason: Accurate high-level folate-metabolism assignment consistent with the enzyme's folate-dependent core reaction.

Gene Description

Existing Annotations Review

Core Functions

Pyridoxal 5'-phosphate cofactor binding: SHMT1 binds PLP through a Schiff base to the conserved active-site Lys-257, which is essential for the core catalytic activity.

References

📚 Additional Documentation

Notes

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