PSPH

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005737 cytoplasm	IBA GO_REF:0000033	KEEP AS NON CORE	Summary: Phylogenetic (IBA) inference that PSPH is active in the cytoplasm. Correct but non-specific; the enzyme is more precisely localized to the cytosol (GO:0005829, supported by IDA). Kept as non-core in favor of the cytosol term. Reason: Cytoplasm is a correct but coarse compartment; the cytosol IDA annotation is the informative location. UniProt: "Cytoplasm, cytosol". Supporting Evidence: file:human/PSPH/PSPH-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0006564 L-serine biosynthetic process	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference that PSPH is involved in L-serine biosynthesis. This is the core biological process of the gene and is independently supported by experimental (IMP, PMID:14673469) and pathway evidence. Reason: Core pathway role. UniProt PATHWAY: L-serine from 3-phospho-D-glycerate, step 3/3. Supporting Evidence: file:human/PSPH/PSPH-uniprot.txt Amino-acid biosynthesis; L-serine biosynthesis; L-serine from
GO:0036424 L-phosphoserine phosphatase activity	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference of the catalytic activity. This is the core molecular function of PSPH and is strongly supported by direct experimental evidence (EXP/IDA/IMP) in this record. GO:0036424 is the current (non-obsolete) term that precisely matches the O-phospho-L-serine + H2O = L-serine + phosphate reaction. Reason: Core catalytic activity, corroborated by multiple experimental annotations. Supporting Evidence: file:human/PSPH/PSPH-uniprot.txt dephosphorylation of O-phospho-L- serine to L-serine
GO:0000287 magnesium ion binding	IBA GO_REF:0000033	ACCEPT	Summary: Phylogenetic inference that PSPH binds Mg2+. Correct and core to catalysis; the enzyme binds 1 Mg2+ per subunit and is Mg2+-dependent. Also supported by IDA (PMID:15291819). Reason: Essential catalytic cofactor. UniProt COFACTOR: "Binds 1 Mg(2+) ion per subunit". Supporting Evidence: file:human/PSPH/PSPH-uniprot.txt Note=Binds 1 Mg(2+) ion per subunit.
GO:0005829 cytosol	IEA GO_REF:0000044	KEEP AS NON CORE	Summary: Electronic mapping from the UniProt subcellular-location vocabulary (cytosol). Consistent with the experimental (IDA) cytosol annotation and with the cytosolic biochemistry of this enzyme. Kept as non-core location, matching the other cytosol annotations. Reason: Correct location, redundant with and supported by the IDA cytosol annotation. Supporting Evidence: file:human/PSPH/PSPH-uniprot.txt SUBCELLULAR LOCATION: Cytoplasm, cytosol
GO:0006564 L-serine biosynthetic process	IEA GO_REF:0000002	ACCEPT	Summary: InterPro2GO electronic annotation (IPR004469, PSP) to L-serine biosynthesis. Correct core BP; redundant with the IBA and IMP annotations to the same term. Reason: Correct pathway assignment from the PSP InterPro family.
GO:0036424 L-phosphoserine phosphatase activity	IEA GO_REF:0000120	ACCEPT	Summary: Combined electronic (InterPro + RHEA:21208) annotation of the catalytic activity. Correct core MF; redundant with the experimental annotations. Reason: Correct catalytic-activity assignment, matching the curated Rhea reaction.
GO:0042802 identical protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	KEEP AS NON CORE	Summary: Self-interaction detected in a proteome-scale binary interactome (Y2H) map. PSPH is a homodimer, so a self-interaction is biologically expected. "Identical protein binding" is the generic self-binding term; the more informative GO:0042803 protein homodimerization activity annotation (PMID:12777757) captures the same biology. Kept as non-core evidence for the obligate homodimer. Reason: Supports the homodimer, but the homodimerization term is the informative form; this generic self-binding IPI is corroborating, not core.
GO:0042802 identical protein binding	IPI PMID:25502805 A massively parallel pipeline to clone DNA variants and exam...	KEEP AS NON CORE	Summary: Self-interaction curated by IntAct from a high-throughput Clone-seq / comparative interactome-scanning pipeline. Consistent with the PSPH homodimer. Generic self-binding term; the homodimerization annotation is the informative form. Reason: Corroborates the homodimer; superseded by the specific homodimerization term.
GO:0042802 identical protein binding	IPI PMID:31515488 Extensive disruption of protein interactions by genetic vari...	KEEP AS NON CORE	Summary: Self-interaction from Fragoza et al., who explicitly characterize the PSPH self-interaction and show that a rare dimerization-disrupting variant (T152I) reduces phosphatase activity to ~59% of wild-type. This is the strongest evidence that the self-association is functionally required for catalysis, but the informative representation is GO:0042803 (homodimerization). Kept as non-core. Reason: Functionally meaningful self-interaction (dimerization needed for activity), but best represented by the homodimerization term rather than generic identical protein binding. Supporting Evidence: PMID:31515488 Since PSPH exists as a dimer in solution and can aggregate when mutations that interfere with dimerization are introduced
GO:0009612 response to mechanical stimulus	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Electronic transfer (Ensembl Compara, GO_REF:0000107) from a rat ortholog (UniProtKB:Q5M819 / ENSRNOP00000001228). This is a physiological expression/regulation phenotype of the rat gene, not a molecular function of human PSPH, and is not supported by any human data here. Over-annotation of a housekeeping metabolic enzyme. Reason: IEA orthology transfer of a rat regulatory-context phenotype; not a core or human-supported function of PSPH.
GO:0031667 response to nutrient levels	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Electronic transfer from the same rat ortholog. Plausible for a serine-pathway enzyme (serine synthesis responds to nutrient/amino-acid status), but this is a transferred regulatory-context phenotype, not a molecular function, and is unsupported by human data. Over-annotation. Reason: IEA orthology transfer of a rat response phenotype; not core to PSPH function.
GO:0033574 response to testosterone	IEA GO_REF:0000107	MARK AS OVER ANNOTATED	Summary: Electronic transfer from the rat ortholog. A tissue/hormone-context expression response of the rat gene, not a molecular function of human PSPH, and unsupported by any human evidence in this record. Over-annotation. Reason: IEA orthology transfer of a rat hormone-response phenotype; not core.
GO:0036424 L-phosphoserine phosphatase activity	TAS PMID:9188776 Human L-3-phosphoserine phosphatase: sequence, expression an...	ACCEPT	Summary: Author statement (TAS) of the catalytic activity from the paper that cloned and biochemically characterized the human enzyme, demonstrating Mg2+-dependent hydrolysis of L-phosphoserine and a phosphoenzyme intermediate. Core MF. Reason: Core catalytic activity established by the original human-enzyme characterization. Supporting Evidence: PMID:9188776 it catalyzed the Mg2(+)-dependent hydrolysis of L-phosphoserine
GO:0036424 L-phosphoserine phosphatase activity	EXP PMID:12213811 Molecular basis for the local conformational rearrangement o...	ACCEPT	Summary: Experimental (structure + mutagenesis) evidence for the catalytic activity; active-site mutations (e.g. E29Q, R65A) abolish L-phosphoserine phosphatase activity. Core MF. Reason: Direct experimental support for the core catalytic function. Supporting Evidence: file:human/PSPH/PSPH-uniprot.txt E->Q: Loss of L-phosphoserine phosphatase activity.
GO:0036424 L-phosphoserine phosphatase activity	EXP PMID:25080166 Phosphoserine phosphatase (PSPH) gene mutation in an intelle...	ACCEPT	Summary: Experimental annotation of the catalytic activity in the context of a PSPH disease variant (A35T) from an intellectual-disability family; the variant decreases L-phosphoserine phosphatase activity. Core MF. Reason: Experimental support for the catalytic activity (disease-variant characterization). Supporting Evidence: file:human/PSPH/PSPH-uniprot.txt in PSPHD; decreased L-phosphoserine
GO:0036424 L-phosphoserine phosphatase activity	EXP PMID:9222972 Phosphoserine phosphatase deficiency in a patient with Willi...	ACCEPT	Summary: Experimental evidence tied to the first phosphoserine phosphatase deficiency patient, whose fibroblasts/lymphoblasts had ~25% of normal PSPH activity. Core MF. Reason: Reduced enzyme activity in patient cells supports the catalytic function of PSPH. Supporting Evidence: PMID:9222972 the phosphoserine phosphatase (EC 3.1.3.3.) activity in lymphoblasts and fibroblasts amounted to about 25% of normal values
GO:0005829 cytosol	IDA PMID:1965857 Phosphoserine phosphatase of human brain: partial purificati...	KEEP AS NON CORE	Summary: Direct evidence that PSPH is a cytosolic enzyme, from purification of the enzyme from human brain. Correct location; this is the informative cytosol annotation. Localization is a support attribute rather than the core evolved function. Reason: Correct experimentally-supported location; retained as the location for core functions but not itself the core function. Supporting Evidence: PMID:1965857 Phosphoserine phosphatase (PSPase), a cytosolic enzyme
GO:0036424 L-phosphoserine phosphatase activity	IMP PMID:14673469 Mutations responsible for 3-phosphoserine phosphatase defici...	ACCEPT	Summary: Mutational (IMP) evidence: PSPHD-causing variants D32N and M52T reduce/abolish the enzyme's activity on recombinant protein, demonstrating that PSPH enables L-phosphoserine phosphatase activity. Core MF. Reason: Disease-variant mutagenesis directly supports the catalytic function. Supporting Evidence: PMID:14673469 Met52Thr almost abolished the enzymatic activity, whereas the Asp32Asn mutation caused a 50% decrease in Vmax
GO:0006564 L-serine biosynthetic process	IMP PMID:14673469 Mutations responsible for 3-phosphoserine phosphatase defici...	ACCEPT	Summary: IMP evidence linking PSPH to L-serine biosynthesis: loss-of-function disease variants cause serine deficiency, placing the gene in the biosynthetic pathway. Core BP. Reason: Disease-variant evidence supports PSPH's role in L-serine biosynthesis. Supporting Evidence: PMID:14673469 the only known case of L-3-phosphoserine phosphatase deficiency
GO:0036424 L-phosphoserine phosphatase activity	IDA PMID:15291819 How calcium inhibits the magnesium-dependent enzyme human ph...	ACCEPT	Summary: Direct assay of the Mg2+-dependent enzyme and its inhibition by Ca2+, supporting the catalytic activity. Core MF. Reason: Direct biochemical assay of the catalytic activity. Supporting Evidence: PMID:15291819 the Mg(2+)-dependent enzyme human phosphoserine
GO:0005829 cytosol	TAS Reactome:R-HSA-977324	KEEP AS NON CORE	Summary: Reactome traceable-author statement placing the PSPH:Mg2+ dimer reaction (dephosphorylation of O-phospho-L-serine) in the cytosol. Consistent with the experimental cytosol localization. Kept as non-core location. Reason: Correct location from Reactome, redundant with the IDA cytosol annotation. Supporting Evidence: Reactome:R-HSA-977324 PSPH:Mg2+ dimer dephosphorylates O-P-Ser
GO:0000287 magnesium ion binding	IDA PMID:15291819 How calcium inhibits the magnesium-dependent enzyme human ph...	ACCEPT	Summary: Direct (structural/biochemical) evidence that PSPH binds Mg2+ in its active site; replacement by Ca2+ inhibits the enzyme. Essential catalytic cofactor. Core MF. Reason: Direct evidence for the essential Mg2+ cofactor. Supporting Evidence: PMID:15291819 The sixfold coordinated Mg(2+) ion present in the active site of HPSP
GO:0006563 L-serine metabolic process	IDA PMID:15291819 How calcium inhibits the magnesium-dependent enzyme human ph...	KEEP AS NON CORE	Summary: IDA to the broader "L-serine metabolic process". Correct but a more general parent of the specific L-serine biosynthetic process (GO:0006564), which is the informative BP for this enzyme. Kept as non-core to avoid redundancy with the biosynthetic term. Reason: Correct but subsumed by the more specific L-serine biosynthetic process annotation; retained as non-core.
GO:0042803 protein homodimerization activity	IPI PMID:12777757 High-resolution structure of human phosphoserine phosphatase...	ACCEPT	Summary: PSPH is a homodimer, established crystallographically (open-conformation structure). Dimerization is functionally relevant: a dimer-disrupting variant lowers catalytic activity (PMID:31515488). This is the informative self-association term (preferred over generic identical protein binding), and it is a genuine structural attribute of the active enzyme; the core evolved function is the catalytic activity, with homodimerization as a supporting quaternary-structure function. Reason: Well-supported obligate homodimer (multiple crystal structures; UniProt SUBUNIT "Homodimer"); functionally required for full activity. Supporting Evidence: PMID:12777757 HPSP is a dimeric enzyme responsible for the third and final step

Gene Description

Existing Annotations Review

Core Functions

Mg2+-dependent hydrolysis of O-phospho-L-serine to L-serine and inorganic phosphate (EC 3.1.3.3), the third and final, committed step of de novo L-serine biosynthesis. Catalysis proceeds via a covalent phosphoaspartyl-enzyme intermediate (Asp20 nucleophile) and requires one bound Mg2+ per subunit.

Binding of the essential catalytic Mg2+ cofactor (1 ion per subunit) in the active site; substitution by Ca2+ inhibits the enzyme.

Homodimerization: the active enzyme is an obligate homodimer, and disruption of the self-interaction reduces catalytic activity.

References

📚 Additional Documentation

Notes

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