PSAT1 is human phosphoserine aminotransferase (EC 2.6.1.52), a cytosolic, pyridoxal 5'-phosphate (PLP)-dependent transaminase that catalyzes the second step of the phosphorylated pathway of de novo L-serine biosynthesis. It transfers the amino group from L-glutamate to 3-phosphohydroxypyruvate, yielding O-phospho-L-serine and 2-oxoglutarate; this reaction is thermodynamically favorable and helps drive the overall pathway toward L-serine. The enzyme is a homodimer, with each of the two PLP cofactors bound (via a Schiff base to Lys200) at the monomer-monomer interface and shared between the subunits. PSAT1 belongs to the class-V PLP-dependent aminotransferase family (SerC subfamily). L-serine produced by this pathway is a precursor for glycine, cysteine, D-serine, phospholipids, and nucleotides, and is especially important in the central nervous system, where serine is poorly transported across the blood-brain barrier. Loss-of-function variants cause autosomal recessive serine deficiency disorders, ranging from phosphoserine aminotransferase deficiency (seizures, microcephaly, psychomotor retardation) to the lethal Neu-Laxova syndrome 2. Beyond its housekeeping metabolic role, PSAT1 has a described noncanonical activity in which, following CAMK2A-mediated phosphorylation, it interacts with and stabilizes GPX4 to suppress ferroptosis.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004648 O-phospho-L-serine:2-oxoglutarate transaminase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (PAN-GO) inference of the core catalytic activity of PSAT1, the phosphoserine aminotransferase reaction. This is the defining molecular function of the gene and is independently supported by direct experimental and structural evidence in human PSAT. Supporting Evidence: file:human/PSAT1/PSAT1-uniprot.txt Catalyzes the second step, that is the pyridoxal 5'-phosphate-dependent |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: Phylogenetic inference that PSAT1 acts in the cytoplasm. This is correct but less precise than the direct IDA annotation to cytosol (GO:0005829); it is a valid ancestor term and can be retained as non-core supporting localization. Proposed replacements: cytosol |
| GO:0006564 L-serine biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference of the core biological process. PSAT1 catalyzes step 2/3 of the phosphorylated pathway of L-serine biosynthesis; strongly supported by direct experimental evidence and disease genetics. Supporting Evidence: file:human/PSAT1/PSAT1-uniprot.txt PATHWAY: Amino-acid biosynthesis; L-serine biosynthesis; L-serine from |
| GO:0030170 pyridoxal phosphate binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic inference that PSAT1 binds pyridoxal 5'-phosphate. This is correct and central to catalysis; the cofactor is covalently bound at Lys200 and confirmed in the crystal structures. A core cofactor-binding function. Supporting Evidence: file:human/PSAT1/PSAT1-uniprot.txt Binds 2 pyridoxal phosphate molecules per dimer, each cofactor is |
| GO:0004648 O-phospho-L-serine:2-oxoglutarate transaminase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic inference (ARBA/EC 2.6.1.52/RHEA:14329/InterPro) of the phosphoserine aminotransferase activity. Correct and redundant with the experimental IDA/EXP annotations to the same term. |
| GO:0006564 L-serine biosynthetic process | IEA GO_REF:0000002 | ACCEPT | Summary: InterPro2GO electronic inference of the L-serine biosynthetic process. Correct and redundant with the experimental IDA annotation to the same term. |
| GO:0005515 protein binding | IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" from a high-throughput neurodegenerative-disease interactome screen (IntAct partners CALR, CDH1, DLST, NEK7). This term is uninformative about PSAT1 function and does not identify a specific molecular activity; it is an over-annotation rather than a core function. Not removed per policy for IPI protein-binding annotations. |
| 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 the HuRI human binary interactome (Y2H). This is consistent with the biologically established PSAT1 homodimer, so the annotation is credible; however self-dimerization is a structural property rather than the core catalytic function, so it is retained as non-core. Supporting Evidence: file:human/PSAT1/PSAT1-uniprot.txt Homodimer. |
| GO:0005829 cytosol | IDA GO_REF:0000052 | ACCEPT | Summary: Direct immunofluorescence localization (Human Protein Atlas) to the cytosol. Consistent with the known cytosolic site of the phosphorylated serine-biosynthesis pathway and with Reactome. This is the accurate subcellular location of PSAT1. |
| GO:0004648 O-phospho-L-serine:2-oxoglutarate transaminase activity | EXP PMID:36851825 L-serine biosynthesis in the human central nervous system: S... | ACCEPT | Summary: Direct functional and structural characterization of recombinant human PSAT establishing the phosphoserine aminotransferase activity (PLP-dependent transamination of 3-phosphohydroxypyruvate and L-glutamate), with kinetic parameters and OPS-bound crystal structures. Core catalytic function. Supporting Evidence: PMID:36851825 Phosphoserine aminotransferase (PSAT) catalyzes the intermediate PMID:36851825 pyridoxal 5'-phosphate-dependent transamination of |
| GO:0004648 O-phospho-L-serine:2-oxoglutarate transaminase activity | IDA PMID:40281343 PSAT1 impairs ferroptosis and reduces immunotherapy efficacy... | ACCEPT | Summary: Direct assay of PSAT1 phosphoserine aminotransferase activity; the K200A active-site mutant abolishes the activity, confirming catalytic function is PLP-dependent at Lys200. Core catalytic function. Supporting Evidence: file:human/PSAT1/PSAT1-uniprot.txt K->A: Abolished phosphoserine aminotransferase |
| GO:0110076 negative regulation of ferroptosis | IDA PMID:40281343 PSAT1 impairs ferroptosis and reduces immunotherapy efficacy... | KEEP AS NON CORE | Summary: Noncanonical, phosphorylation-dependent moonlighting role. Upon CAMK2A-mediated phosphorylation at Ser337 (downstream of IFN-gamma), PSAT1 binds GPX4 and provides 2-oxoglutarate to PHD3/EGLN3, promoting GPX4 Pro159 hydroxylation and stabilization, thereby suppressing ferroptosis. This is a genuine but context-dependent regulatory activity distinct from the housekeeping serine-biosynthesis role, so it is kept as non-core. Supporting Evidence: PMID:40281343 interact with glutathione peroxidase 4 (GPX4) and stabilize the protein, counteracting |
| GO:0004648 O-phospho-L-serine:2-oxoglutarate transaminase activity | IDA PMID:37627284 Phosphoserine Aminotransferase Pathogenetic Variants in Seri... | ACCEPT | Summary: Direct characterization of recombinant human PSAT catalytic activity as part of a functional analysis of serine-deficiency-disorder variants, with in vitro reconstruction of the phosphorylated pathway. Core catalytic function. Supporting Evidence: PMID:37627284 phosphoserine aminotransferase (PSAT) and phosphoserine phosphatase |
| GO:0006564 L-serine biosynthetic process | IDA PMID:37627284 Phosphoserine Aminotransferase Pathogenetic Variants in Seri... | ACCEPT | Summary: Direct evidence that PSAT1 functions in L-serine biosynthesis via the phosphorylated pathway, demonstrated by in vitro reconstruction of the pathway and by the effects of pathogenic variants on pathway flux. Core biological process. Supporting Evidence: PMID:37627284 converts the glycolytic intermediate |
| GO:0005829 cytosol | TAS Reactome:R-HSA-977333 | ACCEPT | Summary: Reactome traceable statement placing the PSAT1-catalyzed transamination in the cytosol. Consistent with the HPA IDA localization; accurate subcellular location. Supporting Evidence: Reactome:R-HSA-977333 transfer onto 3-phosphonooxpyruvate (3POPA) is catalysed by PSAT1 dimer which needs pyridoxal phosphate (PXLP) as cofactor |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | KEEP AS NON CORE | Summary: Detection in a high-throughput urinary exosome proteomics dataset. Abundant cytosolic metabolic enzymes are frequently recovered in exosome preparations; this is a valid HDA observation but not part of the core cytosolic catalytic function, so it is kept as non-core. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | KEEP AS NON CORE | Summary: Detection in a high-throughput B-cell exosome proteomics dataset; corroborates the exosome recovery seen in PMID:19056867. Same interpretation - a non-core high-throughput localization for an abundant cytosolic enzyme. |
| GO:0004648 O-phospho-L-serine:2-oxoglutarate transaminase activity | NAS PMID:10637769 Phosphoserine aminotransferase, the second step-catalyzing e... | ACCEPT | Summary: Author statement (based on characterization of the mammalian, bovine phosphoserine aminotransferase) assigning the phosphoserine aminotransferase activity. Correct and superseded by later direct human experimental evidence for the same term. Supporting Evidence: PMID:10637769 phosphoserine aminotransferase, the second step-catalyzing enzyme for serine biosynthesis |
| GO:0006564 L-serine biosynthetic process | NAS PMID:10637769 Phosphoserine aminotransferase, the second step-catalyzing e... | ACCEPT | Summary: Author statement assigning PSAT to L-serine biosynthesis; the paper explicitly frames the enzyme as the second step-catalyzing enzyme for serine biosynthesis. Correct and redundant with the human IDA annotation. Supporting Evidence: PMID:10637769 the second step-catalyzing enzyme for serine biosynthesis |
| GO:0008615 pyridoxine biosynthetic process | NAS PMID:10637769 Phosphoserine aminotransferase, the second step-catalyzing e... | MARK AS OVER ANNOTATED | Summary: Over-annotation. PSAT1 uses pyridoxal 5'-phosphate (vitamin B6) as an essential cofactor for its transaminase reaction, but it does not synthesize pyridoxine/vitamin B6. Human PSAT1 has no role in pyridoxine biosynthesis, and the cited paper characterizes the serine-biosynthesis transaminase, not a B6-biosynthetic activity. This NAS annotation conflates cofactor usage with cofactor biosynthesis. |
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Download this section (compressed HTML)Q: Under what physiological or pathological conditions (e.g. inflamed tumor microenvironment) is the noncanonical PSAT1-GPX4 ferroptosis-suppression activity engaged, and how does it partition against the housekeeping serine-biosynthesis role?
Q: Does isoform 2 (alpha; lacking residues 291-336) retain catalytic activity, and what is its physiological relevance given that isoform 1 is considered the primary transcript?
Experiment: Structure-guided separation-of-function analysis using the K200A (catalysis-dead) and S337A (phosphorylation-dead) mutants to dissect the metabolic serine-biosynthesis role from the ferroptosis-regulatory role in cells and in serine-deficiency models.
Hypothesis: PSAT1 catalytic activity and GPX4-stabilizing activity are genetically separable functions.
Type: genetic manipulation/biochemistry
Experiment: Quantitative flux analysis of the reconstituted phosphorylated pathway with purified PHGDH, PSAT1, and PSPH to measure how patient-derived PSAT1 variants alter L-serine output, linking specific kinetic defects to disease severity.
Hypothesis: Disease severity in PSATD/NLS2 tracks quantitatively with the reduction in pathway flux caused by each PSAT1 variant.
Type: enzymology/metabolic flux
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