PFAS (O15067) — review notes

Identity and function

• Gene/protein: PFAS = phosphoribosylformylglycinamidine synthase (FGAM synthase; FGAMS);
  also called formylglycinamide ribonucleotide amidotransferase (FGAR-AT / FGARAT). UniProt
  PUR4_HUMAN, O15067. HGNC:8863. EC 6.3.5.3.
• Reaction (RHEA:17129): N2-formyl-N1-(5-phospho-β-D-ribosyl)glycinamide (FGAR) + L-glutamine
• ATP + H2O → 2-formamido-N1-(5-O-phospho-β-D-ribosyl)acetamidine (FGAM) + L-glutamate + ADP +
  phosphate + H+.
• Pathway: fourth step of de novo purine synthesis (DNPS); IMP biosynthesis via de novo pathway.
  PMID:10548741. Deep research (falcon) unavailable — HTTP 402, out of credits.
• Domain architecture (UniProt): N-terminal FGAR-AT / PurL synthetase region (ATP-binding,
  Mg2+-binding) + C-terminal class-I glutamine amidotransferase (GATase-1) domain (residues
  1064–1302; catalytic Cys1158 nucleophile). Glutamine amidotransferase keyword.
• Localization: cytoplasm/cytosol [UniProt SUBCELLULAR LOCATION: Cytoplasm; Reactome R-HSA-73812
  "the enzyme is cytosolic"]. Also detected in B-cell exosome proteome (HDA, PMID:20458337) as one of
  539 proteins — non-specific mass-spec catalog, not a functional localization.
• Biology: houses-keeping DNPS enzyme; a component of the purinosome (multi-enzyme DNPS complex).
  No well-established Mendelian disease; of interest in cancer metabolism / nucleotide demand.

Publications (all abstract-only in cache)

• PMID:10548741 (Patterson et al., Gene 1999): cloned the human FGARAT cDNA/genomic clone;
  P1 clone complements purine-auxotroph AdeB CHO mutants deficient in FGARAT activity+protein;
  maps to 17p13. Source of the IDA MF (enables GO:0004642) and NAS BP (de novo IMP) annotations.
• PMID:27590927 (Baresova et al., Mol Genet Metab 2016): CRISPR-Cas9 knockouts of individual DNPS
  enzymes in HeLa; substrate accumulation and impaired purinosome assembly. Source of MGI IMP/IDA
  annotations. Abstract frames DNPS ("ten reactions catalysed by six enzymes") without naming PFAS;
  full text (not cached) assays the FGAR-AT step. Per curation policy, defer to MGI curator.
• PMID:20458337 (Buschow et al., Immunol Cell Biol 2010): B-cell exosome MS proteome, 539 proteins;
  source of HDA extracellular-exosome CC.

Annotation decisions (summary)

Core: MF GO:0004642 (FGAM synthase activity); BP GO:0006189 (de novo IMP biosynthesis) and
GO:0006164 (purine nucleotide biosynthetic process); CC GO:0005829 (cytosol).

• GO:0004642 MF (IBA, IEA, TAS x1, IMP, IDA x2): ACCEPT — well-supported core MF.
• GO:0005737 cytoplasm (IBA, IEA): ACCEPT.
• GO:0005829 cytosol (TAS Reactome): ACCEPT — most specific correct CC.
• GO:0006189 de novo IMP (IBA-absent; IEA, IMP, IDA, NAS): ACCEPT core BP.
• GO:0006164 purine nucleotide biosynthetic process (IBA): ACCEPT (broader parent, correct).
• GO:0006541 L-glutamine metabolic process (IEA, Ensembl ortholog): KEEP_AS_NON_CORE — true
  (glutamine is the amide donor) but a side/co-substrate process, not the core purine-synthesis role.
• GO:0009410 response to xenobiotic stimulus (IEA, Ensembl rat ortholog): MARK_AS_OVER_ANNOTATED —
  not the enzyme's core function; over-propagated from a rat ortholog phenotype.
• GO:0009168 purine ribonucleoside monophosphate biosynthesis (TAS Reactome): ACCEPT (pathway-level).
• GO:0006177 GMP biosynthetic process (IMP acts_upstream_of_or_within; IDA involved_in):
  KEEP_AS_NON_CORE — downstream branch (IMP→GMP); PFAS acts upstream via IMP, not a GMP-synthesis enzyme.
• GO:0044208 de novo AMP biosynthesis (IMP, IDA): KEEP_AS_NON_CORE — downstream branch (IMP→AMP).
• GO:0097294 de novo XMP biosynthesis (IMP, IDA): KEEP_AS_NON_CORE — downstream branch (IMP→XMP).
• GO:0070062 extracellular exosome (HDA): MARK_AS_OVER_ANNOTATED — bulk MS catalog, not a
  functional/biosynthetically meaningful localization for a cytosolic DNPS enzyme.

Downstream-branch BPs (GMP/AMP/XMP) capture that loss of PFAS depletes all purine nucleotides
(acts_upstream_of_or_within is the correct qualifier), but the enzyme's own reaction is upstream at
the IMP-precursor step, so these are non-core. Per policy, experimental (IMP/IDA/HDA) annotations
whose full text is uncached are not REMOVEd.