PYCR1 (human) — gene review notes

UniProt: P32322 (P5CR1_HUMAN); HGNC:9721; NCBI Gene 5831; chromosome 17q25.
Source files read: PYCR1-uniprot.txt, PYCR1-goa.tsv, cached publications/PMID_*.md,
reactome/R-HSA-70664.md. No deep-research file (falcon out of credits) — notes are
grounded directly in the local records.

Core identity and function

PYCR1 is pyrroline-5-carboxylate reductase 1, EC 1.5.1.2, a mitochondrial
NAD(P)H-dependent oxidoreductase that catalyzes the last step of proline
biosynthesis: reduction of (S)-1-pyrroline-5-carboxylate (P5C) to L-proline.

• [file:human/PYCR1/PYCR1-uniprot.txt "Oxidoreductase that catalyzes the last step in proline"] /
  "biosynthesis, which corresponds to the reduction of pyrroline-5-" (CC FUNCTION, lines 238-239).
• UniProt CATALYTIC ACTIVITY: L-proline + NADP(+) = (S)-1-pyrroline-5-carboxylate + NADPH + 2 H(+)
  (RHEA:14109) and the NAD(+) counterpart (RHEA:14105); EC=1.5.1.2. PhysiologicalDirection is
  right-to-left, i.e. P5C -> proline.
• UniProt PATHWAY: [file:human/PYCR1/PYCR1-uniprot.txt "Amino-acid biosynthesis; L-proline biosynthesis; L-proline"]
  from L-glutamate 5-semialdehyde: step 1/1.
• Cofactor preference: [file:human/PYCR1/PYCR1-uniprot.txt "concentrations, has higher specific activity in the presence of NADH"]
  (physiologic conditions). Consistent with Reactome using the NADH reaction.
• GO term IDs verified against current ontology (OLS): GO:0004735 pyrroline-5-carboxylate reductase
  activity; GO:0055129 L-proline biosynthetic process; GO:1902792 pyrroline-5-carboxylate reductase
  complex; GO:0005759 mitochondrial matrix — all non-obsolete, labels current.

Structure / assembly

• Homodecamer = pentamer of dimers. PMID:16730026
  (first human crystal structure; also mutagenesis of Glu221, Rossmann motif).
• PMID:28258219
  pentamer-of-dimers assembly (sedimentation velocity + crystallography). This paper corrected the
  earlier mis-assignment of the cofactor site: NADPH binds the N-terminal Rossmann fold, ~25 Å from
  the previously proposed C-terminal site. T238A mutant has decreased P5C reductase activity.
• Early biochemistry: PMID:2722838 12-mer
  (human erythrocyte enzyme; NADH vs NADPH kinetics; note this paper argued a possible NADP+-
  generating role in erythrocytes, i.e. proline oxidation direction — a cell-type-specific nuance).

Localization

• Mitochondrion / mitochondrial matrix.
• PMID:19648921 (co-localization).
• PMID:23024808
  (subcellular fractionation; PYCR1 & PYCR2 mitochondrial, PYCRL cytoplasmic).
• Reactome places the reaction in the mitochondrial matrix (R-HSA-70664, TAS).

Substrate/route specialization (De Ingeniis 2012, PMID:23024808, full text)

• PMID:23024808; under some
  conditions (no extracellular proline, high ornithine) it can also use the ornithine route, but this
  is unlikely physiological. PYCR2 exclusively glutamate route; PYCRL exclusively ornithine route.
• NADH-preferring, product-(proline)-inhibited (mitochondrial PYCRs).

Disease

• UniProt DISEASE: ARCL2B [MIM:612940] and ARCL3B [MIM:614438] — autosomal recessive cutis laxa,
  progeroid/De Barsy-like. Caused by PYCR1 variants (evidence PubMed:19576563, 19648921, 22052856).
• PMID:19648921 (Nat Genet): mutations cause cutis laxa with progeroid features; patient fibroblasts
  show altered mitochondrial morphology, membrane potential, and
  PMID:19648921.

Interactions / non-core roles

• DJ-1/PARK7: PMID:23743200 vitro;
  PMID:23743200;
  PMID:23743200;
  PMID:23743200;
  PMID:23743200
  — shared anti-oxidative-stress pathway.
• ORAOV1/LTO1: PMID:24930674
  and ROS production in esophageal cancer.
• TNPO2: binary interaction from HuRI interactome (PMID:32296183) — generic protein binding only.

Curation decisions (summary)

• Core: GO:0004735 (MF), GO:0055129 (BP), GO:1902792 (complex), GO:0005759 mitochondrial matrix
  (location). All catalytic-activity, proline-biosynthesis, complex, and mitochondrial-localization
  annotations ACCEPTed (experimental IDA/IBA/IEA/TAS all concordant).
• KEEP_AS_NON_CORE: oxidative-stress response (GO:0034599), regulation of mitochondrial membrane
  potential (GO:0051881), the over-specific GO:1903377 (neuron intrinsic apoptotic — cell lines used,
  not neuron-specific), and the two identical-protein-binding (homo-oligomerization) annotations.
• MARK_AS_OVER_ANNOTATED (not REMOVE — experimental IPI): the three bare "protein binding"
  (GO:0005515) annotations (DJ-1, TNPO2, ORAOV1/LTO1). Interactions are real but the plain MF term is
  uninformative; per policy these IPI annotations are marked over-annotated rather than removed.
• No annotations REMOVEd. No experimental annotations removed.