id: P32322
gene_symbol: PYCR1
product_type: PROTEIN
status: INITIALIZED
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PYCR1 (pyrroline-5-carboxylate reductase 1) is a mitochondrial NAD(P)H-dependent
  oxidoreductase (EC 1.5.1.2) that catalyzes the final, committed step of proline
  biosynthesis: the reduction of (S)-1-pyrroline-5-carboxylate (P5C) to L-proline.
  P5C is the common intermediate produced from glutamate (via P5C synthase) or from
  ornithine (via ornithine aminotransferase); PYCR1 acts primarily on the glutamate
  route. The enzyme is a homodecamer assembled as five homodimers, with each subunit
  built from an N-terminal Rossmann-fold dinucleotide-binding domain and a C-terminal
  dimerization domain. At physiological substrate and cofactor concentrations it has
  higher activity with NADH than NADPH, and it is competitively inhibited by its
  product proline. Beyond supplying proline for protein synthesis and collagen,
  PYCR1 participates in the proline/P5C redox cycle that shuttles reducing equivalents
  between mitochondria and cytosol, linking it to redox homeostasis and the cellular
  response to oxidative stress. Loss-of-function variants in PYCR1 cause autosomal
  recessive cutis laxa type 2B and 3B (progeroid/De Barsy-like phenotypes), with
  altered mitochondrial morphology and membrane potential and increased apoptosis
  under oxidative stress. PYCR1 is frequently overexpressed in cancers, where
  proline biosynthesis supports tumor growth.
alternative_products:
- name: '1'
  id: P32322-1
- name: '2'
  id: P32322-2
  sequence_note: VSP_044507
- name: '3'
  id: P32322-3
  sequence_note: VSP_054616
existing_annotations:
- term:
    id: GO:0004735
    label: pyrroline-5-carboxylate reductase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: enables
  review:
    summary: >-
      Core catalytic molecular function of PYCR1, robustly supported experimentally in
      human (kinetics and crystal structures) and conserved across the P5C reductase
      family. The phylogenetic (IBA) inference is fully consistent with the direct
      evidence.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/PYCR1/PYCR1-uniprot.txt
      supporting_text: Oxidoreductase that catalyzes the last step in proline
- term:
    id: GO:0055129
    label: L-proline biosynthetic process
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  qualifier: involved_in
  review:
    summary: >-
      Core biological process. PYCR1 catalyzes the final step of L-proline biosynthesis;
      the IBA inference matches the experimental human data and the UniProt pathway
      annotation (L-proline from L-glutamate 5-semialdehyde, step 1/1).
    action: ACCEPT
    supported_by:
    - reference_id: file:human/PYCR1/PYCR1-uniprot.txt
      supporting_text: 'Amino-acid biosynthesis; L-proline biosynthesis; L-proline'
- term:
    id: GO:0004735
    label: pyrroline-5-carboxylate reductase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: enables
  review:
    summary: >-
      Electronic (ARBA/InterPro/Rhea/EC) assignment of the core catalytic activity.
      Redundant with the experimental IDA annotations but correct; keep as supporting
      the core function.
    action: ACCEPT
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: located_in
  review:
    summary: >-
      Electronic localization to mitochondrion, consistent with experimental IDA
      subcellular-fractionation and co-localization evidence. Correct; the more specific
      mitochondrial matrix term is also annotated.
    action: ACCEPT
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IEA
  original_reference_id: GO_REF:0000117
  qualifier: involved_in
  review:
    summary: >-
      ARBA electronic annotation duplicating the experimental IMP annotation (PMID:19648921),
      where fibroblasts from affected individuals showed increased apoptosis upon oxidative
      stress. A genuine but non-core role of PYCR1; retain as non-core.
    action: KEEP_AS_NON_CORE
- term:
    id: GO:0055129
    label: L-proline biosynthetic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  qualifier: involved_in
  review:
    summary: >-
      Electronic (ARBA/InterPro/UniPathway) assignment of the core proline biosynthesis
      process. Redundant with experimental IDA/IBA annotations but correct.
    action: ACCEPT
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:23743200
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" from a physical interaction with DJ-1/PARK7. Uninformative as
      a molecular function term (it does not describe what PYCR1 does), so mark as
      over-annotated rather than accept. The underlying interaction is real (DJ-1 directly
      binds PYCR1 and enhances its activity) and is captured biologically elsewhere.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:23743200
      supporting_text: DJ-1 directly bound to PYCR1 in vivo and in
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:32296183
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" from a high-throughput binary interactome (HuRI) screen
      (interaction with TNPO2). Uninformative molecular-function term; the interaction is
      not known to correspond to a specific biological function of PYCR1. Mark as
      over-annotated.
    action: MARK_AS_OVER_ANNOTATED
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:16730026
  qualifier: enables
  review:
    summary: >-
      Self-association reported from the crystal structure, which showed a decameric
      architecture of five homodimers. "Identical protein binding" is a defensible
      capture of the obligate homo-oligomerization that underlies catalysis, but it is
      not the core function; keep as non-core. The oligomeric state is better represented
      by the pyrroline-5-carboxylate reductase complex annotation.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:16730026
      supporting_text: a decameric architecture with five homodimer subunits
- term:
    id: GO:0042802
    label: identical protein binding
  evidence_type: IPI
  original_reference_id: PMID:2722838
  qualifier: enables
  review:
    summary: >-
      Self-association from early sizing-chromatography work on purified human erythrocyte
      P5C reductase, which showed a 300,000-350,000 Mr native species consistent with a
      10- to 12-mer. Supports homo-oligomerization; keep as non-core (see the complex
      annotation for the oligomeric assembly).
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:2722838
      supporting_text: suggesting that the native enzyme exists as a 10- to
- term:
    id: GO:1902792
    label: pyrroline-5-carboxylate reductase complex
  evidence_type: IDA
  original_reference_id: PMID:28258219
  qualifier: part_of
  review:
    summary: >-
      PYCR1 assembles into a homodecamer (pentamer of dimers), directly demonstrated by
      crystallography and sedimentation velocity. This complex is the catalytically active
      form. Accurate and informative; accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:28258219
      supporting_text: PYCR1 forms a concentration-dependent decamer in solution, consistent
        with the
- term:
    id: GO:0004735
    label: pyrroline-5-carboxylate reductase activity
  evidence_type: IDA
  original_reference_id: PMID:23024808
  qualifier: enables
  review:
    summary: >-
      Direct enzymatic characterization of human PYCR1 (catalytic activity, kinetics,
      cofactor preference, product inhibition). Strong support for the core molecular
      function. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: file:human/PYCR1/PYCR1-uniprot.txt
      supporting_text: concentrations, has higher specific activity in the presence of NADH
- term:
    id: GO:0004735
    label: pyrroline-5-carboxylate reductase activity
  evidence_type: IDA
  original_reference_id: PMID:28258219
  qualifier: enables
  review:
    summary: >-
      Direct kinetic and mutational characterization of human PYCR1, including the T238A
      mutant with decreased P5C reductase activity confirming the catalytic mechanism.
      Strong support for the core function. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:28258219
      supporting_text: catalyzing the NAD(P)H-dependent reduction of Δ1-pyrroline-5-carboxylate
        (P5C) to proline
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:23024808
  qualifier: located_in
  review:
    summary: >-
      Subcellular fractionation localized PYCR1 (and PYCR2) to the mitochondria. Correct
      localization; the more specific mitochondrial matrix is also annotated. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:23024808
      supporting_text: are localized in the mitochondria, and primarily involved in the
        conversion of glutamate to proline
- term:
    id: GO:0055129
    label: L-proline biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:23024808
  qualifier: involved_in
  review:
    summary: >-
      Direct isotope-tracing evidence that PYCR1 contributes to proline biosynthesis,
      primarily production of proline from glutamate. Core biological process. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:23024808
      supporting_text: PYCR1 contributes primarily to production of proline from glutamate
- term:
    id: GO:0055129
    label: L-proline biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:28258219
  qualifier: involved_in
  review:
    summary: >-
      Structural/kinetic study framing PYCR1 as the final enzyme in proline biosynthesis.
      Supports the core biological process. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:28258219
      supporting_text: is the final enzyme in proline biosynthesis
- term:
    id: GO:0004735
    label: pyrroline-5-carboxylate reductase activity
  evidence_type: IDA
  original_reference_id: PMID:23743200
  qualifier: enables
  review:
    summary: >-
      Core catalytic activity annotated from the DJ-1/PYCR1 study, which measured PYCR1
      enzymatic activity (enhanced in vitro by DJ-1). Consistent with the core function;
      accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:23743200
      supporting_text: DJ-1 enhanced the enzymatic activity of PYCR1 in vitro
- term:
    id: GO:1903377
    label: negative regulation of oxidative stress-induced neuron intrinsic apoptotic
      signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:23743200
  qualifier: involved_in
  review:
    summary: >-
      Highly specific process term derived from the DJ-1/PYCR1 oxidative-stress-protection
      study. The paper reports that cells knocked down for DJ-1 and PYCR1 showed lower
      viability under oxidative stress, placing PYCR1 on an anti-oxidative-stress pathway,
      but the "neuron intrinsic apoptotic signaling" specificity is an over-reach: the
      cited experiments used cell lines and did not establish a neuron-specific apoptotic
      pathway. This is a plausible but non-core, over-specified role; retain as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:23743200
      supporting_text: cells knocked down for DJ-1 and PYCR1 showed lower viability under
        oxidative stress conditions
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:24930674
  qualifier: enables
  review:
    summary: >-
      Bare "protein binding" from the interaction of PYCR1 (P5C reductase) with ORAOV1/LTO1
      demonstrated by peptide mass fingerprinting. Uninformative molecular-function term;
      the physical interaction is real but does not describe PYCR1's function. Mark as
      over-annotated.
    action: MARK_AS_OVER_ANNOTATED
    supported_by:
    - reference_id: PMID:24930674
      supporting_text: ORAOV1 bound to pyrroline-5-carboxylate reductase (PYCR), which is
        associated with proline metabolism
- term:
    id: GO:0005759
    label: mitochondrial matrix
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-70664
  qualifier: located_in
  review:
    summary: >-
      Reactome traceable-author-statement placing the PYCR1 decamer reaction in the
      mitochondrial matrix, consistent with the mitochondrial localization established
      experimentally. Appropriate and more specific than "mitochondrion"; accept.
    action: ACCEPT
    supported_by:
    - reference_id: Reactome:R-HSA-70664
      supporting_text: PYCR1 decamer reduces (S)-1-pyrroline-5-carboxylate to L-Pro
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:23743200
  qualifier: located_in
  review:
    summary: >-
      PYCR1 co-localized with DJ-1 in mitochondria. Correct localization; accept
      (mitochondrial matrix is the more specific annotation).
    action: ACCEPT
    supported_by:
    - reference_id: PMID:23743200
      supporting_text: DJ-1 and PYCR1 colocalized in mitochondria
- term:
    id: GO:0051881
    label: regulation of mitochondrial membrane potential
  evidence_type: IMP
  original_reference_id: PMID:23743200
  qualifier: involved_in
  review:
    summary: >-
      The DJ-1/PYCR1 study reports that both proteins are involved in regulation of
      mitochondrial membrane potential (differently). Also supported independently by
      the cutis-laxa fibroblast work (PMID:19648921), which found altered mitochondrial
      membrane potential in patient cells. A genuine downstream/physiological effect of
      PYCR1 dysfunction rather than its core function; retain as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:23743200
      supporting_text: involved in regulation of mitochondrial membrane potential
- term:
    id: GO:0004735
    label: pyrroline-5-carboxylate reductase activity
  evidence_type: IDA
  original_reference_id: PMID:16730026
  qualifier: enables
  review:
    summary: >-
      Direct enzymatic/mutagenesis characterization (Glu221) from the first human PYCR1
      crystal structure. Strong support for the core catalytic activity. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:16730026
      supporting_text: catalyzes the reduction of Delta(1)-pyrroline-5-carboxylate (P5C)
        to proline using NAD(P)H as the cofactor
- term:
    id: GO:0055129
    label: L-proline biosynthetic process
  evidence_type: IDA
  original_reference_id: PMID:16730026
  qualifier: involved_in
  review:
    summary: >-
      Core biological process supported by the structural/enzymatic study. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:16730026
      supporting_text: catalyzes the reduction of Delta(1)-pyrroline-5-carboxylate (P5C)
        to proline
- term:
    id: GO:0005739
    label: mitochondrion
  evidence_type: IDA
  original_reference_id: PMID:19648921
  qualifier: located_in
  review:
    summary: >-
      Co-localization study in the cutis-laxa paper showed PYCR1 localizes to
      mitochondria. Correct localization; accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:19648921
      supporting_text: an enzyme involved in proline metabolism, localizes to mitochondria
- term:
    id: GO:0034599
    label: cellular response to oxidative stress
  evidence_type: IMP
  original_reference_id: PMID:19648921
  qualifier: involved_in
  review:
    summary: >-
      Fibroblasts from PYCR1-deficient (cutis laxa) individuals showed increased apoptosis
      upon oxidative stress, implicating PYCR1 in the cellular response to oxidative stress.
      A genuine but non-core, disease-related role; retain as non-core.
    action: KEEP_AS_NON_CORE
    supported_by:
    - reference_id: PMID:19648921
      supporting_text: increased apoptosis rate upon oxidative stress were evident in fibroblasts
        from affected individuals
- term:
    id: GO:0004735
    label: pyrroline-5-carboxylate reductase activity
  evidence_type: TAS
  original_reference_id: PMID:1730675
  qualifier: enables
  review:
    summary: >-
      Original cDNA-cloning paper; PYCR1 complemented proline auxotrophy in yeast and the
      enzyme catalyzes the NAD(P)H-dependent conversion of P5C to proline. Traceable
      author statement supporting the core catalytic activity. Accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:1730675
      supporting_text: catalyzes the NAD(P)H-dependent
- term:
    id: GO:0055129
    label: L-proline biosynthetic process
  evidence_type: TAS
  original_reference_id: PMID:1730675
  qualifier: involved_in
  review:
    summary: >-
      Cloning by complementation of proline auxotrophy establishes PYCR1's role in proline
      biosynthesis. Core biological process; accept.
    action: ACCEPT
    supported_by:
    - reference_id: PMID:1730675
      supporting_text: two of which gained proline prototrophy
core_functions:
- description: >-
    Catalyzes the terminal step of L-proline biosynthesis: the NAD(P)H-dependent
    reduction of (S)-1-pyrroline-5-carboxylate (P5C) to L-proline, acting mainly on
    P5C derived from glutamate. Functions as a mitochondrial homodecamer with higher
    activity toward NADH than NADPH at physiological concentrations and is competitively
    inhibited by product proline.
  molecular_function:
    id: GO:0004735
    label: pyrroline-5-carboxylate reductase activity
  directly_involved_in:
  - id: GO:0055129
    label: L-proline biosynthetic process
  in_complex:
    id: GO:1902792
    label: pyrroline-5-carboxylate reductase complex
  locations:
  - id: GO:0005759
    label: mitochondrial matrix
  supported_by:
  - reference_id: file:human/PYCR1/PYCR1-uniprot.txt
    supporting_text: Oxidoreductase that catalyzes the last step in proline
  - reference_id: PMID:28258219
    supporting_text: catalyzing the NAD(P)H-dependent reduction of Δ1-pyrroline-5-carboxylate
      (P5C) to proline
references:
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000117
  title: Electronic Gene Ontology annotations created by ARBA machine learning models
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: file:human/PYCR1/PYCR1-uniprot.txt
  title: UniProtKB P32322 (P5CR1_HUMAN) record
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Authoritative UniProt record; establishes the core catalytic activity (EC 1.5.1.2),
      NADH cofactor preference, mitochondrial localization, homodecamer assembly, proline
      biosynthesis pathway (step 1/1), and the ARCL2B/ARCL3B disease associations.
- id: PMID:16730026
  title: Crystal structure of human pyrroline-5-carboxylate reductase.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      First human PYCR1 crystal structure; decameric (five homodimers) architecture,
      Rossmann motif and Glu221 catalytic role, and NAD(P)H-dependent P5C-to-proline
      catalysis. Directly supports the core MF, homo-oligomerization, and complex.
- id: PMID:1730675
  title: Cloning human pyrroline-5-carboxylate reductase cDNA by complementation in
    Saccharomyces cerevisiae.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Original human PYCR1 cDNA cloning by complementation of yeast proline auxotrophy;
      establishes the gene identity, EC 1.5.1.2 activity, and role in proline biosynthesis.
- id: PMID:19648921
  title: Mutations in PYCR1 cause cutis laxa with progeroid features.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Landmark disease paper linking PYCR1 loss-of-function to ARCL2B/ARCL3B; demonstrates
      mitochondrial localization, altered mitochondrial morphology/membrane potential, and
      increased apoptosis under oxidative stress in patient fibroblasts.
- id: PMID:23024808
  title: Functional specialization in proline biosynthesis of melanoma.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Full-text available; isotope-tracing and kinetic dissection of PYCR1/PYCR2/PYCRL.
      Shows PYCR1 is mitochondrial and contributes primarily to proline production from
      glutamate, with NADH preference and product (proline) inhibition.
- id: PMID:23743200
  title: DJ-1 cooperates with PYCR1 in cell protection against oxidative stress.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Reports a direct DJ-1(PARK7)-PYCR1 interaction that enhances PYCR1 activity, joint
      mitochondrial co-localization, and a shared anti-oxidative-stress pathway; basis for
      the oxidative-stress and membrane-potential annotations. Abstract-only in cache.
- id: PMID:24930674
  title: Frequent amplification of ORAOV1 gene in esophageal squamous cell cancer
    promotes an aggressive phenotype via proline metabolism and ROS production.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      ORAOV1/LTO1 binds PYCR (peptide mass fingerprinting) and modulates proline metabolism
      and ROS in esophageal cancer; source of the LTO1 protein-binding annotation. The
      binding is real but the plain "protein binding" MF term is uninformative.
- id: PMID:2722838
  title: Purified human erythrocyte pyrroline-5-carboxylate reductase. Preferential
    oxidation of NADPH.
  findings: []
  reference_review:
    relevance: MEDIUM
    correctness: VERIFIED
    review_notes: >-
      Early biochemical purification of human P5C reductase; native 10-12-mer assembly,
      NADH/NADPH kinetics and cofactor preference. Supports homo-oligomerization and the
      catalytic activity.
- id: PMID:28258219
  title: Resolving the cofactor-binding site in the proline biosynthetic enzyme human
    pyrroline-5-carboxylate reductase 1.
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Definitive structural/kinetic study locating the NADPH cofactor site in the
      N-terminal Rossmann fold, confirming the decameric (pentamer-of-dimers) assembly,
      and validating catalysis via the T238A mutant. Supports core MF, complex, and BP.
- id: PMID:32296183
  title: A reference map of the human binary protein interactome.
  findings: []
  reference_review:
    relevance: LOW
    correctness: VERIFIED
    review_notes: >-
      HuRI high-throughput yeast two-hybrid interactome (source of the TNPO2 binary
      interaction). Provides only a generic "protein binding" datapoint with no functional
      annotation for PYCR1.
- id: Reactome:R-HSA-70664
  title: PYCR1 decamer reduces (S)-1-pyrroline-5-carboxylate to L-Pro
  findings: []
  reference_review:
    relevance: HIGH
    correctness: VERIFIED
    review_notes: >-
      Reactome reaction placing the PYCR1 decamer reaction in the mitochondrial matrix;
      supports the core catalytic activity and the mitochondrial matrix localization.