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.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004735 pyrroline-5-carboxylate reductase activity | IBA GO_REF:0000033 | ACCEPT | 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. Supporting Evidence: file:human/PYCR1/PYCR1-uniprot.txt Oxidoreductase that catalyzes the last step in proline |
| GO:0055129 L-proline biosynthetic process | IBA GO_REF:0000033 | ACCEPT | 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). Supporting Evidence: file:human/PYCR1/PYCR1-uniprot.txt Amino-acid biosynthesis; L-proline biosynthesis; L-proline |
| GO:0004735 pyrroline-5-carboxylate reductase activity | IEA GO_REF:0000120 | ACCEPT | 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. |
| GO:0005739 mitochondrion | IEA GO_REF:0000120 | ACCEPT | 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. |
| GO:0034599 cellular response to oxidative stress | IEA GO_REF:0000117 | KEEP AS NON CORE | 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. |
| GO:0055129 L-proline biosynthetic process | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic (ARBA/InterPro/UniPathway) assignment of the core proline biosynthesis process. Redundant with experimental IDA/IBA annotations but correct. |
| GO:0005515 protein binding | IPI PMID:23743200 DJ-1 cooperates with PYCR1 in cell protection against oxidat... | MARK AS OVER ANNOTATED | 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. Supporting Evidence: PMID:23743200 DJ-1 directly bound to PYCR1 in vivo and in |
| GO:0005515 protein binding | IPI PMID:32296183 A reference map of the human binary protein interactome. | MARK AS OVER ANNOTATED | 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. |
| GO:0042802 identical protein binding | IPI PMID:16730026 Crystal structure of human pyrroline-5-carboxylate reductase... | KEEP AS NON CORE | 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. Supporting Evidence: PMID:16730026 a decameric architecture with five homodimer subunits |
| GO:0042802 identical protein binding | IPI PMID:2722838 Purified human erythrocyte pyrroline-5-carboxylate reductase... | KEEP AS NON CORE | 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). Supporting Evidence: PMID:2722838 suggesting that the native enzyme exists as a 10- to |
| GO:1902792 pyrroline-5-carboxylate reductase complex | IDA PMID:28258219 Resolving the cofactor-binding site in the proline biosynthe... | ACCEPT | 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. Supporting Evidence: PMID:28258219 PYCR1 forms a concentration-dependent decamer in solution, consistent with the |
| GO:0004735 pyrroline-5-carboxylate reductase activity | IDA PMID:23024808 Functional specialization in proline biosynthesis of melanom... | ACCEPT | Summary: Direct enzymatic characterization of human PYCR1 (catalytic activity, kinetics, cofactor preference, product inhibition). Strong support for the core molecular function. Accept. Supporting Evidence: file:human/PYCR1/PYCR1-uniprot.txt concentrations, has higher specific activity in the presence of NADH |
| GO:0004735 pyrroline-5-carboxylate reductase activity | IDA PMID:28258219 Resolving the cofactor-binding site in the proline biosynthe... | ACCEPT | 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. Supporting Evidence: PMID:28258219 catalyzing the NAD(P)H-dependent reduction of Ξ1-pyrroline-5-carboxylate (P5C) to proline |
| GO:0005739 mitochondrion | IDA PMID:23024808 Functional specialization in proline biosynthesis of melanom... | ACCEPT | Summary: Subcellular fractionation localized PYCR1 (and PYCR2) to the mitochondria. Correct localization; the more specific mitochondrial matrix is also annotated. Accept. Supporting Evidence: PMID:23024808 are localized in the mitochondria, and primarily involved in the conversion of glutamate to proline |
| GO:0055129 L-proline biosynthetic process | IDA PMID:23024808 Functional specialization in proline biosynthesis of melanom... | ACCEPT | Summary: Direct isotope-tracing evidence that PYCR1 contributes to proline biosynthesis, primarily production of proline from glutamate. Core biological process. Accept. Supporting Evidence: PMID:23024808 PYCR1 contributes primarily to production of proline from glutamate |
| GO:0055129 L-proline biosynthetic process | IDA PMID:28258219 Resolving the cofactor-binding site in the proline biosynthe... | ACCEPT | Summary: Structural/kinetic study framing PYCR1 as the final enzyme in proline biosynthesis. Supports the core biological process. Accept. Supporting Evidence: PMID:28258219 is the final enzyme in proline biosynthesis |
| GO:0004735 pyrroline-5-carboxylate reductase activity | IDA PMID:23743200 DJ-1 cooperates with PYCR1 in cell protection against oxidat... | ACCEPT | 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. Supporting Evidence: PMID:23743200 DJ-1 enhanced the enzymatic activity of PYCR1 in vitro |
| GO:1903377 negative regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway | IMP PMID:23743200 DJ-1 cooperates with PYCR1 in cell protection against oxidat... | KEEP AS NON CORE | 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. Supporting Evidence: PMID:23743200 cells knocked down for DJ-1 and PYCR1 showed lower viability under oxidative stress conditions |
| GO:0005515 protein binding | IPI PMID:24930674 Frequent amplification of ORAOV1 gene in esophageal squamous... | MARK AS OVER ANNOTATED | 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. Supporting Evidence: PMID:24930674 ORAOV1 bound to pyrroline-5-carboxylate reductase (PYCR), which is associated with proline metabolism |
| GO:0005759 mitochondrial matrix | TAS Reactome:R-HSA-70664 | ACCEPT | 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. Supporting Evidence: Reactome:R-HSA-70664 PYCR1 decamer reduces (S)-1-pyrroline-5-carboxylate to L-Pro |
| GO:0005739 mitochondrion | IDA PMID:23743200 DJ-1 cooperates with PYCR1 in cell protection against oxidat... | ACCEPT | Summary: PYCR1 co-localized with DJ-1 in mitochondria. Correct localization; accept (mitochondrial matrix is the more specific annotation). Supporting Evidence: PMID:23743200 DJ-1 and PYCR1 colocalized in mitochondria |
| GO:0051881 regulation of mitochondrial membrane potential | IMP PMID:23743200 DJ-1 cooperates with PYCR1 in cell protection against oxidat... | KEEP AS NON CORE | 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. Supporting Evidence: PMID:23743200 involved in regulation of mitochondrial membrane potential |
| GO:0004735 pyrroline-5-carboxylate reductase activity | IDA PMID:16730026 Crystal structure of human pyrroline-5-carboxylate reductase... | ACCEPT | Summary: Direct enzymatic/mutagenesis characterization (Glu221) from the first human PYCR1 crystal structure. Strong support for the core catalytic activity. Accept. Supporting Evidence: PMID:16730026 catalyzes the reduction of Delta(1)-pyrroline-5-carboxylate (P5C) to proline using NAD(P)H as the cofactor |
| GO:0055129 L-proline biosynthetic process | IDA PMID:16730026 Crystal structure of human pyrroline-5-carboxylate reductase... | ACCEPT | Summary: Core biological process supported by the structural/enzymatic study. Accept. Supporting Evidence: PMID:16730026 catalyzes the reduction of Delta(1)-pyrroline-5-carboxylate (P5C) to proline |
| GO:0005739 mitochondrion | IDA PMID:19648921 Mutations in PYCR1 cause cutis laxa with progeroid features. | ACCEPT | Summary: Co-localization study in the cutis-laxa paper showed PYCR1 localizes to mitochondria. Correct localization; accept. Supporting Evidence: PMID:19648921 an enzyme involved in proline metabolism, localizes to mitochondria |
| GO:0034599 cellular response to oxidative stress | IMP PMID:19648921 Mutations in PYCR1 cause cutis laxa with progeroid features. | KEEP AS NON CORE | 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. Supporting Evidence: PMID:19648921 increased apoptosis rate upon oxidative stress were evident in fibroblasts from affected individuals |
| GO:0004735 pyrroline-5-carboxylate reductase activity | TAS PMID:1730675 Cloning human pyrroline-5-carboxylate reductase cDNA by comp... | ACCEPT | 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. Supporting Evidence: PMID:1730675 catalyzes the NAD(P)H-dependent |
| GO:0055129 L-proline biosynthetic process | TAS PMID:1730675 Cloning human pyrroline-5-carboxylate reductase cDNA by comp... | ACCEPT | Summary: Cloning by complementation of proline auxotrophy establishes PYCR1's role in proline biosynthesis. Core biological process; accept. Supporting Evidence: PMID:1730675 two of which gained proline prototrophy |
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