PRODH encodes proline dehydrogenase 1 (proline oxidase, POX; EC 1.5.5.2), a FAD-dependent flavoenzyme bound to the matrix face of the mitochondrial inner membrane. It catalyzes the first, committed step of proline catabolism: the oxidation of L-proline to (S)-1-pyrroline-5-carboxylate (P5C), which is then converted by ALDH4A1/P5C dehydrogenase to L-glutamate. Rather than using a soluble acceptor, PRODH donates the electrons abstracted from proline through its FAD cofactor to ubiquinone in the respiratory electron transport chain, coupling proline oxidation to mitochondrial bioenergetics. Beyond its catabolic role, PRODH is a transcriptional target of p53 (originally identified as the p53-induced gene PIG6): its catalytic turnover can generate reactive oxygen species, giving it a secondary role in redox signaling and apoptosis. In humans the gene lies at chromosome 22q11.2 within the velocardiofacial/DiGeorge deletion interval; loss-of-function and hypomorphic variants cause hyperprolinemia type 1, and reduced PRODH activity is a susceptibility factor for schizophrenia.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0004657 proline dehydrogenase activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to the defining catalytic activity of PRODH: FAD-dependent proline dehydrogenase (EC 1.5.5.2). This is the core molecular function of the gene and is corroborated by direct experimental evidence. Reason: GO:0004657 (L-proline + a quinone = (S)-1-pyrroline-5-carboxylate + a quinol + H+) matches exactly the UniProt catalytic activity and EC 1.5.5.2. Correct term at the correct level of specificity; selected as the core molecular function. Supporting Evidence: file:human/PRODH/PRODH-uniprot.txt Converts proline to delta-1-pyrroline-5-carboxylate. file:human/PRODH/PRODH-uniprot.txt Reaction=L-proline + a quinone = (S)-1-pyrroline-5-carboxylate + a |
| GO:0006562 L-proline catabolic process | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to the core biological process: breakdown of L-proline. PRODH catalyzes the first step of this pathway. Reason: This is the central catabolic process in which PRODH participates; its deficiency causes hyperprolinemia (accumulation of proline). Correct process term; selected as the core biological process. Supporting Evidence: file:human/PRODH/PRODH-uniprot.txt L-proline degradation into L- |
| GO:0005739 mitochondrion | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation localizing PRODH activity to the mitochondrion. Correct but general; the specific location is the mitochondrial inner membrane (matrix face). Reason: PRODH is a mitochondrial enzyme, so this compartment assignment is correct. More precise inner-membrane / matrix terms are also annotated and are preferred as the core location. Supporting Evidence: file:human/PRODH/PRODH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix. |
| GO:0071949 FAD binding | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetic (IBA) annotation to FAD binding. PRODH is a flavoprotein that requires FAD as its redox cofactor; corroborated experimentally. Reason: FAD is the catalytic prosthetic group of PRODH (UniProt COFACTOR, ECO:0000269 from PubMed:15662599); a mutant with reduced FAD affinity (T466M) loses activity. Core cofactor-binding function. Supporting Evidence: file:human/PRODH/PRODH-uniprot.txt Name=FAD; Xref=ChEBI:CHEBI:57692; |
| GO:0004657 proline dehydrogenase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic annotation (InterPro / RHEA:23784 / EC 1.5.5.2 mapping) to the core proline dehydrogenase activity. Redundant with the IBA, IDA and TAS annotations to the same term. Reason: Correct core molecular function, independently derived from sequence and reaction mappings and consistent with the experimental evidence. Supporting Evidence: file:human/PRODH/PRODH-uniprot.txt Reaction=L-proline + a quinone = (S)-1-pyrroline-5-carboxylate + a |
| GO:0005739 mitochondrion | IEA GO_REF:0000117 | ACCEPT | Summary: Electronic (ARBA) annotation to the mitochondrion. Correct but general relative to the inner-membrane/matrix annotations. Reason: Consistent with the mitochondrial localization of PRODH. Redundant with the more specific inner-membrane and matrix terms. Supporting Evidence: file:human/PRODH/PRODH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix. |
| GO:0005759 mitochondrial matrix | IEA GO_REF:0000044 | ACCEPT | Summary: Electronic annotation (UniProt Subcellular Location mapping, SL-0170) to the mitochondrial matrix, matching the UniProt SUBCELLULAR LOCATION statement. Reason: UniProt records PRODH localization as "Mitochondrion matrix"; the enzyme is an inner-membrane-associated flavoprotein whose catalytic domain faces the matrix. Consistent with the (preferred, functionally informative) inner-membrane term. Supporting Evidence: file:human/PRODH/PRODH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix. |
| GO:0006562 L-proline catabolic process | IEA GO_REF:0000002 | ACCEPT | Summary: Electronic (InterPro2GO) annotation to L-proline catabolic process, the core process for PRODH. Redundant with the IBA and TAS annotations. Reason: Correct core biological process, derived from the proline oxidase InterPro signature; consistent with experimental and phylogenetic evidence. Supporting Evidence: file:human/PRODH/PRODH-uniprot.txt L-proline degradation into L- |
| GO:0006562 L-proline catabolic process | TAS Reactome:R-HSA-70688 | ACCEPT | Summary: Traceable-author (Reactome "Proline catabolism") annotation to the core biological process. Reactome models PRODH as catalyzing the first step of proline breakdown. Reason: Correct core process, curated from the Reactome proline catabolism pathway; concordant with all other lines of evidence. Supporting Evidence: file:human/PRODH/PRODH-uniprot.txt L-proline degradation into L- |
| GO:0005743 mitochondrial inner membrane | TAS Reactome:R-HSA-70670 | ACCEPT | Summary: Traceable-author (Reactome) annotation to the mitochondrial inner membrane. PRODH is tightly bound to the inner mitochondrial membrane, where its FAD passes electrons to ubiquinone in the respiratory chain. Reason: This is the functionally informative core location: PRODH is an inner-membrane-bound flavoenzyme feeding electrons into the ETC. Selected as the core cellular component (matrix reflects the orientation of the catalytic domain). Supporting Evidence: PMID:15662599 mitochondrial inner-membrane enzyme that catalyzes the first step in the proline Reactome:R-HSA-70670 coupled to the conversion of FAD to FADH2 is the first step in proline breakdown |
| GO:0016649 oxidoreductase activity, acting on the CH-NH group of donors, quinone or similar compound as acceptor | EXP PMID:15662599 Functional consequences of PRODH missense mutations. | ACCEPT | Summary: Experimental (EXP) annotation to the general oxidoreductase class (CH-NH donor, quinone acceptor). This is the direct parent of proline dehydrogenase activity (GO:0004657) and captures the quinone-linked mechanism. Reason: Correct and mechanistically apt (PRODH uses a quinone as electron acceptor), but more general than the specific GO:0004657 term derived from the same paper. Retained; the specific proline dehydrogenase activity is the core molecular function. Supporting Evidence: file:human/PRODH/PRODH-uniprot.txt Reaction=L-proline + a quinone = (S)-1-pyrroline-5-carboxylate + a |
| GO:0005739 mitochondrion | HTP PMID:34800366 Quantitative high-confidence human mitochondrial proteome an... | ACCEPT | Summary: High-throughput (HTP) mitochondrial-proteome annotation localizing PRODH to the mitochondrion. Consistent with the curated inner-membrane/matrix location. Reason: PRODH was detected in a high-confidence human mitochondrial proteome dataset, corroborating its mitochondrial localization. Correct but general. Supporting Evidence: file:human/PRODH/PRODH-uniprot.txt SUBCELLULAR LOCATION: Mitochondrion matrix. |
| GO:1903376 regulation of oxidative stress-induced neuron intrinsic apoptotic signaling pathway | IDA PMID:23743200 DJ-1 cooperates with PYCR1 in cell protection against oxidat... | KEEP AS NON CORE | Summary: Experimental (IDA) annotation to regulation of oxidative-stress-induced neuron intrinsic apoptotic signaling. PRODH catalytic turnover generates ROS, linking it to redox and apoptotic signaling; this is a genuine but secondary, non-catabolic role. Reason: The redox/apoptosis role of PRODH is real and downstream of its enzymatic activity, but it is a secondary regulatory function rather than the gene's core catabolic role, so it is kept as non-core. Note that the cached abstract of PMID:23743200 foregrounds DJ-1/PARK7 and PYCR1 (proline biosynthesis) and does not mention PRODH; per curation policy an experimental (IDA) annotation is not removed on the basis of an abstract-only view of the paper. Supporting Evidence: file:human/PRODH/PRODH-uniprot.txt During p53/TP53-induced apoptosis. |
| GO:0019470 trans-4-hydroxy-L-proline catabolic process | TAS PMID:21998747 Structural and biochemical studies of human 4-hydroxy-2-oxog... | MARK AS OVER ANNOTATED | Summary: Traceable-author annotation to hydroxyproline catabolism. However, the cited paper (human HOGA structure) attributes the first step of 4-hydroxy-L-proline degradation to hydroxyproline oxidase (HPOX), which is the distinct paralog PRODH2/HYPDH, not PRODH. Reason: PRODH oxidizes L-proline (EC 1.5.5.2); trans-4-hydroxy-L-proline is the substrate of the paralogous enzyme PRODH2 (hydroxyproline dehydrogenase / HPOX). PMID:21998747 describes the 4-Hyp pathway using "hydroxyproline oxidase (HPOX)" and does not implicate PRODH, so this appears to be a paralog mis-attribution / over-annotation. Because the annotation is TAS (not experimental) and the substrate is wrong for PRODH, it is marked as over-annotated rather than accepted; it is not removed (conservative handling of a non-IEA annotation). Supporting Evidence: PMID:21998747 hydroxyproline oxidase (HPOX) |
| GO:0004657 proline dehydrogenase activity | IDA PMID:15662599 Functional consequences of PRODH missense mutations. | ACCEPT | Summary: Direct experimental (IDA) annotation to proline dehydrogenase activity. Bender et al. 2005 assayed POX (PRODH) activity for wild-type and mutant proteins, directly demonstrating this catalytic function. Reason: Strongest evidence for the core molecular function: direct enzymatic assay of human PRODH. Anchors the EC 1.5.5.2 / FAD-cofactor assignment. Core function. Supporting Evidence: PMID:15662599 mitochondrial inner-membrane enzyme that catalyzes the first step in the proline file:human/PRODH/PRODH-uniprot.txt Converts proline to delta-1-pyrroline-5-carboxylate. |
| GO:0071949 FAD binding | IDA PMID:15662599 Functional consequences of PRODH missense mutations. | ACCEPT | Summary: Direct experimental (IDA) annotation to FAD binding, from Bender et al. 2005, who showed a PRODH mutant (T466M) with strongly reduced affinity for FAD and that a severe allele responds in vitro to high FAD concentrations. Reason: Direct evidence that FAD is the functional cofactor of PRODH; a variant that impairs FAD binding abolishes activity. Core cofactor-binding function. Supporting Evidence: file:human/PRODH/PRODH-uniprot.txt Name=FAD; Xref=ChEBI:CHEBI:57692; |
| GO:0008631 intrinsic apoptotic signaling pathway in response to oxidative stress | NAS PMID:9305847 A model for p53-induced apoptosis. | KEEP AS NON CORE | Summary: Non-traceable-author-statement (NAS) annotation to oxidative-stress intrinsic apoptotic signaling. PRODH (as the p53-induced gene PIG6) is part of the p53/ROS-mediated apoptotic program described by Polyak et al. 1997. Reason: This is a genuine secondary role: PRODH is a p53 transcriptional target whose proline-oxidation-derived ROS contribute to apoptosis. It is downstream of and distinct from the enzyme's core catabolic function, so it is kept as non-core. Supporting Evidence: file:human/PRODH/PRODH-uniprot.txt During p53/TP53-induced apoptosis. |
| GO:0004657 proline dehydrogenase activity | TAS PMID:10192398 The gene encoding proline dehydrogenase modulates sensorimot... | ACCEPT | Summary: Traceable-author (TAS) annotation to proline dehydrogenase activity. Gogos et al. 1999 characterized PRODH as the human proline dehydrogenase homologue of Drosophila sluggish-A. Reason: Correct core molecular function; concordant with the IDA, IBA and IEA annotations to the same term. Supporting Evidence: PMID:10192398 proline dehydrogenase responsible for the behavioural phenotype |
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