CYP4V2 is a heme-containing cytochrome P450 associated with the endoplasmic reticulum. It uses oxygen and electrons supplied by cytochrome P450 reductase to hydroxylate fatty acids, including laurate, myristate, palmitate, eicosapentaenoate and docosahexaenoate. Terminal hydroxylation predominates, with smaller penultimate-carbon products observed for the polyunsaturated substrates. CYP4V2 is expressed in several tissues, including retinal pigment epithelium and cornea. Biallelic pathogenic variants cause Bietti crystalline dystrophy; its fatty-acid chemistry may contribute to retinal lipid homeostasis, although the decisive endogenous substrate and disease mechanism remain incompletely resolved.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001523 retinoid metabolic process | TAS Reactome:R-HSA-2453902 | MARK AS OVER ANNOTATED | Summary: The modeled CYP4V2 step acts on DHA rather than on a retinoid. Reason: Reactome places the genuine CYP4V2 DHA-to-22-hydroxy-DHA reaction inside its retinoid-cycle pathway. The enzyme has demonstrated fatty-acid chemistry and ocular lipid context, but this inspected event establishes no performed retinoid-processing step or structural/cofactor contribution to one. MARK_AS_OVER_ANNOTATED is a deliberate conservative judgment about propagation from that broader pathway context: the retinoid-specific assertion exceeds the demonstrated role. The reviewed assays do not comprehensively exclude other CYP4V2 retinoid functions. Supporting Evidence: Reactome:R-HSA-2453902 Reactome:R-HSA-6786239 file:human/CYP4V2/CYP4V2-source-evidence.yaml |
| GO:0004497 monooxygenase activity | IEA GO_REF:0000120 | MODIFY | Summary: The positive monooxygenase assertion can be refined to measured fatty-acid activities. Reason: The literal InterPro features occur on the target, and current ARBA00028788 branch 0 matches IPR002401, IPR050196 and Mammalia. Independent human enzyme assays resolve terminal hydroxylation of C12 and longer fatty acids, plus minor omega-1 products from EPA and DHA. Refine the broad parent to these chemically distinct activities. The terminal hydroxylase terms are already represented by other source assertions; refinement does not imply additional independent experiments or equal physiological importance of all substrates. The omega-1 refinement is supported by the identified human-enzyme products in PMID:22772592; it is not inferred from the electronic rule alone. The broad paired-donor parent adds no distinct reaction coverage, explaining its separate TOO_GENERAL disposition. Proposed replacements: medium-chain fatty acid omega-hydroxylase activity long-chain fatty acid omega-hydroxylase activity long-chain fatty acid omega-1 hydroxylase activity Supporting Evidence: file:human/CYP4V2/CYP4V2-uniprot.txt file:human/CYP4V2/CYP4V2-source-evidence.yaml |
| GO:0005506 iron ion binding | IEA GO_REF:0000002 | ACCEPT | Summary: CYP4V2 binds the iron of its catalytic heme cofactor. Reason: All four literal InterPro features are present. The conserved P450 signature spans residues 460β469; the official Cys467 axial-heme-iron feature is inferred by homology. Purified human CYP4V2 independently has the heme-containing mass and characteristic reduced-CO spectrum. This is catalytic heme iron binding, not evidence for an unrelated free-iron transport role. Supporting Evidence: file:human/CYP4V2/CYP4V2-uniprot.txt file:human/CYP4V2/CYP4V2-source-evidence.yaml |
| GO:0005515 protein binding | IPI PMID:28514442 Architecture of the human interactome defines protein commun... | KEEP AS NON CORE | Summary: The GATC association is retained as contextual interaction evidence. Reason: The literal IntAct record joins human CYP4V2 (Q6ZWL3), a C-terminally tagged bait, to GATC (O43716), the prey, in a HEK293T anti-tag coimmunoprecipitation experiment. This supports the recorded association; it does not demonstrate a binary interface, a physiological complex in retinal cells or a specific catalytic role for GATC in CYP4V2 turnover. Generic binding is not retained as a core molecular function. The 2017 primary Methods describe HA-based affinity purification and mass spectrometry. Contextual retention follows the explicit ClinGen project curation instruction in projects/CLINGEN_MENDELIAN.md; the supported association supplies no established, more specific molecular-function replacement. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | KEEP AS NON CORE | Summary: The GATC association is retained as contextual interaction evidence. Reason: The literal IntAct record joins human CYP4V2 (Q6ZWL3), a C-terminally tagged bait, to GATC (O43716), the prey, in a HEK293T anti-tag coimmunoprecipitation experiment. This supports the recorded association; it does not demonstrate a binary interface, a physiological complex in retinal cells or a specific catalytic role for GATC in CYP4V2 turnover. Generic binding is not retained as a core molecular function. The cached 2021 record contains introduction/discussion rather than complete Methods despite its full-text flag; assay details here come from the explicit IntAct record, not an uninspected Methods section. Contextual retention follows the explicit ClinGen project curation instruction in projects/CLINGEN_MENDELIAN.md; the supported association supplies no established, more specific molecular-function replacement. |
| GO:0005789 endoplasmic reticulum membrane | IDA PMID:22772592 CYP4V2 in Bietti's crystalline dystrophy: ocular localizatio... | ACCEPT | Summary: Human retinal pigment epithelial CYP4V2 localizes to endoplasmic reticulum. Reason: The original Methods and Results describe anti-CYP4V2 staining and colocalization with calreticulin in ARPE-19 cells, with antibody-specificity controls against other CYP4 proteins. The text supports the curatorβs ER membrane assignment together with membrane biochemical preparations and the predicted N-terminal anchor. Supplemental Figure 1 pixels were not recovered; no independently observed membrane orientation or short-product localization is claimed. |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: The literal ER membrane vocabulary mapping agrees with experimental localization. Reason: SL-0097 is present in the official record and traces to PMID:22772592. Its human-cell localization Results and membrane enzyme work support this assignment. The predicted 13β33 transmembrane helix is distinguished from experimentally resolved topology. |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-6786239 | ACCEPT | Summary: The exact DHA catalyst entity places CYP4V2 in ER membrane. Reason: Reactome 6786239 reaches catalyst 6786235, physical entity 6786215 and reference entity 409027/UniProt Q6ZWL3. The entity covers residues 1β525 and has the ER membrane compartment. This real target path agrees with independent localization; it does not establish the location or activity of the 503-residue splice form. Supporting Evidence: Reactome:R-HSA-6786239 file:human/CYP4V2/CYP4V2-source-evidence.yaml |
| GO:0006631 fatty acid metabolic process | IEA GO_REF:0000041 | ACCEPT | Summary: CYP4V2 directly participates in fatty-acid metabolism. Reason: The official UPA00199 fatty-acid metabolism cross-reference agrees with target enzyme assays. CYP4V2 itself catalyzes terminal hydroxylation of saturated and polyunsaturated fatty acids and also forms smaller omega-1 products from EPA and DHA. This broader positive process places both outcomes in their substrate context; it is not inferred merely from disease phenotypes or retinal expression. |
| GO:0010430 fatty acid omega-oxidation | IDA PMID:19661213 Expression and characterization of CYP4V2 as a fatty acid om... | ACCEPT | Summary: CYP4V2 performs the initial hydroxylation step of fatty-acid omega-oxidation. Reason: Human CYP4V2 expressed in Sf9 cells and reconstituted with reductase, cytochrome b5 and NADPH forms terminal hydroxy products from laurate, myristate and palmitate. Product identification and kinetic Results establish the initial hydroxylation step of fatty-acid omega-oxidation. The process also includes subsequent alcohol/aldehyde oxidation and beta-oxidation, which need not all be catalyzed by the same enzyme. Supporting Evidence: PMID:19661213 myristic acid was selectively Ο-hydroxylated by CYP4V2 |
| GO:0010430 fatty acid omega-oxidation | IDA PMID:22772592 CYP4V2 in Bietti's crystalline dystrophy: ocular localizatio... | ACCEPT | Summary: CYP4V2 directly omega-hydroxylates EPA and DHA. Reason: Purified human CYP4V2 with reductase/b5 and NADPH produces 20-hydroxy-EPA and 22-hydroxy-DHA. Original Figure 5 includes NADPH-negative controls, and the Methods/Results describe chromatographic/mass-spectral identification against biosynthetic standards. Quantitation uses saturated same-chain hydroxy-fatty-acid standards; it is not a complete kinetic characterization of physiological retinal flux. The enzyme performs the initial omega hydroxylation step itself. Supporting Evidence: PMID:22772592 formation of 22-hydroxy-DHA and 20-hydroxy-EPA |
| GO:0016125 sterol metabolic process | TAS Reactome:R-HSA-211976 | MARK AS OVER ANNOTATED | Summary: The CYP4V2 reaction in this broad pathway acts on a fatty acid rather than a sterol. Reason: Reactome places the genuine CYP4V2 DHA-to-22-hydroxy-DHA reaction within its endogenous-sterol pathway. This event establishes lipid hydroxylation; its C22 substrate and product lack the steroid skeleton required by the checked sterol definition. No performed sterol-processing step or structural/cofactor contribution to one was established in the inspected target path. MARK_AS_OVER_ANNOTATED deliberately flags excessive specificity inherited from the broader lipid-pathway context. This conservative mapping judgment does not claim that a comprehensive CYP4V2 sterol substrate panel was negative. Supporting Evidence: Reactome:R-HSA-211976 Reactome:R-HSA-6786239 file:human/CYP4V2/CYP4V2-source-evidence.yaml |
| GO:0016705 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen | IEA GO_REF:0000002 | TOO GENERAL | Summary: Paired-donor oxygenation is correct but less specific than the retained hydroxylase activities. Reason: The four matching InterPro features support the P450 fold/cofactor mechanism. Human enzyme turnover establishes specific fatty-acid hydroxylase descendants that already represent this chemistry. The broad parent is not independently informative, and no rule failure is alleged. Supporting Evidence: file:human/CYP4V2/CYP4V2-uniprot.txt file:human/CYP4V2/CYP4V2-source-evidence.yaml |
| GO:0016709 oxidoreductase activity, acting on paired donors, with incorporation or reduction of molecular oxygen, NAD(P)H as one donor, and incorporation of one atom of oxygen | TAS Reactome:R-HSA-6786239 | MODIFY | Summary: Refine the DHA reaction to long-chain fatty-acid omega-hydroxylase activity. Reason: The literal Reactome event is DHA terminal hydroxylation. Its net reaction consumes NADPH, but the reconstituted enzyme receives electrons through P450 reductase rather than directly from NADPH. The specific long-chain omega-hydroxylase term captures the actual C22 reaction and appropriate flavoprotein donor chemistry; it is already represented by a separate annotation based on saturated substrates. Proposed replacements: long-chain fatty acid omega-hydroxylase activity |
| GO:0020037 heme binding | IEA GO_REF:0000002 | ACCEPT | Summary: Heme is an integral catalytic cofactor of CYP4V2. Reason: The three literal InterPro mappings agree with target sequence features and direct purification evidence: mass spectrometry and the reduced-CO absorption spectrum support heme-containing human CYP4V2. The official residue-specific covalent/axial assignments are homology inferences, not new site-mapping experiments in the inspected paper. |
| GO:0102033 long-chain fatty acid omega-hydroxylase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Human CYP4V2 directly hydroxylates terminal carbons of long-chain fatty acids. Reason: Official RHEA:40199 is C16 hexadecanoate terminal hydroxylation and RHEA:40203 is C14 tetradecanoate terminal hydroxylation and EC 1.14.14.80 is consistent with the activity. The direct 2009 assay supports these substrates; the 2012 work adds EPA and DHA. The checked GO term uses 13β22 carbons, so myristate belongs here despite the 2009 paperβs broader colloquial use of medium-chain. |
| GO:0140981 medium-chain fatty acid omega-hydroxylase activity | IEA GO_REF:0000116 | ACCEPT | Summary: Laurate terminal hydroxylation supports the medium-chain-specific activity. Reason: The literal RHEA:38947 reaction is dodecanoate to 12-hydroxydodecanoate, supported by human CYP4V2 turnover. The checked GO term spans C6βC12 and therefore covers the positive C12 substrate. It does not claim activity on every medium-chain fatty acid: the inspected C8 assay did not detect turnover. |
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Q: Does the 503-residue splice product form a stable active enzyme in human tissues?
Q: What are the in-vivo contribution and quantitative selectivity of omega-1 versus terminal hydroxylation?
Q: Does the CYP4V2βGATC association occur in native retinal cells, and what functional role, if any, does it have?
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