HSD17B4 encodes the peroxisomal multifunctional enzyme type 2 (MFE-2/MFP-2), also known as D-bifunctional protein (DBP), a 736-residue enzyme of the peroxisomal matrix that catalyzes the second (hydration) and third (dehydrogenation) reactions of peroxisomal fatty-acid beta-oxidation with D (R) stereochemistry. It is a multidomain protein: an N-terminal (3R)-hydroxyacyl-CoA dehydrogenase domain of the short-chain dehydrogenase/reductase (SDR) family with an NAD(+)-binding Rossmann fold (historically named 17-beta-hydroxysteroid dehydrogenase type 4), a central D-specific enoyl-CoA hydratase 2 / (3R)-3-hydroxyacyl-CoA dehydratase domain of the MaoC/hot-dog fold, and a C-terminal SCP2-like sterol-carrier / lipid-transfer domain. The full-length protein is bifunctional and forms homodimers; in vivo it is proteolytically processed into separate dehydrogenase and hydratase chains. DBP is the main bifunctional enzyme handling very-long-chain fatty acids, 2-methyl-branched-chain (pristanic) acids, C27 bile-acid intermediates (di- and trihydroxycholestanoic acid), and long-chain dicarboxylic acids, and it participates in the peroxisomal beta-oxidation step that retroconverts C24:6n-3 to docosahexaenoic acid (DHA). Its 3-oxoacyl-CoA product is passed to the peroxisomal thiolase step (SCPx/ACAA1). Loss of function causes D-bifunctional protein deficiency, a severe Zellweger-like neonatal peroxisomal disorder, while milder hypomorphic alleles cause Perrault syndrome (sensorineural deafness with ovarian dysgenesis).
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0106386 (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity, the N-terminal dehydrogenase catalytic activity of DBP. This is one of the two core enzymatic functions and is directly supported by biochemistry (see IDA annotations to the same term). Supporting Evidence: file:human/HSD17B4/HSD17B4-uniprot.txt a (3R)-3-hydroxyacyl-CoA + NAD(+) = a 3-oxoacyl-CoA + NADH + |
| GO:0005777 peroxisome | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred peroxisomal localization; correct. DBP is a peroxisomal-matrix enzyme with a C-terminal PTS1-like targeting motif, consistent with IDA immunofluorescence. Supporting Evidence: file:human/HSD17B4/HSD17B4-uniprot.txt SUBCELLULAR LOCATION: Peroxisome |
| GO:0006635 fatty acid beta-oxidation | IBA GO_REF:0000033 | ACCEPT | Summary: Phylogenetically-inferred involvement in fatty acid beta-oxidation, the core biological process for DBP (it catalyzes reactions 2 and 3 of the peroxisomal beta-oxidation cycle). Supporting Evidence: file:human/HSD17B4/HSD17B4-uniprot.txt Bifunctional enzyme acting on the peroxisomal fatty acid |
| GO:0005777 peroxisome | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic peroxisome localization (UniProt subcellular-location/ARBA). Correct and redundant with the experimentally-supported peroxisome/peroxisomal-matrix annotations. |
| GO:0006629 lipid metabolic process | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Electronic ARBA annotation to the very general parent term 'lipid metabolic process'. Not wrong but far less informative than fatty acid beta-oxidation; a high-level grouping term. |
| GO:0016616 oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor | IEA GO_REF:0000117 | MODIFY | Summary: Electronic ARBA annotation to a broad oxidoreductase grouping term. This is a correct but non-specific ancestor of the actual (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity; the specific term GO:0106386 should be used instead. Proposed replacements: (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity |
| GO:0018812 3-hydroxyacyl-CoA dehydratase activity | IEA GO_REF:0000120 | MODIFY | Summary: Electronic annotation to the dehydratase activity of the central hydratase-2 domain. Correct in essence; the D-specific term GO:0080023 ((2E)-enoyl-CoA hydratase activity, i.e. (3R)-3-hydroxyacyl-CoA = (2E)-enoyl-CoA + H2O) is the stereochemistry-precise term. Proposed replacements: (2E)-enoyl-CoA hydratase activity |
| GO:0033989 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-enoyl-CoA hydratase activity | IEA GO_REF:0000120 | KEEP AS NON CORE | Summary: Electronic Rhea/EC-based annotation for the bile-acid (THCA-CoA) hydratase reaction (EC 4.2.1.107), a substrate-specific instance of DBP's hydratase-2 activity. This is a genuine, experimentally-supported substrate (di/trihydroxycholestanoic acid) so the term is retained as a substrate-specific non-core activity of the central hydratase domain. Supporting Evidence: file:human/HSD17B4/HSD17B4-uniprot.txt EC=4.2.1.107 |
| GO:0080023 (2E)-enoyl-CoA hydratase activity | IEA GO_REF:0000120 | ACCEPT | Summary: Electronic Rhea-based annotation to the D-specific (2E)-enoyl-CoA hydratase activity (EC 4.2.1.119); reaction (3R)-3-hydroxyacyl-CoA = (2E)-enoyl-CoA + H2O. This is the precise term for DBP's central hydratase-2 catalytic activity and is one of the two core functions. Supporting Evidence: file:human/HSD17B4/HSD17B4-uniprot.txt EC=4.2.1.119 |
| GO:0102158 very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity | IEA GO_REF:0000116 | KEEP AS NON CORE | Summary: Electronic Rhea-based annotation to the VLCFA-specific instance of DBP's D-hydratase activity. Consistent with DBP being the main hydratase for very-long-chain fatty acids; a substrate-specific child of the core hydratase-2 activity. Supporting Evidence: file:human/HSD17B4/HSD17B4-uniprot.txt a very-long-chain (3R)-3-hydroxyacyl-CoA = a very-long-chain |
| GO:0106386 (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity | IEA GO_REF:0000116 | ACCEPT | Summary: Electronic Rhea-based annotation to the core dehydrogenase activity. Correct and redundant with the IDA/IBA annotations to the same term. Supporting Evidence: file:human/HSD17B4/HSD17B4-uniprot.txt a (3R)-3-hydroxyacyl-CoA + NAD(+) = a 3-oxoacyl-CoA + NADH + |
| GO:0006635 fatty acid beta-oxidation | IEA GO_REF:0000041 | ACCEPT | Summary: Electronic UniPathway-based annotation to fatty acid beta-oxidation, the core process. Correct and redundant with the IDA/IBA evidence. Supporting Evidence: file:human/HSD17B4/HSD17B4-uniprot.txt PATHWAY: Lipid metabolism; fatty acid beta-oxidation. |
| GO:0005777 peroxisome | IDA GO_REF:0000052 | ACCEPT | Summary: Immunofluorescence (HPA) peroxisome localization. Directly supports the core peroxisomal localization of DBP. |
| GO:0106386 (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity | IDA PMID:10706581 Peroxisomal fatty acid oxidation disorders and 58 kDa sterol... | ACCEPT | Summary: Direct assay evidence for the (3R)-3-hydroxyacyl-CoA dehydrogenase activity, measured via recombinant human D-bifunctional protein used to generate the bile-acid dehydrogenation product. Core catalytic activity. Supporting Evidence: PMID:10706581 expressing human D-bifunctional protein |
| GO:0106386 (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity | IDA PMID:15060085 Identification of the peroxisomal beta-oxidation enzymes inv... | ACCEPT | Summary: Direct enzyme-activity measurement of recombinant human DBP dehydrogenase on long-chain and dicarboxylic acyl-CoA substrates. Core catalytic activity. Supporting Evidence: PMID:15060085 direct enzyme measurements with human recombinant |
| GO:0106386 (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity | IDA PMID:9089413 Structure of D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl... | ACCEPT | Summary: Direct biochemical characterization of the purified/recombinant human bifunctional protein showing dehydrogenase activity; the full-length cDNA product has both dehydratase and dehydrogenase activities. Core catalytic activity, with defined kinetics. Supporting Evidence: PMID:9089413 exhibited both the dehydratase and dehydrogenase activities |
| GO:0106386 (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity | IDA PMID:9482850 Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: reso... | ACCEPT | Summary: Direct evidence that the D-bifunctional protein has 3-hydroxyacyl-CoA dehydrogenase activity, and expression of the Gly16Ser variant showed loss of this activity, confirming the dehydrogenase domain. Core catalytic activity. Supporting Evidence: PMID:9482850 enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activity |
| GO:0106386 (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity | IMP PMID:9482850 Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: reso... | ACCEPT | Summary: Mutant-phenotype evidence (Gly16Ser in the NAD+-binding loop) abolishing the dehydrogenase activity, on the processed dehydrogenase chain (PRO_0000400082). Confirms the N-terminal dehydrogenase catalytic activity is required and mapped to this domain. Supporting Evidence: PMID:9482850 the G46A mutation causes the loss of the 3-hydroxyacyl-CoA dehydrogenase activity |
| GO:0004303 estradiol 17-beta-dehydrogenase [NAD(P)+] activity | IDA PMID:7487879 Molecular cloning of a novel widely expressed human 80 kDa 1... | MARK AS OVER ANNOTATED | Summary: From the original cloning paper, which reported a unidirectional oxidative 17-beta-HSD (estradiol dehydrogenase) activity when the enzyme was over-expressed in mammalian cells. This is the historical basis of the 17-beta-HSD type 4 name, but the physiological substrates are fatty-acyl-CoAs, not steroids; UniProt's FUNCTION section describes only fatty-acid/bile-acid metabolism. This steroid activity is an in-vitro side reaction and an over-annotation of the enzyme's core evolved role. Retained (experimental IDA) but flagged. Supporting Evidence: PMID:7487879 17 beta-HSD IV enzyme displays a specific unidirectional oxidative 17 beta-HSD activity |
| GO:0004300 enoyl-CoA hydratase activity | IDA PMID:10706581 Peroxisomal fatty acid oxidation disorders and 58 kDa sterol... | MODIFY | Summary: Direct evidence for enoyl-CoA hydratase activity (the enoyl-CoA of the bile-acid intermediate THCA is hydrated by recombinant human DBP). Correct; this is the parent of the D-specific hydratase-2 activity. MODIFY to the stereochemistry-precise term GO:0080023. Proposed replacements: (2E)-enoyl-CoA hydratase activity Supporting Evidence: PMID:10706581 preincubating the enoyl-CoA of the bile acid intermediate THCA |
| GO:0004300 enoyl-CoA hydratase activity | IDA PMID:15060085 Identification of the peroxisomal beta-oxidation enzymes inv... | MODIFY | Summary: Direct enzyme-activity measurement of the DBP hydratase on long-chain / dicarboxylic substrates. Correct but non-specific; MODIFY to the D-specific hydratase-2 term GO:0080023. Proposed replacements: (2E)-enoyl-CoA hydratase activity Supporting Evidence: PMID:15060085 direct enzyme measurements with human recombinant |
| GO:0004300 enoyl-CoA hydratase activity | IDA PMID:9482850 Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: reso... | MODIFY | Summary: Direct evidence that DBP has enoyl-CoA hydratase activity; the enoyl-CoA hydratase activity was normal in a patient with an isolated dehydrogenase defect, confirming the distinct hydratase function. MODIFY to the D-specific term GO:0080023. Proposed replacements: (2E)-enoyl-CoA hydratase activity Supporting Evidence: PMID:9482850 the enoyl-CoA hydratase activity of d -bifunctional protein was normal |
| GO:0006635 fatty acid beta-oxidation | IDA PMID:10706581 Peroxisomal fatty acid oxidation disorders and 58 kDa sterol... | ACCEPT | Summary: Direct evidence connecting DBP to peroxisomal beta-oxidation of bile-acid intermediates. Core biological process. Supporting Evidence: PMID:10706581 peroxisomal oxidation of branched-chain fatty acids |
| GO:0006635 fatty acid beta-oxidation | IDA PMID:15060085 Identification of the peroxisomal beta-oxidation enzymes inv... | ACCEPT | Summary: Direct evidence that DBP is one of the main enzymes in peroxisomal beta-oxidation of long-chain dicarboxylic acids. Core biological process. Supporting Evidence: PMID:15060085 the main enzymes involved in beta-oxidation of C16DCA are SCOX, both LBP and DBP |
| GO:0006635 fatty acid beta-oxidation | IDA PMID:9482850 Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: reso... | ACCEPT | Summary: Direct evidence that DBP plays an essential, non-redundant role in the peroxisomal beta-oxidation pathway. Core biological process. Supporting Evidence: PMID:9482850 plays an essential role in the peroxisomal Ξ²-oxidation pathway |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-192331 | ACCEPT | Summary: Reactome TAS localizing DBP to the peroxisomal matrix in the context of the bile-acid (THCA-CoA hydration) reaction. Correct and the most precise localization term; the peroxisomal matrix is the functional compartment for DBP catalysis. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-193455 | ACCEPT | Summary: Reactome TAS localizing DBP to the peroxisomal matrix (bile-acid intermediate dehydrogenation reaction). Correct core localization. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-193508 | ACCEPT | Summary: Reactome TAS localizing DBP to the peroxisomal matrix (bile-acid intermediate reaction). Correct core localization. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-193535 | ACCEPT | Summary: Reactome TAS localizing DBP to the peroxisomal matrix (bile-acid intermediate hydration reaction). Correct core localization. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-2066778 | ACCEPT | Summary: Reactome TAS localizing DBP to the peroxisomal matrix (hydration step in DHA-synthesis beta-oxidation). Correct core localization. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-2066780 | ACCEPT | Summary: Reactome TAS localizing DBP to the peroxisomal matrix (dehydrogenation step in DHA-synthesis beta-oxidation). Correct core localization. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-389986 | ACCEPT | Summary: Reactome TAS localizing DBP to the peroxisomal matrix (pristanoyl-CoA hydration step). Correct core localization. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-389995 | ACCEPT | Summary: Reactome TAS localizing DBP to the peroxisomal matrix (pristanoyl-CoA dehydrogenation step). Correct core localization. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-390251 | ACCEPT | Summary: Reactome TAS localizing DBP to the peroxisomal matrix (VLCFA 3-hydroxyacyl-CoA dehydrogenation step). Correct core localization. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-390252 | ACCEPT | Summary: Reactome TAS localizing DBP to the peroxisomal matrix (VLCFA enoyl-CoA hydration step). Correct core localization. |
| GO:0005782 peroxisomal matrix | TAS Reactome:R-HSA-9033235 | ACCEPT | Summary: Reactome TAS localizing DBP to the peroxisomal matrix as PEX5 import cargo (translocation from cytosol to matrix). Correct destination compartment for the imported enzyme. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9033235 | KEEP AS NON CORE | Summary: Reactome TAS placing DBP in the cytosol as newly-synthesized PTS1 cargo before import. This reflects the transient import route, not the functional compartment; DBP acts in the peroxisomal matrix. Non-core. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9033236 | KEEP AS NON CORE | Summary: Reactome TAS placing DBP in the cytosol as PEX5 cargo binding the docking/translocation module. Import-route intermediate, not the functional compartment. Non-core. |
| GO:0001649 osteoblast differentiation | HDA PMID:16210410 Differential expression profiling of membrane proteins by qu... | MARK AS OVER ANNOTATED | Summary: High-throughput proteomics screen of membrane-protein expression changes in a mesenchymal stem cell line undergoing osteoblast differentiation. DBP was detected as a differentially expressed protein, not shown to have any functional role in differentiation. An expression correlation, not a functional involvement; over-annotation. Supporting Evidence: PMID:16210410 changes in expression of membrane protein markers |
| GO:0016020 membrane | HDA PMID:16210410 Differential expression profiling of membrane proteins by qu... | MARK AS OVER ANNOTATED | Summary: From a membrane-protein proteomics screen; DBP co-fractionated in a membrane-enriched preparation. DBP is a soluble peroxisomal-matrix enzyme, not an integral membrane protein; this is a co-fractionation artifact / over-annotation of location. Supporting Evidence: PMID:16210410 expression profiling of membrane proteins by quantitative |
| GO:0005777 peroxisome | IDA PMID:15599942 Peroxisomal branched chain fatty acid beta-oxidation pathway... | ACCEPT | Summary: Direct evidence (branched-chain fatty-acid beta-oxidation study in prostate) supporting peroxisomal localization and activity of DBP. Correct core localization. Supporting Evidence: PMID:15599942 D-bifunctional protein (DBP)-is also upregulated in prostate cancer |
| GO:0042803 protein homodimerization activity | IDA PMID:15644212 Crystal structure of 2-enoyl-CoA hydratase 2 from human pero... | KEEP AS NON CORE | Summary: Crystal structure of the human MFE-2 hydratase-2 domain, which forms a hot-dog-fold dimer; the full-length enzyme is a homodimer. Homodimerization is a real structural property but is a supporting feature of the active enzyme rather than a distinct core molecular function; retained as non-core. Supporting Evidence: PMID:15644212 having a two-domain subunit structure |
| GO:0018812 3-hydroxyacyl-CoA dehydratase activity | IDA PMID:9482850 Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: reso... | MODIFY | Summary: Direct evidence for the D-hydroxyacyl-CoA dehydratase / enoyl-CoA hydratase activity of DBP (normal hydratase activity in a dehydrogenase-defect patient). Correct; MODIFY to the stereochemistry-precise D term GO:0080023. Proposed replacements: (2E)-enoyl-CoA hydratase activity Supporting Evidence: PMID:9482850 the enoyl-CoA hydratase activity of d -bifunctional protein was normal |
| GO:0005777 peroxisome | NAS PMID:9482850 Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: reso... | ACCEPT | Summary: Non-traceable author statement that DBP is a peroxisomal beta-oxidation enzyme. Correct core localization, supported more strongly by IDA/TAS annotations. Supporting Evidence: PMID:9482850 a new peroxisomal Ξ²-oxidation enzyme was recently described |
| GO:0036111 very long-chain fatty-acyl-CoA metabolic process | IDA PMID:9482850 Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: reso... | KEEP AS NON CORE | Summary: Direct evidence that DBP is involved in VLCFA metabolism: DBP-deficient patients accumulate straight-chain very-long-chain fatty acids, and DBP may be the main VLCFA beta-oxidation enzyme. A biologically important substrate class; keep, though it is a specialization of the core fatty acid beta-oxidation process. Supporting Evidence: PMID:9482850 accumulates straight-chain fatty acids (VLCFA) both in plasma and fibroblasts |
| GO:0018812 3-hydroxyacyl-CoA dehydratase activity | IDA PMID:9089413 Structure of D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl... | MODIFY | Summary: Direct biochemical evidence: the purified human bifunctional protein has dehydratase activity, and a truncated C-terminal fragment retains only dehydratase activity, mapping it to the hydratase-2 domain. Correct; MODIFY to the D-specific term GO:0080023. Proposed replacements: (2E)-enoyl-CoA hydratase activity Supporting Evidence: PMID:9089413 exhibited only the dehydratase activity |
| GO:0036112 medium-chain fatty-acyl-CoA metabolic process | IDA PMID:9089413 Structure of D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl... | KEEP AS NON CORE | Summary: Direct evidence from kinetic characterization on medium-chain substrates (e.g. D-3-hydroxy- octanoyl-CoA, decanoyl-CoA). A substrate-specific specialization of DBP's beta-oxidation activity; retained as non-core. Supporting Evidence: file:human/HSD17B4/HSD17B4-uniprot.txt KM=10 uM for D-3-hydroxy-octanoyl-CoA |
| GO:0042803 protein homodimerization activity | IDA PMID:9089413 Structure of D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl... | KEEP AS NON CORE | Summary: Direct evidence that the native enzyme is a homodimer (of the 77-kDa polypeptide). Structural property supporting the active enzyme; retained as non-core. Supporting Evidence: PMID:9089413 the native enzyme is a homodimer of 77-kDa |
| GO:0005778 peroxisomal membrane | HDA PMID:21525035 PEX14 is required for microtubule-based peroxisome motility ... | MARK AS OVER ANNOTATED | Summary: HDA localization to the peroxisomal membrane, from a proteomics study whose subject is PEX14 and microtubule-based peroxisome motility (DBP is not its focus). DBP is a soluble matrix enzyme; membrane co-purification reflects peroxisome-membrane proteome preparation, not integral membrane localization. Over-annotation of location. Supporting Evidence: PMID:21525035 isolating native peroxisomal membrane protein complexes from cultured human cells |
| GO:0006635 fatty acid beta-oxidation | IDA PMID:10400999 Enoyl-CoA hydratase deficiency: identification of a new type... | ACCEPT | Summary: Direct evidence: DBP is involved in peroxisomal beta-oxidation of VLCFAs, branched-chain fatty acids and bile-acid intermediates; a new hydratase-domain deficiency was defined here. Core biological process. Supporting Evidence: PMID:10400999 D-bifunctional protein is involved in the peroxisomal beta-oxidation of very long chain fatty acids, branched chain fatty acids and bile acid intermediates |
| GO:0018812 3-hydroxyacyl-CoA dehydratase activity | IDA PMID:10400999 Enoyl-CoA hydratase deficiency: identification of a new type... | MODIFY | Summary: Direct evidence for the enoyl-CoA hydratase (dehydratase) domain activity; two patients had an isolated defect in the enoyl-CoA hydratase domain of DBP (Asn457Tyr). Correct; MODIFY to the D-specific term GO:0080023. Proposed replacements: (2E)-enoyl-CoA hydratase activity Supporting Evidence: PMID:10400999 an isolated defect in the enoyl-CoA hydratase domain of D-bifunctional protein |
| GO:0005777 peroxisome | NAS PMID:7487879 Molecular cloning of a novel widely expressed human 80 kDa 1... | ACCEPT | Summary: Non-traceable author statement of peroxisomal localization from the original cloning paper (the C-terminal region is similar to sterol carrier protein 2, a peroxisomal marker). Correct core localization, supported more strongly by IDA/TAS annotations. Supporting Evidence: PMID:7487879 amino acids 596-736 which are similar to human sterol |
| GO:0008209 androgen metabolic process | IDA PMID:7487879 Molecular cloning of a novel widely expressed human 80 kDa 1... | MARK AS OVER ANNOTATED | Summary: From the original cloning paper reporting 17-beta-HSD (steroid) activity in over-expressing cells. DBP's physiological substrates are fatty-acyl-CoAs, not androgens; UniProt's FUNCTION section describes only fatty-acid/bile-acid metabolism. This steroid-metabolism process is a side reaction and an over-annotation of the enzyme's core role. Retained (experimental IDA) but flagged. Supporting Evidence: PMID:7487879 Reactions of oestrogens and androgens at position C-17 are catalysed by 17 beta-hydroxysteroid dehydrogenases |
| GO:0008210 estrogen metabolic process | IDA PMID:7487879 Molecular cloning of a novel widely expressed human 80 kDa 1... | MARK AS OVER ANNOTATED | Summary: From the original cloning paper reporting oxidative 17-beta-estradiol dehydrogenase activity in over-expressing cells. As with androgen metabolism, this is an in-vitro steroid side activity, not the enzyme's physiological (fatty-acid) role; over-annotation. Retained (experimental IDA) but flagged. Supporting Evidence: PMID:7487879 17 beta-HSD IV enzyme displays a specific unidirectional oxidative 17 beta-HSD activity |
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Download this section (compressed HTML)Q: Given that DBP's physiological substrates are fatty-acyl-CoAs, should the historical 17-beta-hydroxysteroid dehydrogenase (estradiol/androgen/estrogen) activities be retained as curated functions, or reclassified as in-vitro side activities?
Q: Which peroxisomal beta-oxidation substrate classes (VLCFA vs pristanic/bile-acid vs dicarboxylic vs PUFA/DHA) depend most non-redundantly on DBP versus the L-bifunctional protein (EHHADH)?
Experiment: Substrate-resolved metabolomics of DBP-null versus EHHADH-null cells to quantify the non-redundant contribution of DBP to each acyl-CoA class (VLCFA, pristanoyl, DHCA/THCA, C16DCA, C24:6n-3).
Experiment: Structure-guided mutagenesis of the hydratase-2 substrate-binding loops to test whether the reported steroid dehydrogenase activity and the fatty-acyl dehydrogenase activity can be separated, clarifying the physiological relevance of the 17-beta-HSD activity.
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