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
|
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.
HSD17B4 encodes the peroxisomal multifunctional enzyme type 2 (MFE-2 / MFP-2), also
called D-bifunctional protein (DBP) and historically "17-beta-hydroxysteroid
dehydrogenase type 4 (17Ξ²-HSD4)". It is a 736-aa peroxisomal-matrix enzyme that catalyzes
steps 2 and 3 of peroxisomal fatty-acid beta-oxidation with D (R) stereochemistry.
The protein is multidomain (UniProt P51659 FT):
- N-terminal (3R)-hydroxyacyl-CoA dehydrogenase domain (aa 1β305; SDR/Rossmann fold, NAD+
binding), historically the "17Ξ²-HSD" part [file:human/HSD17B4/HSD17B4-uniprot.txt "REGION 1..305 /note=\"(3R)-hydroxyacyl-CoA dehydrogenase\""].
- Central enoyl-CoA hydratase 2 / D-3-hydroxyacyl-CoA dehydratase domain (aa 322β622;
MaoC-like hot-dog fold) [file:human/HSD17B4/HSD17B4-uniprot.txt "REGION 322..622 /note=\"Enoyl-CoA hydratase 2\""].
- C-terminal SCP2 sterol-carrier / lipid-transfer domain (aa 624β736)
[file:human/HSD17B4/HSD17B4-uniprot.txt "DOMAIN 624..736 /note=\"SCP2\""].
The mature protein carries a C-terminal peroxisomal targeting motif (aa 734β736, "AKL")
[file:human/HSD17B4/HSD17B4-uniprot.txt "MOTIF 734..736 /note=\"Microbody targeting signal\""] and is imported
into the peroxisomal matrix. In vivo it is processed by the peroxisomal protease TYSND1 into
separate dehydrogenase and hydratase chains (PRO_0000400082 aa 1β311, PRO_0000400083 aa
312β736), but the full-length protein is bifunctional PMID:9089413.
DBP performs the 2nd (hydration) and 3rd (dehydrogenation) reactions of each beta-oxidation
cycle, in D/R stereochemistry:
The 3-oxoacyl-CoA product is handed to the peroxisomal thiolase step (SCPx/ACAA1) to complete
the cycle. UniProt FUNCTION: "Catalyzes two of the four reactions in fatty acid degradation:
hydration of 2-enoyl-CoA (trans-2-enoyl-CoA) to produce (3R)-3-hydroxyacyl-CoA, and
dehydrogenation of (3R)-3-hydroxyacyl-CoA to produce 3-ketoacyl-CoA (3-oxoacyl-CoA), which is
further metabolized by SCPx." [file:human/HSD17B4/HSD17B4-uniprot.txt "Catalyzes two of the four reactions in fatty"].
The bifunctional purified enzyme has both activities; a proteolytic C-terminal fragment
retains only the dehydratase PMID:9089413.
Original cloning identified the cDNA as identical to 17Ξ²-HSD IV PMID:9089413.
Although first characterized as a 17Ξ²-hydroxysteroid dehydrogenase (from a porcine
17Ξ²-estradiol dehydrogenase probe), DBP's physiological substrates are fatty acyl-CoAs,
not steroids. It is the main bifunctional enzyme for:
- Very-long-chain fatty acids (VLCFAs) β DBP deficiency accumulates straight-chain VLCFA
PMID:9482850;
the D enzyme is suspected to be the main VLCFA beta-oxidation enzyme PMID:9482850.
- 2-methyl-branched-chain (pristanic) acids and C27 bile-acid intermediates (DHCA/THCA)
PMID:9482850.
- Long-chain dicarboxylic acids β DBP is among the main beta-oxidation enzymes for C16DCA
PMID:15060085.
- DHA (C22:6n-3) biosynthesis β peroxisomal beta-oxidation of C24:6n-3 to C22:6n-3 needs DBP
PMID:11734571.
The 1995 cloning paper reports only a "specific unidirectional oxidative 17Ξ²-HSD activity"
when over-expressed PMID:7487879;
this is the source of the estradiol/androgen/estrogen-dehydrogenase annotations. Physiologically
these steroid activities are minor/secondary side reactions of the fatty-acid oxidoreductase;
UniProt's RecName is "Peroxisomal multifunctional enzyme type 2", and the FUNCTION section
describes only fatty-acid/bile-acid metabolism, not steroid metabolism. The steroid MF/BP
annotations (GO:0004303, GO:0008209, GO:0008210) are therefore over-annotations of the
enzyme's core evolved role, but they rest on an IDA experiment (PMID:7487879) and are not
removed per curation policy.
Peroxisome / peroxisomal matrix. UniProt: "SUBCELLULAR LOCATION: Peroxisome"
[file:human/HSD17B4/HSD17B4-uniprot.txt "SUBCELLULAR LOCATION: Peroxisome"]. Supported by IDA
immunofluorescence (PMID:15599942, HPA GO_REF:0000052), Reactome peroxisomal-matrix TAS, and
the C-terminal PTS1-like microbody targeting signal. Cytosol/membrane/peroxisomal-membrane
annotations reflect the import route (PTS1 cargo transits cytosol before import; Reactome
R-HSA-9033235/9033236 model the PEX5 import machinery) or proteomics co-fractionation, not the
functional site of catalysis.
Homodimer [file:human/HSD17B4/HSD17B4-uniprot.txt "SUBUNIT: Homodimer"]. Crystal structures
solved for each domain: SCP2-like domain (1IKT), hydratase 2 (1S9C), dehydrogenase+NAD (1ZBQ).
The hydratase-2 crystal structure shows a hot-dog-fold dimer able to accommodate bulky C26,
pristanic and DHCA/THCA CoA esters PMID:15644212.
Homodimerization annotations (GO:0042803) are IDA-supported (PMID:15644212, PMID:9089413).
Two catalytic MFs constitute the core evolved function:
1. GO:0080023 (2E)-enoyl-CoA hydratase activity β definition "a (3R)-3-hydroxyacyl-CoA = a
(2E)-enoyl-CoA + H2O", i.e. the D-specific hydratase 2 (EC 4.2.1.119). (The GOA IDA
annotations use the less specific parent GO:0004300 enoyl-CoA hydratase activity and
GO:0018812 3-hydroxyacyl-CoA dehydratase activity; GO:0080023 is the D-specific,
stereochemistry-correct term.)
2. GO:0106386 (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity β EC 1.1.1.n12.
Directly involved in: GO:0006635 fatty acid beta-oxidation; bile acid biosynthesis. Location:
GO:0005782 peroxisomal matrix.
id: P51659
gene_symbol: HSD17B4
product_type: PROTEIN
status: INITIALIZED
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: >-
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).
existing_annotations:
- term:
id: GO:0106386
label: (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: enables
review:
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).
action: ACCEPT
supported_by:
- reference_id: file:human/HSD17B4/HSD17B4-uniprot.txt
supporting_text: "a (3R)-3-hydroxyacyl-CoA + NAD(+) = a 3-oxoacyl-CoA + NADH +"
- term:
id: GO:0005777
label: peroxisome
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: is_active_in
review:
summary: >-
Phylogenetically-inferred peroxisomal localization; correct. DBP is a peroxisomal-matrix
enzyme with a C-terminal PTS1-like targeting motif, consistent with IDA immunofluorescence.
action: ACCEPT
supported_by:
- reference_id: file:human/HSD17B4/HSD17B4-uniprot.txt
supporting_text: "SUBCELLULAR LOCATION: Peroxisome"
- term:
id: GO:0006635
label: fatty acid beta-oxidation
evidence_type: IBA
original_reference_id: GO_REF:0000033
qualifier: involved_in
review:
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).
action: ACCEPT
supported_by:
- reference_id: file:human/HSD17B4/HSD17B4-uniprot.txt
supporting_text: "Bifunctional enzyme acting on the peroxisomal fatty acid"
- term:
id: GO:0005777
label: peroxisome
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: located_in
review:
summary: >-
Electronic peroxisome localization (UniProt subcellular-location/ARBA). Correct and
redundant with the experimentally-supported peroxisome/peroxisomal-matrix annotations.
action: ACCEPT
- term:
id: GO:0006629
label: lipid metabolic process
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: involved_in
review:
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.
action: MARK_AS_OVER_ANNOTATED
- term:
id: GO:0016616
label: oxidoreductase activity, acting on the CH-OH group of donors, NAD or NADP as acceptor
evidence_type: IEA
original_reference_id: GO_REF:0000117
qualifier: enables
review:
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.
action: MODIFY
proposed_replacement_terms:
- id: GO:0106386
label: (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity
- term:
id: GO:0018812
label: 3-hydroxyacyl-CoA dehydratase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: enables
review:
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.
action: MODIFY
proposed_replacement_terms:
- id: GO:0080023
label: (2E)-enoyl-CoA hydratase activity
- term:
id: GO:0033989
label: 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-enoyl-CoA hydratase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: enables
review:
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.
action: KEEP_AS_NON_CORE
supported_by:
- reference_id: file:human/HSD17B4/HSD17B4-uniprot.txt
supporting_text: "EC=4.2.1.107"
- term:
id: GO:0080023
label: (2E)-enoyl-CoA hydratase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
qualifier: enables
review:
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.
action: ACCEPT
supported_by:
- reference_id: file:human/HSD17B4/HSD17B4-uniprot.txt
supporting_text: "EC=4.2.1.119"
- term:
id: GO:0102158
label: very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity
evidence_type: IEA
original_reference_id: GO_REF:0000116
qualifier: enables
review:
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.
action: KEEP_AS_NON_CORE
supported_by:
- reference_id: file:human/HSD17B4/HSD17B4-uniprot.txt
supporting_text: "a very-long-chain (3R)-3-hydroxyacyl-CoA = a very-long-chain"
- term:
id: GO:0106386
label: (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity
evidence_type: IEA
original_reference_id: GO_REF:0000116
qualifier: enables
review:
summary: >-
Electronic Rhea-based annotation to the core dehydrogenase activity. Correct and
redundant with the IDA/IBA annotations to the same term.
action: ACCEPT
supported_by:
- reference_id: file:human/HSD17B4/HSD17B4-uniprot.txt
supporting_text: "a (3R)-3-hydroxyacyl-CoA + NAD(+) = a 3-oxoacyl-CoA + NADH +"
- term:
id: GO:0006635
label: fatty acid beta-oxidation
evidence_type: IEA
original_reference_id: GO_REF:0000041
qualifier: involved_in
review:
summary: >-
Electronic UniPathway-based annotation to fatty acid beta-oxidation, the core process.
Correct and redundant with the IDA/IBA evidence.
action: ACCEPT
supported_by:
- reference_id: file:human/HSD17B4/HSD17B4-uniprot.txt
supporting_text: "PATHWAY: Lipid metabolism; fatty acid beta-oxidation."
- term:
id: GO:0005777
label: peroxisome
evidence_type: IDA
original_reference_id: GO_REF:0000052
qualifier: located_in
review:
summary: >-
Immunofluorescence (HPA) peroxisome localization. Directly supports the core peroxisomal
localization of DBP.
action: ACCEPT
- term:
id: GO:0106386
label: (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity
evidence_type: IDA
original_reference_id: PMID:10706581
qualifier: enables
review:
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.
action: ACCEPT
supported_by:
- reference_id: PMID:10706581
supporting_text: "expressing human D-bifunctional protein"
- term:
id: GO:0106386
label: (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity
evidence_type: IDA
original_reference_id: PMID:15060085
qualifier: enables
review:
summary: >-
Direct enzyme-activity measurement of recombinant human DBP dehydrogenase on long-chain
and dicarboxylic acyl-CoA substrates. Core catalytic activity.
action: ACCEPT
supported_by:
- reference_id: PMID:15060085
supporting_text: "direct enzyme measurements with human recombinant"
- term:
id: GO:0106386
label: (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity
evidence_type: IDA
original_reference_id: PMID:9089413
qualifier: enables
review:
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.
action: ACCEPT
supported_by:
- reference_id: PMID:9089413
supporting_text: "exhibited both the dehydratase and dehydrogenase activities"
- term:
id: GO:0106386
label: (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity
evidence_type: IDA
original_reference_id: PMID:9482850
qualifier: enables
review:
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.
action: ACCEPT
supported_by:
- reference_id: PMID:9482850
supporting_text: "enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activity"
- term:
id: GO:0106386
label: (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity
evidence_type: IMP
original_reference_id: PMID:9482850
qualifier: enables
review:
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.
action: ACCEPT
supported_by:
- reference_id: PMID:9482850
supporting_text: "the G46A mutation causes the loss of the 3-hydroxyacyl-CoA dehydrogenase activity"
- term:
id: GO:0004303
label: estradiol 17-beta-dehydrogenase [NAD(P)+] activity
evidence_type: IDA
original_reference_id: PMID:7487879
qualifier: enables
review:
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.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:7487879
supporting_text: "17 beta-HSD IV enzyme displays a specific unidirectional oxidative 17 beta-HSD activity"
- term:
id: GO:0004300
label: enoyl-CoA hydratase activity
evidence_type: IDA
original_reference_id: PMID:10706581
qualifier: enables
review:
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.
action: MODIFY
proposed_replacement_terms:
- id: GO:0080023
label: (2E)-enoyl-CoA hydratase activity
supported_by:
- reference_id: PMID:10706581
supporting_text: "preincubating the enoyl-CoA of the bile acid intermediate THCA"
- term:
id: GO:0004300
label: enoyl-CoA hydratase activity
evidence_type: IDA
original_reference_id: PMID:15060085
qualifier: enables
review:
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.
action: MODIFY
proposed_replacement_terms:
- id: GO:0080023
label: (2E)-enoyl-CoA hydratase activity
supported_by:
- reference_id: PMID:15060085
supporting_text: "direct enzyme measurements with human recombinant"
- term:
id: GO:0004300
label: enoyl-CoA hydratase activity
evidence_type: IDA
original_reference_id: PMID:9482850
qualifier: enables
review:
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.
action: MODIFY
proposed_replacement_terms:
- id: GO:0080023
label: (2E)-enoyl-CoA hydratase activity
supported_by:
- reference_id: PMID:9482850
supporting_text: "the enoyl-CoA hydratase activity of d -bifunctional protein was normal"
- term:
id: GO:0006635
label: fatty acid beta-oxidation
evidence_type: IDA
original_reference_id: PMID:10706581
qualifier: involved_in
review:
summary: >-
Direct evidence connecting DBP to peroxisomal beta-oxidation of bile-acid intermediates.
Core biological process.
action: ACCEPT
supported_by:
- reference_id: PMID:10706581
supporting_text: "peroxisomal oxidation of branched-chain fatty acids"
- term:
id: GO:0006635
label: fatty acid beta-oxidation
evidence_type: IDA
original_reference_id: PMID:15060085
qualifier: involved_in
review:
summary: >-
Direct evidence that DBP is one of the main enzymes in peroxisomal beta-oxidation of
long-chain dicarboxylic acids. Core biological process.
action: ACCEPT
supported_by:
- reference_id: PMID:15060085
supporting_text: "the main enzymes involved in beta-oxidation of C16DCA are SCOX, both LBP and DBP"
- term:
id: GO:0006635
label: fatty acid beta-oxidation
evidence_type: IDA
original_reference_id: PMID:9482850
qualifier: involved_in
review:
summary: >-
Direct evidence that DBP plays an essential, non-redundant role in the peroxisomal
beta-oxidation pathway. Core biological process.
action: ACCEPT
supported_by:
- reference_id: PMID:9482850
supporting_text: "plays an essential role in the peroxisomal Ξ²-oxidation pathway"
- term:
id: GO:0005782
label: peroxisomal matrix
evidence_type: TAS
original_reference_id: Reactome:R-HSA-192331
qualifier: located_in
review:
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.
action: ACCEPT
- term:
id: GO:0005782
label: peroxisomal matrix
evidence_type: TAS
original_reference_id: Reactome:R-HSA-193455
qualifier: located_in
review:
summary: >-
Reactome TAS localizing DBP to the peroxisomal matrix (bile-acid intermediate
dehydrogenation reaction). Correct core localization.
action: ACCEPT
- term:
id: GO:0005782
label: peroxisomal matrix
evidence_type: TAS
original_reference_id: Reactome:R-HSA-193508
qualifier: located_in
review:
summary: >-
Reactome TAS localizing DBP to the peroxisomal matrix (bile-acid intermediate reaction).
Correct core localization.
action: ACCEPT
- term:
id: GO:0005782
label: peroxisomal matrix
evidence_type: TAS
original_reference_id: Reactome:R-HSA-193535
qualifier: located_in
review:
summary: >-
Reactome TAS localizing DBP to the peroxisomal matrix (bile-acid intermediate hydration
reaction). Correct core localization.
action: ACCEPT
- term:
id: GO:0005782
label: peroxisomal matrix
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2066778
qualifier: located_in
review:
summary: >-
Reactome TAS localizing DBP to the peroxisomal matrix (hydration step in DHA-synthesis
beta-oxidation). Correct core localization.
action: ACCEPT
- term:
id: GO:0005782
label: peroxisomal matrix
evidence_type: TAS
original_reference_id: Reactome:R-HSA-2066780
qualifier: located_in
review:
summary: >-
Reactome TAS localizing DBP to the peroxisomal matrix (dehydrogenation step in
DHA-synthesis beta-oxidation). Correct core localization.
action: ACCEPT
- term:
id: GO:0005782
label: peroxisomal matrix
evidence_type: TAS
original_reference_id: Reactome:R-HSA-389986
qualifier: located_in
review:
summary: >-
Reactome TAS localizing DBP to the peroxisomal matrix (pristanoyl-CoA hydration step).
Correct core localization.
action: ACCEPT
- term:
id: GO:0005782
label: peroxisomal matrix
evidence_type: TAS
original_reference_id: Reactome:R-HSA-389995
qualifier: located_in
review:
summary: >-
Reactome TAS localizing DBP to the peroxisomal matrix (pristanoyl-CoA dehydrogenation
step). Correct core localization.
action: ACCEPT
- term:
id: GO:0005782
label: peroxisomal matrix
evidence_type: TAS
original_reference_id: Reactome:R-HSA-390251
qualifier: located_in
review:
summary: >-
Reactome TAS localizing DBP to the peroxisomal matrix (VLCFA 3-hydroxyacyl-CoA
dehydrogenation step). Correct core localization.
action: ACCEPT
- term:
id: GO:0005782
label: peroxisomal matrix
evidence_type: TAS
original_reference_id: Reactome:R-HSA-390252
qualifier: located_in
review:
summary: >-
Reactome TAS localizing DBP to the peroxisomal matrix (VLCFA enoyl-CoA hydration step).
Correct core localization.
action: ACCEPT
- term:
id: GO:0005782
label: peroxisomal matrix
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9033235
qualifier: located_in
review:
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.
action: ACCEPT
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9033235
qualifier: located_in
review:
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.
action: KEEP_AS_NON_CORE
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9033236
qualifier: located_in
review:
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.
action: KEEP_AS_NON_CORE
- term:
id: GO:0001649
label: osteoblast differentiation
evidence_type: HDA
original_reference_id: PMID:16210410
qualifier: involved_in
review:
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.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:16210410
supporting_text: "changes in expression of membrane protein markers"
- term:
id: GO:0016020
label: membrane
evidence_type: HDA
original_reference_id: PMID:16210410
qualifier: located_in
review:
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.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:16210410
supporting_text: "expression profiling of membrane proteins by quantitative"
- term:
id: GO:0005777
label: peroxisome
evidence_type: IDA
original_reference_id: PMID:15599942
qualifier: located_in
review:
summary: >-
Direct evidence (branched-chain fatty-acid beta-oxidation study in prostate) supporting
peroxisomal localization and activity of DBP. Correct core localization.
action: ACCEPT
supported_by:
- reference_id: PMID:15599942
supporting_text: "D-bifunctional protein (DBP)-is also upregulated in prostate cancer"
- term:
id: GO:0042803
label: protein homodimerization activity
evidence_type: IDA
original_reference_id: PMID:15644212
qualifier: enables
review:
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.
action: KEEP_AS_NON_CORE
supported_by:
- reference_id: PMID:15644212
supporting_text: "having a two-domain subunit structure"
- term:
id: GO:0018812
label: 3-hydroxyacyl-CoA dehydratase activity
evidence_type: IDA
original_reference_id: PMID:9482850
qualifier: enables
review:
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.
action: MODIFY
proposed_replacement_terms:
- id: GO:0080023
label: (2E)-enoyl-CoA hydratase activity
supported_by:
- reference_id: PMID:9482850
supporting_text: "the enoyl-CoA hydratase activity of d -bifunctional protein was normal"
- term:
id: GO:0005777
label: peroxisome
evidence_type: NAS
original_reference_id: PMID:9482850
qualifier: located_in
review:
summary: >-
Non-traceable author statement that DBP is a peroxisomal beta-oxidation enzyme. Correct
core localization, supported more strongly by IDA/TAS annotations.
action: ACCEPT
supported_by:
- reference_id: PMID:9482850
supporting_text: "a new peroxisomal Ξ²-oxidation enzyme was recently described"
- term:
id: GO:0036111
label: very long-chain fatty-acyl-CoA metabolic process
evidence_type: IDA
original_reference_id: PMID:9482850
qualifier: involved_in
review:
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.
action: KEEP_AS_NON_CORE
supported_by:
- reference_id: PMID:9482850
supporting_text: "accumulates straight-chain fatty acids (VLCFA) both in plasma and fibroblasts"
- term:
id: GO:0018812
label: 3-hydroxyacyl-CoA dehydratase activity
evidence_type: IDA
original_reference_id: PMID:9089413
qualifier: enables
review:
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.
action: MODIFY
proposed_replacement_terms:
- id: GO:0080023
label: (2E)-enoyl-CoA hydratase activity
supported_by:
- reference_id: PMID:9089413
supporting_text: "exhibited only the dehydratase activity"
- term:
id: GO:0036112
label: medium-chain fatty-acyl-CoA metabolic process
evidence_type: IDA
original_reference_id: PMID:9089413
qualifier: involved_in
review:
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.
action: KEEP_AS_NON_CORE
supported_by:
- reference_id: file:human/HSD17B4/HSD17B4-uniprot.txt
supporting_text: "KM=10 uM for D-3-hydroxy-octanoyl-CoA"
- term:
id: GO:0042803
label: protein homodimerization activity
evidence_type: IDA
original_reference_id: PMID:9089413
qualifier: enables
review:
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.
action: KEEP_AS_NON_CORE
supported_by:
- reference_id: PMID:9089413
supporting_text: "the native enzyme is a homodimer of 77-kDa"
- term:
id: GO:0005778
label: peroxisomal membrane
evidence_type: HDA
original_reference_id: PMID:21525035
qualifier: located_in
review:
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.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:21525035
supporting_text: "isolating native peroxisomal membrane protein complexes from cultured human cells"
- term:
id: GO:0006635
label: fatty acid beta-oxidation
evidence_type: IDA
original_reference_id: PMID:10400999
qualifier: involved_in
review:
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.
action: ACCEPT
supported_by:
- reference_id: PMID:10400999
supporting_text: "D-bifunctional protein is involved in the peroxisomal beta-oxidation of very long chain fatty acids, branched chain fatty acids and bile acid intermediates"
- term:
id: GO:0018812
label: 3-hydroxyacyl-CoA dehydratase activity
evidence_type: IDA
original_reference_id: PMID:10400999
qualifier: enables
review:
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.
action: MODIFY
proposed_replacement_terms:
- id: GO:0080023
label: (2E)-enoyl-CoA hydratase activity
supported_by:
- reference_id: PMID:10400999
supporting_text: "an isolated defect in the enoyl-CoA hydratase domain of D-bifunctional protein"
- term:
id: GO:0005777
label: peroxisome
evidence_type: NAS
original_reference_id: PMID:7487879
qualifier: located_in
review:
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.
action: ACCEPT
supported_by:
- reference_id: PMID:7487879
supporting_text: "amino acids 596-736 which are similar to human sterol"
- term:
id: GO:0008209
label: androgen metabolic process
evidence_type: IDA
original_reference_id: PMID:7487879
qualifier: involved_in
review:
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.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:7487879
supporting_text: "Reactions of oestrogens and androgens at position C-17 are catalysed by 17 beta-hydroxysteroid dehydrogenases"
- term:
id: GO:0008210
label: estrogen metabolic process
evidence_type: IDA
original_reference_id: PMID:7487879
qualifier: involved_in
review:
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.
action: MARK_AS_OVER_ANNOTATED
supported_by:
- reference_id: PMID:7487879
supporting_text: "17 beta-HSD IV enzyme displays a specific unidirectional oxidative 17 beta-HSD activity"
core_functions:
- description: >-
D-specific enoyl-CoA hydratase 2 (D-3-hydroxyacyl-CoA dehydratase) activity: the central
MaoC/hot-dog-fold domain hydrates a (2E)-enoyl-CoA to a (3R)-3-hydroxyacyl-CoA (EC 4.2.1.119),
the second reaction of each peroxisomal beta-oxidation cycle, acting on very-long-chain,
2-methyl-branched (pristanic) and bile-acid-intermediate acyl-CoAs in the peroxisomal matrix.
supported_by:
- reference_id: file:human/HSD17B4/HSD17B4-uniprot.txt
supporting_text: "hydration of 2-enoyl-CoA (trans-2-enoyl-CoA) to"
- reference_id: PMID:9089413
supporting_text: "exhibited only the dehydratase activity"
molecular_function:
id: GO:0080023
label: (2E)-enoyl-CoA hydratase activity
directly_involved_in:
- id: GO:0006635
label: fatty acid beta-oxidation
locations:
- id: GO:0005782
label: peroxisomal matrix
- description: >-
(3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity: the N-terminal SDR/Rossmann-fold domain
oxidizes a (3R)-3-hydroxyacyl-CoA with NAD+ to a 3-oxoacyl-CoA (EC 1.1.1.n12), the third
reaction of each peroxisomal beta-oxidation cycle; the 3-oxoacyl-CoA product is handed to the
peroxisomal thiolase step. Acts on the same VLCFA, branched-chain and bile-acid substrates.
supported_by:
- reference_id: file:human/HSD17B4/HSD17B4-uniprot.txt
supporting_text: "dehydrogenation of (3R)-3-"
- reference_id: PMID:9482850
supporting_text: "enoyl-CoA hydratase and 3-hydroxyacyl-CoA dehydrogenase activity"
molecular_function:
id: GO:0106386
label: (3R)-3-hydroxyacyl-CoA dehydrogenase (NAD+) activity
directly_involved_in:
- id: GO:0006635
label: fatty acid beta-oxidation
locations:
- id: GO:0005782
label: peroxisomal matrix
proposed_new_terms: []
suggested_questions:
- question: >-
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?
- question: >-
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)?
suggested_experiments:
- description: >-
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).
- description: >-
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.
references:
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000041
title: Gene Ontology annotation based on UniPathway vocabulary mapping
findings: []
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
- id: GO_REF:0000116
title: Automatic Gene Ontology annotation based on Rhea mapping
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: PMID:10400999
title: 'Enoyl-CoA hydratase deficiency: identification of a new type of D-bifunctional
protein deficiency.'
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
PubMed-verified. Defines an isolated hydratase-domain deficiency of DBP (Asn457Tyr) and
states DBP's role in beta-oxidation of VLCFA, branched-chain and bile-acid intermediates.
- id: PMID:10706581
title: Peroxisomal fatty acid oxidation disorders and 58 kDa sterol carrier protein
X (SCPx). Activity measurements in liver and fibroblasts using a newly developed
method.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
Abstract-only cache. Uses recombinant human D-bifunctional protein to generate the
bile-acid enoyl-CoA substrate; supports DBP hydratase/dehydrogenase activity on bile-acid
intermediates. Primary focus is SCPx, so relevance is medium.
- id: PMID:15060085
title: Identification of the peroxisomal beta-oxidation enzymes involved in the
degradation of long-chain dicarboxylic acids.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Abstract-only cache. Direct enzyme measurements with recombinant human DBP; identifies DBP
as one of the main enzymes in peroxisomal beta-oxidation of C16 dicarboxylic acid.
- id: PMID:15599942
title: Peroxisomal branched chain fatty acid beta-oxidation pathway is upregulated
in prostate cancer.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
Abstract-only cache. Shows DBP is upregulated with increased activity in prostate cancer;
supports peroxisomal localization/activity. Physiological/disease context rather than core
mechanism.
- id: PMID:15644212
title: Crystal structure of 2-enoyl-CoA hydratase 2 from human peroxisomal multifunctional
enzyme type 2.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Abstract-only cache. Crystal structure of the human MFE-2 hydratase-2 domain; explains
accommodation of bulky C26, pristanic and DHCA/THCA CoA esters and supports homodimerization.
- id: PMID:16210410
title: Differential expression profiling of membrane proteins by quantitative proteomics
in a human mesenchymal stem cell line undergoing osteoblast differentiation.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: >-
Abstract-only cache. High-throughput membrane-proteomics screen; DBP detected as a
differentially expressed protein. Basis of the osteoblast-differentiation and membrane
annotations, both of which are over-annotations (expression change / co-fractionation).
- id: PMID:21525035
title: PEX14 is required for microtubule-based peroxisome motility in human cells.
findings: []
reference_review:
relevance: LOW
correctness: VERIFIED
review_notes: >-
Abstract-only cache. Study of PEX14 and peroxisome motility, not HSD17B4; DBP appears only
as a co-purified peroxisomal-membrane-preparation protein. Basis of an over-annotated
peroxisomal-membrane location.
- id: PMID:7487879
title: Molecular cloning of a novel widely expressed human 80 kDa 17 beta-hydroxysteroid
dehydrogenase IV.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Abstract-only cache. Original cloning of the 736-aa protein as 17-beta-HSD IV; reports a
unidirectional oxidative 17-beta-HSD activity. Source of the steroid-activity annotations,
which are in-vitro side activities relative to the enzyme's physiological fatty-acid role.
- id: PMID:9089413
title: Structure of D-3-hydroxyacyl-CoA dehydratase/D-3-hydroxyacyl-CoA dehydrogenase
bifunctional protein.
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Abstract-only cache. Shows the full-length human enzyme is bifunctional (dehydratase +
dehydrogenase), a truncated C-terminal fragment retains only dehydratase, and the native
enzyme is a homodimer; cDNA identical to 17-beta-HSD IV. Directly supports both core MFs.
- id: PMID:9482850
title: 'Peroxisomal D-hydroxyacyl-CoA dehydrogenase deficiency: resolution of the
enzyme defect and its molecular basis in bifunctional protein deficiency.'
findings: []
reference_review:
relevance: HIGH
correctness: VERIFIED
review_notes: >-
Full text available (PMC19272). First case of DBP deficiency; Gly16Ser in the NAD+-binding
loop abolishes the dehydrogenase activity while hydratase activity is normal; DBP is
essential and non-redundant, and likely the main VLCFA beta-oxidation enzyme.
- id: PMID:11734571
title: Identification of the peroxisomal beta-oxidation enzymes involved in the
biosynthesis of docosahexaenoic acid.
findings: []
reference_review:
relevance: MEDIUM
correctness: VERIFIED
review_notes: >-
Abstract-only cache. Shows DBP is among the main enzymes in the peroxisomal beta-oxidation
of C24:6n-3 to DHA (C22:6n-3). Cited by UniProt for the PUFA/DHA function; supports the
DHA-synthesis role.
- id: Reactome:R-HSA-192331
title: 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-enoyl-CoA (THCA-CoA) is
hydrated to (24R, 25R) 3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoyl-CoA
findings: []
- id: Reactome:R-HSA-193455
title: (24R, 25R) 3alpha,7alpha,12alpha,24-tetrahydroxy-5beta-cholestanoyl-CoA is
oxidized to 3alpha,7alpha,12alpha-trihydroxy-5beta-cholest-24-one-CoA
findings: []
- id: Reactome:R-HSA-193508
title: (24R, 25R) 3alpha,7alpha,24-trihydroxy-5beta-cholestanoyl-CoA is oxidized
to 3alpha,7alpha-dihydroxy-5beta-cholest-24-one-CoA
findings: []
- id: Reactome:R-HSA-193535
title: 25(S) 3alpha,7alpha-dihydroxy-5beta-cholest-24-enoyl-CoA is hydrated to (24R,
25R) 3alpha,7alpha,24-trihydroxy-5beta-cholestanoyl-CoA
findings: []
- id: Reactome:R-HSA-2066778
title: Hydration of delta2-tetracosaheptaenoyl-CoA to 3-hydroxy tetracosahexaenoyl-CoA
findings: []
- id: Reactome:R-HSA-2066780
title: Dehydrogenation of 3-hydroxy tetracosahexaenoyl-CoA
findings: []
- id: Reactome:R-HSA-389986
title: trans-2,3-dehydropristanoyl-CoA + H2O => 3-hydroxypristanoyl-CoA
findings: []
- id: Reactome:R-HSA-389995
title: 3-hydroxypristanoyl-CoA + NAD+ => 3-ketoxypristanoyl-CoA + NADH + H+
findings: []
- id: Reactome:R-HSA-390251
title: HSD17B4 dehydrogenates 3-hydroxyhexacosanoyl-CoA
findings: []
- id: Reactome:R-HSA-390252
title: HSD17B4 hydrates trans-2,3-dehydrohexacosanoyl-CoA
findings: []
- id: Reactome:R-HSA-9033235
title: Cargo of PEX5S,L translocates from the cytosol to the peroxisomal matrix
findings: []
- id: Reactome:R-HSA-9033236
title: PEX5S,L:Cargo binds PEX13:PEX14:PEX2:PEX10:PEX12 (Docking and Translocation
Module)
findings: []