HSD17B12

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0005783 endoplasmic reticulum	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Phylogenetic (IBA) localization of the KAR/HSD17B12 orthology group to the endoplasmic reticulum. Correct but less precise than the experimentally supported ER membrane localization; the enzyme acts as an integral ER membrane protein. Reason: The ER as a whole is subsumed by the more specific and experimentally supported endoplasmic reticulum membrane (GO:0005789). Retained as a valid but non-core, less-specific localization. Supporting Evidence: file:human/HSD17B12/HSD17B12-uniprot.txt Endoplasmic reticulum membrane
GO:0016491 oxidoreductase activity	IBA GO_REF:0000033	MARK AS OVER ANNOTATED	Summary: Phylogenetic (IBA) assignment of generic oxidoreductase activity. Correct at the top level but far too general; the specific NADPH-dependent 3-oxoacyl-CoA reductase activity (GO:0141040) is experimentally established. Reason: Root-level oxidoreductase parent of the specific KAR activity captured by GO:0141040; uninformative as a standalone annotation. Supporting Evidence: file:human/HSD17B12/HSD17B12-uniprot.txt reducing 3-ketoacyl-CoA to 3-
GO:0004303 estradiol 17-beta-dehydrogenase [NAD(P)+] activity	IEA GO_REF:0000120	KEEP AS NON CORE	Summary: Electronic (RHEA/EC 1.1.1.62) mapping of estradiol 17-beta-dehydrogenase activity. This mirrors the experimentally measured estrone->estradiol activity (see the EXP annotation from PMID:16166196), but the physiological substrate of HSD17B12 is fatty-acyl-CoA, not steroids. Reason: A genuinely measured in-vitro activity (EC 1.1.1.62) but not the core physiological function; retained as non-core steroid-metabolism activity. Supporting Evidence: file:human/HSD17B12/HSD17B12-uniprot.txt May also catalyze
GO:0005783 endoplasmic reticulum	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: ARBA machine-learning electronic localization to the endoplasmic reticulum. Consistent with the experimentally supported ER membrane localization but less specific. Reason: Subsumed by the more specific ER membrane (GO:0005789) location. Supporting Evidence: file:human/HSD17B12/HSD17B12-uniprot.txt Endoplasmic reticulum membrane
GO:0005789 endoplasmic reticulum membrane	IEA GO_REF:0000044	ACCEPT	Summary: Electronic (UniProt SubCell) mapping to ER membrane, matching the experimentally determined subcellular location of this multi-pass ER membrane enzyme. Reason: Correct and specific localization; independently supported by experimental evidence (PMID:12482854) and by three predicted transmembrane helices plus a C-terminal di-lysine ER-retention motif. Supporting Evidence: file:human/HSD17B12/HSD17B12-uniprot.txt Multi-pass membrane protein
GO:0008610 lipid biosynthetic process	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: ARBA electronic assignment to lipid biosynthesis. Correct in direction but very general relative to the specific role in fatty-acid elongation / VLCFA biosynthesis. Reason: High-level parent of the specific fatty-acid elongation process; the more precise fatty-acid elongation terms are experimentally supported. Supporting Evidence: file:human/HSD17B12/HSD17B12-uniprot.txt allows the addition of two carbons to the chain of
GO:0016614 oxidoreductase activity, acting on CH-OH group of donors	IEA GO_REF:0000117	MARK AS OVER ANNOTATED	Summary: ARBA electronic assignment of the CH-OH-donor oxidoreductase parent class. Correct branch but a general parent of the specific 3-oxoacyl-CoA reductase activity. Reason: Parent term of the experimentally supported GO:0141040; redundant with the specific activity. Supporting Evidence: file:human/HSD17B12/HSD17B12-uniprot.txt reducing 3-ketoacyl-CoA to 3-
GO:0018454 acetoacetyl-CoA reductase activity	IEA GO_REF:0000116	MODIFY	Summary: Rhea-mapping electronic annotation. The mapped Rhea reactions (RHEA:39151/39311/39323/39459) are the very-long-chain and polyunsaturated 3-oxoacyl-CoA reductions catalyzed by KAR, i.e. exactly the KAR step, not the short-chain (C4) acetoacetyl-CoA reductase (poly-hydroxybutyrate-type) activity that this term denotes. The label mis-generalizes the mapped chemistry. Reason: The underlying Rhea reactions are the very-long-chain 3-oxoacyl-CoA reductions already captured precisely and experimentally by GO:0141040; "acetoacetyl-CoA reductase" is a less-appropriate label for this ER fatty-acid elongation enzyme. Proposed replacements: very-long-chain 3-oxoacyl-CoA reductase activity Supporting Evidence: file:human/HSD17B12/HSD17B12-uniprot.txt reducing 3-ketoacyl-CoA to 3-
GO:0141040 very-long-chain 3-oxoacyl-CoA reductase activity	IEA GO_REF:0000120	ACCEPT	Summary: Electronic (RHEA/EC 1.1.1.330) mapping to the correct, specific molecular function of HSD17B12/KAR. Redundant with, and confirmed by, the experimental (EXP/IDA) annotations to the same term. Reason: Correct, specific KAR activity; the canonical UniProt reaction is "a very-long-chain (3R)-3-hydroxyacyl-CoA + NADP(+) = a very-long-chain 3-oxoacyl-CoA + NADPH + H(+)" (EC 1.1.1.330). This is the core molecular function. Supporting Evidence: file:human/HSD17B12/HSD17B12-uniprot.txt a 3-ketoacyl-CoA reductase activity, reducing 3-ketoacyl-CoA to 3-
GO:0005515 protein binding	IPI PMID:24169621 Elucidating novel hepatitis C virus-host interactions using ...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a high-throughput hepatitis C virus host-factor screen (IntAct partner Q9WMX2, an HCV protein). Uninformative as a molecular function; the physical interaction does not by itself define a function. Reason: Per curation policy, bare protein binding (GO:0005515) is retained (not removed) but flagged as uninformative; this is a virus-host high-throughput hit with no bearing on the gene's biochemical function.
GO:0005515 protein binding	IPI PMID:25416956 A proteome-scale map of the human interactome network.	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a proteome-scale human interactome map (partner UBQLN1, Q9UMX0). High-throughput binary interaction; uninformative as a molecular function. Reason: Uninformative bare protein binding from a large-scale interactome; retained per policy but not a functional annotation.
GO:0005515 protein binding	IPI PMID:32296183 A reference map of the human binary protein interactome.	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from the HuRI reference human binary interactome (partner UBQLN1 isoform, Q9UMX0-2). Uninformative high-throughput interaction. Reason: Uninformative bare protein binding from a large-scale binary interactome map.
GO:0005515 protein binding	IPI PMID:32814053 Interactome Mapping Provides a Network of Neurodegenerative ...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a neurodegenerative-disease interactome map. This GOA row collapses several IntAct partners reported under this reference (HRAS P01112, GSN P06396, FGFR3 P22607, CHAT P28329-3, UBQLN1 Q9UMX0). Uninformative high-throughput interactions. Reason: Uninformative bare protein binding from a large-scale interactome; no functional content.
GO:0005515 protein binding	IPI PMID:35384245 Physical and functional interactome atlas of human receptor ...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from a receptor-tyrosine-kinase interactome atlas (partner FGFR3, P22607). Uninformative high-throughput interaction. Reason: Uninformative bare protein binding from a large-scale RTK interactome screen.
GO:0035338 long-chain fatty-acyl-CoA biosynthetic process	TAS Reactome:R-HSA-75876	ACCEPT	Summary: Reactome-curated (TAS) placement of HSD17B12/KAR in the synthesis of very-long-chain fatty acyl-CoAs. Correctly captures the biological process of the elongation cycle in which KAR performs the reduction step. Reason: Accurate process annotation reflecting the KAR reduction step within long/very-long-chain fatty-acyl-CoA elongation; consistent with experimental evidence. Supporting Evidence: file:human/HSD17B12/HSD17B12-uniprot.txt Catalyzes the second of the four reactions of the long-chain
GO:0006633 fatty acid biosynthetic process	IEA GO_REF:0000041	KEEP AS NON CORE	Summary: UniPathway electronic mapping to fatty-acid biosynthesis, matching the UniProt PATHWAY statement "Lipid metabolism; fatty acid biosynthesis". Correct but more general than the specific elongation process. Reason: Correct broad process; the specific and experimentally supported role is in the fatty-acid elongation cycle (GO:0019367 / elongation processes). Supporting Evidence: file:human/HSD17B12/HSD17B12-uniprot.txt Lipid metabolism; fatty acid biosynthesis
GO:0006703 estrogen biosynthetic process	IEA GO_REF:0000041	KEEP AS NON CORE	Summary: UniPathway electronic mapping to estrogen biosynthesis, derived from the historical steroidogenic (estrone->estradiol) characterization. HSD17B12 can catalyze this reaction in vitro, but its established physiological role is fatty-acid elongation, not estrogen production. Reason: Reflects a real measured steroid activity but not the core physiological function; retained as a non-core steroid-metabolism process. Supporting Evidence: file:human/HSD17B12/HSD17B12-uniprot.txt Steroid biosynthesis; estrogen biosynthesis
GO:0141040 very-long-chain 3-oxoacyl-CoA reductase activity	EXP PMID:12482854 Identification of two mammalian reductases involved in the t...	ACCEPT	Summary: Experimental (EXP) evidence from Moon & Horton 2003, which identified and characterized the mammalian 3-ketoacyl-CoA reductase of microsomal fatty-acid elongation. This is the core molecular function of HSD17B12/KAR. Reason: Directly experimentally supported specific KAR activity; the defining core function of the gene product. Supporting Evidence: PMID:12482854 identification and characterization of two mammalian enzymes that catalyze the
GO:0004303 estradiol 17-beta-dehydrogenase [NAD(P)+] activity	EXP PMID:16166196 Characterization of type 12 17beta-hydroxysteroid dehydrogen...	KEEP AS NON CORE	Summary: Experimental evidence from Luu-The et al. 2006 that "type 12 17beta-HSD" efficiently converts estrone (E1) to estradiol (E2) in a heterologous overexpression system. A genuinely measured activity, but the physiological substrate of HSD17B12 is fatty-acyl-CoA; the enzyme's core role is fatty-acid elongation. Reason: Experimentally documented in-vitro steroid activity retained per policy (never removed for an EXP annotation), but marked non-core because it does not represent the enzyme's established physiological function. Supporting Evidence: PMID:16166196 transformation of E1 into E2, thus
GO:0005789 endoplasmic reticulum membrane	EXP PMID:12482854 Identification of two mammalian reductases involved in the t...	ACCEPT	Summary: Experimental evidence that HSD17B12/KAR is an ER membrane enzyme, from the same study that characterized its microsomal fatty-acid elongation activity. Correct, specific, core localization. Reason: Experimentally supported ER membrane localization consistent with the multi-pass membrane topology and di-lysine ER-retention motif. Supporting Evidence: file:human/HSD17B12/HSD17B12-uniprot.txt This endoplasmic reticulum-bound
GO:0019367 fatty acid elongation, saturated fatty acid	IDA PMID:25003994 Two modes of regulation of the fatty acid elongase ELOVL6 by...	ACCEPT	Summary: Direct assay (IDA) from Naganuma & Kihara 2014 reconstituting KAR with the elongase ELOVL6 in proteoliposomes, demonstrating KAR's participation in the saturated fatty-acid (C16->C18) elongation cycle as the reduction (second) step. Reason: Experimentally supported role of KAR in the fatty-acid elongation cycle; a core biological process for this enzyme. Supporting Evidence: PMID:25003994 The second step is catalyzed by 3-ketoacyl-CoA reductase (KAR)
GO:0141040 very-long-chain 3-oxoacyl-CoA reductase activity	IDA PMID:25003994 Two modes of regulation of the fatty acid elongase ELOVL6 by...	ACCEPT	Summary: Direct assay (IDA) confirming KAR reduces 3-ketoacyl-CoA to 3-hydroxyacyl-CoA using NADPH, the specific molecular function of HSD17B12. Core function. Reason: Direct experimental support for the specific KAR molecular function; core. Supporting Evidence: PMID:25003994 reduces 3-ketoacyl-CoA to 3-hydroxyacyl-CoA using NADPH as a cofactor
GO:0141040 very-long-chain 3-oxoacyl-CoA reductase activity	IDA PMID:12482854 Identification of two mammalian reductases involved in the t...	ACCEPT	Summary: Direct assay (IDA) from Moon & Horton 2003 (assigned via FlyBase orthology curation) for the mammalian 3-ketoacyl-CoA reductase activity. Consistent with the EXP/IDA annotations to the same specific term. Core function. Reason: Redundant with, and corroborated by, the other experimental annotations to the core KAR molecular function. Supporting Evidence: PMID:12482854 identification and characterization of two mammalian enzymes that catalyze the
GO:0009923 fatty acid elongase complex	IDA PMID:25003994 Two modes of regulation of the fatty acid elongase ELOVL6 by...	ACCEPT	Summary: Direct evidence (IDA) that KAR associates with the elongase machinery: KAR both stimulates ELOVL6 activity and participates in a "presumed ELOVL6-KAR complex", consistent with membership of the ER fatty-acid elongase complex. Also supported by UniProt interactions with ELOVL1 and CERS2/LASS2. Reason: Experimentally supported physical membership of the ER fatty-acid elongase complex; a core cellular-component annotation for an elongation-cycle enzyme. Supporting Evidence: file:human/HSD17B12/HSD17B12-uniprot.txt Interacts with ELOVL1 and LASS2
GO:0005789 endoplasmic reticulum membrane	TAS Reactome:R-HSA-548818	ACCEPT	Summary: Reactome-curated (TAS) ER membrane localization in the reaction "HSD17B3,12 hydrogenates 3OOD-CoA to 3HODC-CoA". Correct, specific, core localization. Reason: Consistent with experimental ER membrane localization; corroborates the KAR reduction step within the elongation cycle. Supporting Evidence: file:human/HSD17B12/HSD17B12-uniprot.txt Endoplasmic reticulum membrane
GO:0005515 protein binding	IPI PMID:20937905 ELOVL1 production of C24 acyl-CoAs is linked to C24 sphingol...	MARK AS OVER ANNOTATED	Summary: Bare "protein binding" from Ohno et al. 2010, whose full text documents the physical interaction of KAR with ELOVL1 (and, via the elongase machinery, CERS2/LASS2). Biologically meaningful (elongase/sphingolipid machinery) but the GO:0005515 term itself is uninformative. Reason: Retained per policy (IPI physical interaction, never removed). The specific, informative content of this interaction is captured by the fatty acid elongase complex (GO:0009923) part_of annotation; bare protein binding adds no functional information. Supporting Evidence: file:human/HSD17B12/HSD17B12-uniprot.txt Interacts with ELOVL1 and LASS2

Gene Description

Existing Annotations Review

Core Functions

NADPH-dependent 3-ketoacyl-CoA (very-long-chain 3-oxoacyl-CoA) reductase (KAR) that catalyzes the second (reduction) step of the microsomal fatty-acid elongation cycle, reducing 3-oxoacyl-CoA to (3R)-3-hydroxyacyl-CoA.

Uses NADP(H) as the redox cofactor for the reduction reaction, bound via the N-terminal Rossmann-fold NADP-binding region characteristic of SDR enzymes.

Acts as the reduction step of the ER fatty-acid elongation cycle, contributing to the biosynthesis of long- and very-long-chain fatty acids as an integral ER membrane enzyme physically associated with the elongase machinery.

References

📚 Additional Documentation

Notes

📄 View Raw YAML