HACD1 (PTPLA) is one of the two principal human very-long-chain (3R)-3-hydroxyacyl-CoA dehydratases (HACD1 and HACD2), a multi-pass endoplasmic reticulum membrane enzyme (EC 4.2.1.134). It catalyzes the third of the four reactions of the microsomal fatty-acid elongation cycle: dehydration of a (3R)-3-hydroxyacyl-CoA (produced by the 3-ketoacyl-CoA reductase step) to a (2E)-enoyl-CoA plus water, which the trans-2-enoyl-CoA reductase TECR then reduces to complete each two-carbon extension. Through this reaction HACD1 contributes to the biosynthesis of long- and very-long-chain fatty acids that serve as precursors of membrane lipids, sphingolipids and lipid mediators. HACD1 physically associates with the elongase machinery, interacting with ELOVL condensation enzymes and with TECR. It is highly expressed in cardiac and skeletal muscle; biallelic loss-of-function variants cause an autosomal recessive congenital myopathy with type-1 fiber-type disproportion. An alternatively spliced isoform (isoform 2, cementum-attachment protein/CAP) lacks the catalytic region and is enzymatically inactive.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0005789 endoplasmic reticulum membrane | IBA GO_REF:0000033 | ACCEPT | Summary: HACD1 is a multi-pass endoplasmic reticulum membrane enzyme; the ER membrane is where the fatty-acid elongation cycle occurs. This localization is supported by direct experimental evidence and by UniProt, and the IBA call is consistent with the HACD family. Accept as a core location. Supporting Evidence: file:human/HACD1/HACD1-uniprot.txt Endoplasmic reticulum membrane |
| GO:0018812 3-hydroxyacyl-CoA dehydratase activity | IBA GO_REF:0000033 | MODIFY | Summary: Correct in essence but more general than warranted. HACD1 is specifically a very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase (EC 4.2.1.134); the more specific child term GO:0102158 is experimentally supported and better captures the substrate stereochemistry and chain-length. Modify to the specific term. Propagation Review Root cause: TERM SCOPING PROBLEM Failure modes: GRANULARITY MISMATCH Sources checked: PANTHER:PTN000112207 · HACD family (PTHR11035) Family-level IBA to the generic parent dehydratase term; the human ortholog has experimentally-supported very-long-chain specificity (GO:0102158), so the propagated term is correct but under-specific. Proposed replacements: very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity Supporting Evidence: file:human/HACD1/HACD1-uniprot.txt Reaction=a very-long-chain (3R)-3-hydroxyacyl-CoA = a very-long-chain |
| GO:0030148 sphingolipid biosynthetic process | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: HACD1 supplies very-long-chain fatty acids that are incorporated into ceramides and other sphingolipids, so a downstream contribution to sphingolipid biosynthesis is biologically reasonable and is an IBA family call. However, HACD1 does not itself catalyze a sphingolipid biosynthetic reaction; this is an indirect/downstream process rather than a core function. Keep as non-core. |
| GO:0030497 fatty acid elongation | IBA GO_REF:0000033 | ACCEPT | Summary: HACD1 catalyzes the dehydration step of the fatty-acid elongation cycle, so involvement in fatty acid elongation is a correct core biological process. Accept. Supporting Evidence: file:human/HACD1/HACD1-uniprot.txt enzyme catalyzes the dehydration of the 3-hydroxyacyl-CoA intermediate |
| GO:0042761 very long-chain fatty acid biosynthetic process | IBA GO_REF:0000033 | ACCEPT | Summary: HACD1 participates in the elongation cycle that produces very-long-chain fatty acids; UniProt describes it as participating in "the production of VLCFAs of different chain lengths". This is a correct core biological process. Accept. Supporting Evidence: file:human/HACD1/HACD1-uniprot.txt Catalyzes the third of the four reactions of the |
| GO:0005789 endoplasmic reticulum membrane | IEA GO_REF:0000044 | ACCEPT | Summary: UniProt subcellular-location mapping to ER membrane, consistent with the experimental localization and with HACD1 being a multi-pass ER membrane protein. Accept. Supporting Evidence: file:human/HACD1/HACD1-uniprot.txt Endoplasmic reticulum membrane |
| GO:0080023 (2E)-enoyl-CoA hydratase activity | IEA GO_REF:0000116 | MODIFY | Summary: This Rhea-derived term describes the same chemistry (a (3R)-3-hydroxyacyl-CoA = a (2E)-enoyl-CoA + H2O) but as a generic hydratase, framed in the hydration direction. HACD1's physiological role is the dehydration of very-long-chain (3R)-3-hydroxyacyl-CoA, captured precisely by GO:0102158. Modify to the specific, direction-correct term. Proposed replacements: very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity Supporting Evidence: file:human/HACD1/HACD1-uniprot.txt Reaction=a very-long-chain (3R)-3-hydroxyacyl-CoA = a very-long-chain |
| GO:0102158 very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity | IEA GO_REF:0000120 | ACCEPT | Summary: This is the precise molecular function of HACD1 (EC 4.2.1.134, Rhea:45812), matching the UniProt catalytic-activity record and the experimental evidence. Core molecular function. Accept. Supporting Evidence: file:human/HACD1/HACD1-uniprot.txt Reaction=a very-long-chain (3R)-3-hydroxyacyl-CoA = a very-long-chain |
| 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 high-throughput yeast two-hybrid reference interactome (partners include CPLX4, IL10RA, RNF170, TECR and TMEM106C). The term is uninformative about HACD1's molecular function and the partners are not individually characterized for HACD1. Not removed (an IPI protein-binding annotation per policy), but marked as over-annotated. |
| GO:0005515 protein binding | IPI PMID:38422897 The 3-hydroxyacyl-CoA dehydratase 1/2 form complex with tran... | MARK AS OVER ANNOTATED | Summary: Bare "protein binding" recording the biologically meaningful HACD1-TECR interaction (TECR is the reductase acting on HACD1's product in the elongation cycle). The interaction itself is real and functionally relevant, but GO:0005515 is uninformative; a specific adaptor/enzyme-partner or complex term would be preferable. Not removed (IPI), but marked as over-annotated. Supporting Evidence: file:human/HACD1/HACD1-uniprot.txt Interacts with TECR. |
| GO:0035338 long-chain fatty-acyl-CoA biosynthetic process | TAS Reactome:R-HSA-75876 | KEEP AS NON CORE | Summary: Reactome pathway-level annotation placing HACD1 in synthesis of very-long-chain fatty acyl-CoAs. This is a correct process-level assignment but is a broader pathway framing than HACD1's specific dehydration step; the core enzymatic role is captured by GO:0102158 / fatty acid elongation. Keep as non-core. |
| GO:0006633 fatty acid biosynthetic process | IEA GO_REF:0000041 | KEEP AS NON CORE | Summary: General fatty-acid biosynthetic process from UniPathway mapping, consistent with the UniProt PATHWAY statement ("Lipid metabolism; fatty acid biosynthesis"). Correct but more general than the specific elongation/VLCFA terms. Keep as non-core. |
| GO:0018812 3-hydroxyacyl-CoA dehydratase activity | EXP PMID:18554506 Characterization of four mammalian 3-hydroxyacyl-CoA dehydra... | MODIFY | Summary: Experimentally supported dehydratase activity (Ikeda et al. demonstrated that all four human HACD proteins are 3-hydroxyacyl-CoA dehydratases via in-vitro 3-hydroxypalmitoyl-CoA assays and yeast complementation). The essence is correct, but the more specific term GO:0102158 (very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity) is warranted given the demonstrated VLCFA-elongation role. Modify to the specific term. Proposed replacements: very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity Supporting Evidence: PMID:18554506 all four of these human proteins are indeed 3-hydroxyacyl-CoA dehydratases |
| GO:0005789 endoplasmic reticulum membrane | EXP PMID:18554506 Characterization of four mammalian 3-hydroxyacyl-CoA dehydra... | ACCEPT | Summary: Experimentally supported ER membrane localization (UniProt cites this paper for the subcellular location as an ER membrane, multi-pass membrane protein). Core location. Accept. Supporting Evidence: file:human/HACD1/HACD1-uniprot.txt Endoplasmic reticulum membrane |
| GO:0102158 very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity | EXP PMID:18554506 Characterization of four mammalian 3-hydroxyacyl-CoA dehydra... | ACCEPT | Summary: Direct experimental support for the core molecular function. Ikeda et al. established that the human HACD proteins are 3-hydroxyacyl-CoA dehydratases acting in very-long-chain fatty acid synthesis, with an in-vitro KM of 33.6 uM for 3-hydroxypalmitoyl-CoA (UniProt). Core molecular function. Accept. Supporting Evidence: PMID:18554506 3-hydroxyacyl-CoA dehydratases involved in very long-chain fatty acid synthesis |
| GO:0102158 very-long-chain (3R)-3-hydroxyacyl-CoA dehydratase activity | EXP PMID:23933735 Congenital myopathy is caused by mutation of HACD1. | ACCEPT | Summary: Direct experimental support: the disease nonsense mutant p.Tyr248Stop completely abolished HACD1 dehydration of 3-hydroxyacyl-CoA in a [14C]3-hydroxypalmitoyl-CoA assay, confirming the wild-type dehydratase activity. Core molecular function. Accept. Supporting Evidence: PMID:23933735 the enzymatic activity of dehydration of 3-hydroxyacyl-CoA, the third step in the elongation of very long-chain fatty acids (VLCFAs) |
| GO:0005789 endoplasmic reticulum membrane | TAS Reactome:R-HSA-5676637 | ACCEPT | Summary: Reactome author-stated ER membrane localization for the PTPL/HACD dehydration reaction, consistent with the experimental and UniProt evidence. Accept. Supporting Evidence: file:human/HACD1/HACD1-uniprot.txt Endoplasmic reticulum membrane |
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