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Details on Person UniProt:P40939 HADHA

Class:Id	ReferenceGeneProduct:54122
_chainChangeLog	transit peptide:1-36 added on Fri February 6 2015;chain:37-763 added on Fri February 6 2015
_displayName	UniProt:P40939 HADHA
_timestamp	2025-05-21 21:05:03
chain	transit peptide:1-36 chain:37-763
checksum	247FF7B4E48FB484
comment	FUNCTION Mitochondrial trifunctional enzyme catalyzes the last three of the four reactions of the mitochondrial beta-oxidation pathway (PubMed:1550553, PubMed:29915090, PubMed:30850536, PubMed:8135828, PubMed:31604922). The mitochondrial beta-oxidation pathway is the major energy-producing process in tissues and is performed through four consecutive reactions breaking down fatty acids into acetyl-CoA (PubMed:29915090). Among the enzymes involved in this pathway, the trifunctional enzyme exhibits specificity for long-chain fatty acids (PubMed:30850536, PubMed:31604922). Mitochondrial trifunctional enzyme is a heterotetrameric complex composed of two proteins, the trifunctional enzyme subunit alpha/HADHA described here carries the 2,3-enoyl-CoA hydratase and the 3-hydroxyacyl-CoA dehydrogenase activities while the trifunctional enzyme subunit beta/HADHB bears the 3-ketoacyl-CoA thiolase activity (PubMed:29915090, PubMed:30850536, PubMed:8135828). Independently of subunit beta, HADHA also exhibits a cardiolipin acyltransferase activity that participates in cardiolipin remodeling; cardiolipin is a major mitochondrial membrane phospholipid (PubMed:23152787, PubMed:31604922). HADHA may act downstream of Tafazzin/TAZ, that remodels monolysocardiolipin (MLCL) to a cardiolipin intermediate, and then HADHA may continue to remodel this species into mature tetralinoleoyl-cardiolipin (PubMed:31604922). Has also been proposed to act directly on MLCL; capable of acylating MLCL using different acyl-CoA substrates, with highest activity for oleoyl-CoA (PubMed:23152787).CATALYTIC ACTIVITY a (3S)-3-hydroxyacyl-CoA = a (2E)-enoyl-CoA + H2OCATALYTIC ACTIVITY a 4-saturated-(3S)-3-hydroxyacyl-CoA = a (3E)-enoyl-CoA + H2OCATALYTIC ACTIVITY (3S)-hydroxyoctanoyl-CoA = (2E)-octenoyl-CoA + H2OCATALYTIC ACTIVITY (3S)-3-hydroxydodecanoyl-CoA = (2E)-dodecenoyl-CoA + H2OCATALYTIC ACTIVITY (3S)-hydroxyhexadecanoyl-CoA = (2E)-hexadecenoyl-CoA + H2OCATALYTIC ACTIVITY a long-chain (3S)-3-hydroxy fatty acyl-CoA + NAD(+) = a long-chain 3-oxo-fatty acyl-CoA + NADH + H(+)CATALYTIC ACTIVITY (3S)-hydroxyoctanoyl-CoA + NAD(+) = 3-oxooctanoyl-CoA + NADH + H(+)CATALYTIC ACTIVITY (3S)-hydroxydecanoyl-CoA + NAD(+) = 3-oxodecanoyl-CoA + NADH + H(+)CATALYTIC ACTIVITY (3S)-3-hydroxydodecanoyl-CoA + NAD(+) = 3-oxododecanoyl-CoA + NADH + H(+)CATALYTIC ACTIVITY (3S)-hydroxytetradecanoyl-CoA + NAD(+) = 3-oxotetradecanoyl-CoA + NADH + H(+)CATALYTIC ACTIVITY (3S)-hydroxyhexadecanoyl-CoA + NAD(+) = 3-oxohexadecanoyl-CoA + NADH + H(+)CATALYTIC ACTIVITY 1'-[1,2-di-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phospho]-3'-[1-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phospho]-glycerol + hexadecanoyl-CoA = 1'-[1,2-di-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phospho]-3'-[1-(9Z,12Z-octadecadienoyl)-2-hexadecanoyl-sn-glycero-3-phospho]-glycerol + CoACATALYTIC ACTIVITY 1'-[1,2-di-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phospho]-3'-[1-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phospho]-glycerol + (9Z)-octadecenoyl-CoA = 1'-[1,2-di-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phospho]-3'-[1-(9Z,12Z-octadecadienoyl)-2-(9Z-octadecenoyl)-sn-glycero-3-phospho]-glycerol + CoACATALYTIC ACTIVITY 1'-[1,2-di-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phospho]-3'-[1-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phospho]-glycerol + (9Z,12Z)-octadecadienoyl-CoA = 1',3'-bis-[1,2-di-(9Z,12Z-octadecadienoyl)-sn-glycero-3-phospho]-glycerol + CoABIOPHYSICOCHEMICAL PROPERTIES Lipid metabolism; fatty acid beta-oxidation.SUBUNIT Heterotetramer of 2 alpha/HADHA and 2 beta/HADHB subunits; forms the mitochondrial trifunctional enzyme (PubMed:29915090, PubMed:30850536). Also purified as higher order heterooligomers including a 4 alpha/HADHA and 4 beta/HADHB heterooligomer which physiological significance remains unclear (PubMed:29915090, PubMed:8163672). The mitochondrial trifunctional enzyme interacts with MTLN (By similarity).INTERACTION Protein stability and association with mitochondrion inner membrane do not require HADHB.ALTERNATIVE PRODUCTS Up-regulated by thyroid hormone (at protein level).DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.DISEASE The disease is caused by variants affecting the gene represented in this entry.MISCELLANEOUS May be produced at very low levels due to a premature stop codon in the mRNA, leading to nonsense-mediated mRNA decay.SIMILARITY In the N-terminal section; belongs to the enoyl-CoA hydratase/isomerase family.SIMILARITY In the central section; belongs to the 3-hydroxyacyl-CoA dehydrogenase family.SEQUENCE CAUTION Wrong choice of frame.
description	recommendedName: Trifunctional enzyme subunit alpha, mitochondrial alternativeName: 78 kDa gastrin-binding protein alternativeName: fullName evidence="22"Monolysocardiolipin acyltransferase shortName evidence="21"MLCL AT ecNumber evidence="5"2.3.1.- alternativeName: TP-alpha domain recommendedName: Long-chain enoyl-CoA hydratase ecNumber evidence="4 11 12 13"4.2.1.17 /domain domain recommendedName: Long chain 3-hydroxyacyl-CoA dehydrogenase ecNumber evidence="4 11 12 13"1.1.1.211 /domain
geneName	HADHA HADH
identifier	P40939
isSequenceChanged	FALSE
keyword	3D-structure Acetylation Alternative splicing Disease variant Fatty acid metabolism Lipid metabolism Lyase Membrane Methylation Mitochondrion Mitochondrion inner membrane Multifunctional enzyme NAD Oxidoreductase Phosphoprotein Proteomics identification Reference proteome Transferase Transit peptide
modified	[InstanceEdit:9836292] Weiser, Joel, 2023-05-25 [InstanceEdit:9852000] Weiser, Joel, 2023-11-03 [InstanceEdit:9917590] Weiser, Joel, 2024-08-09 [InstanceEdit:9926675] Weiser, Joel, 2024-11-03 [InstanceEdit:9939033] Weiser, Joel, 2025-02-21 [InstanceEdit:9948485] Weiser, Joel, 2025-05-21
name	HADHA
referenceDatabase	[ReferenceDatabase:2] UniProt
referenceGene	[ReferenceDNASequence:8995952] ENSEMBL:ENSG00000084754 HADHA [Homo sapiens]
secondaryIdentifier	ECHA_HUMAN B2R7L4 B4DYP2 Q16679 Q53T69 Q53TA2 Q96GT7 Q9UQC5
sequenceLength	763
species	[Species:48887] Homo sapiens
(isoformParent)	[ReferenceIsoform:8969628] UniProt:P40939-1 HADHA [Homo sapiens] [ReferenceIsoform:8969629] UniProt:P40939-2 HADHA [Homo sapiens]
(referenceEntity)	[EntityWithAccessionedSequence:77264] HADHA [mitochondrial inner membrane] [Homo sapiens]
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No pathways have been reviewed or authored by UniProt:P40939 HADHA (54122)