{"results":[{"entryType":"UniProtKB reviewed (Swiss-Prot)","primaryAccession":"P40939","secondaryAccessions":["B2R7L4","B4DYP2","Q16679","Q53T69","Q53TA2","Q96GT7","Q9UQC5"],"uniProtkbId":"ECHA_HUMAN","entryAudit":{"firstPublicDate":"1995-02-01","lastAnnotationUpdateDate":"2026-09-02","lastSequenceUpdateDate":"2002-04-03","entryVersion":255,"sequenceVersion":2},"annotationScore":5.0,"organism":{"scientificName":"Homo sapiens","commonName":"Human","taxonId":9606,"lineage":["Eukaryota","Metazoa","Chordata","Craniata","Vertebrata","Euteleostomi","Mammalia","Eutheria","Euarchontoglires","Primates","Haplorrhini","Catarrhini","Hominidae","Homo"]},"proteinExistence":"1: Evidence at protein level","proteinDescription":{"recommendedName":{"fullName":{"value":"Trifunctional enzyme subunit alpha, mitochondrial"}},"alternativeNames":[{"fullName":{"value":"78 kDa gastrin-binding protein"}},{"fullName":{"evidences":[{"evidenceCode":"ECO:0000305","source":"PubMed","id":"23152787"}],"value":"Monolysocardiolipin acyltransferase"},"shortNames":[{"evidences":[{"evidenceCode":"ECO:0000305"}],"value":"MLCL AT"}],"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23152787"}],"value":"2.3.1.-"}]},{"fullName":{"value":"TP-alpha"}}],"includes":[{"recommendedName":{"fullName":{"value":"Long-chain enoyl-CoA hydratase"},"shortNames":[{"value":"LCEH"}],"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1550553"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8135828"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8163672"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8651282"}],"value":"4.2.1.17"}]}},{"recommendedName":{"fullName":{"value":"Long chain 3-hydroxyacyl-CoA dehydrogenase"},"shortNames":[{"value":"LCHAD"}],"ecNumbers":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1550553"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8135828"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8163672"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8651282"}],"value":"1.1.1.211"}]}}],"flag":"Precursor"},"genes":[{"geneName":{"value":"HADHA"},"synonyms":[{"value":"HADH"}]}],"comments":[{"texts":[{"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1550553"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"23152787"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"29915090"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"30850536"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"31604922"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8135828"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8163672"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8651282"},{"evidenceCode":"ECO:0000303","source":"PubMed","id":"26474213"},{"evidenceCode":"ECO:0000303","source":"PubMed","id":"29915090"},{"evidenceCode":"ECO:0000303","source":"PubMed","id":"30850536"},{"evidenceCode":"ECO:0000305","source":"PubMed","id":"38372965"}],"value":"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 cycles of four consecutive reactions (PubMed:29915090). Each beta-oxidation cycle shortens the fatty acyl-CoA by two carbons, yielding one acetyl-CoA (for the citric acid cycle), one FADH(2), and one NADH (which donate electrons to the respiratory chain for ATP production) (PubMed:29915090). These cycles repeat until the chain is fully degraded to acetyl-CoA units (PubMed:29915090). Among the enzymes involved in this pathway, the trifunctional protein--responsible for the hydration, dehydrogenation, and thiolysis steps, shows specificity for long-chain fatty acids, such as those from dietary and stored fats (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 (Probable) (PubMed:29915090, PubMed:30850536, PubMed:8135828). These activities have been experimentally confirmed on a few substrates derived from beta-oxidation of long-chain saturated fatty acids such as palmitate (hexadecanoate) and laurate (dodecanoate) (PubMed:1550553, PubMed:8135828, PubMed:8163672, PubMed:8651282). In addition, based on its established catalytic mechanism, and combined genetic interaction or mutant phenotype evidence, it is predicted to act also on other substrates, including long-chain unsaturated fatty acids such as oleate (9Z-octadecenoate), linoleate (9Z,12Z-octadecadienoate), linolenate (9Z,12Z,15Z-octadecatrienoate), and others (Probable) (PubMed:26474213). 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)"}],"commentType":"FUNCTION"},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"a (3S)-3-hydroxyacyl-CoA = a (2E)-enoyl-CoA + H2O","reactionCrossReferences":[{"database":"Rhea","id":"RHEA:16105"},{"database":"ChEBI","id":"CHEBI:15377"},{"database":"ChEBI","id":"CHEBI:57318"},{"database":"ChEBI","id":"CHEBI:58856"}],"ecNumber":"4.2.1.17","evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1550553"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8135828"}]},"physiologicalReactions":[{"directionType":"right-to-left","reactionCrossReference":{"database":"Rhea","id":"RHEA:16107"},"evidences":[{"evidenceCode":"ECO:0000269","source":"PubMed","id":"1550553"},{"evidenceCode":"ECO:0000269","source":"PubMed","id":"8135828"}]}]},{"commentType":"CATALYTIC ACTIVITY","reaction":{"name":"a long-chain 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