Mouse anti-Human/Mouse/Rat sapiens (Human) HADHA Monoclonal Antibody

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 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)

Subcellular Location

Mitochondrion; Mitochondrion inner membrane

Disease Association

Mitochondrial trifunctional protein deficiency 1 (MTPD1) : An autosomal recessive metabolic disorder of long-chain fatty acid oxidation, biochemically characterized by loss of all enzyme activities of the mitochondrial trifunctional protein complex. The disease phenotype ranges from a fatal form characterized by early-onset cardiomyopathy, cardiac failure and early death to less severe, late-onset forms with myopathy, recurrent rhabdomyolysis, and sensorimotor axonal neuropathy as key features. [The disease is caused by variants affecting the gene represented in this entry] | Long-chain 3-hydroxyl-CoA dehydrogenase deficiency (LCHAD deficiency) : The clinical features are very similar to TFP deficiency. Biochemically, LCHAD deficiency is characterized by reduced long-chain 3-hydroxyl-CoA dehydrogenase activity, while the other enzyme activities of the TFP complex are normal or only slightly reduced. [The disease is caused by variants affecting the gene represented in this entry] | Maternal acute fatty liver of pregnancy (AFLP) : Severe maternal illness occurring during pregnancies with affected fetuses. This disease is associated with LCHAD deficiency and characterized by sudden unexplained infant death or hypoglycemia and abnormal liver enzymes (Reye-like syndrome). [The disease is caused by variants affecting the gene represented in this entry]

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)

Pathway

Lipid metabolism; fatty acid beta-oxidation

• Kamijo T. et al. Structural analysis of cDNAs for subunits of human mitochondrial fatty acid beta-oxidation trifunctional protein. — Biochem. Biophys. Res. Commun. (1994)
• Zhang Q.X. et al. Structures of the human cDNA and gene encoding the 78 kDa gastrin-binding protein and of a related pseudogene. — Biochim. Biophys. Acta (1994)
• Ota T. et al. Complete sequencing and characterization of 21,243 full-length human cDNAs. — Nat. Genet. (2004)
• Hillier L.W. et al. Generation and annotation of the DNA sequences of human chromosomes 2 and 4. — Nature (2005)
• Mural R.J. et al. PubMed: CI-5GBD0VIIJ7C63 (SEP-)
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). — Genome Res. (2004)
• Orii K.E. et al. Genes for the human mitochondrial trifunctional protein alpha- and beta-subunits are divergently transcribed from a common promoter region. — J. Biol. Chem. (1999)
• Carpenter K. et al. Human liver long-chain 3-hydroxyacyl-coenzyme A dehydrogenase is a multifunctional membrane-bound beta-oxidation enzyme of mitochondria. — Biochem. Biophys. Res. Commun. (1992)