HADHA

Trifunctional enzyme subunit alpha, mitochondrial also known as hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit is a protein that in humans is encoded by the HADHA gene. Mutations in HADHA have been associated with trifunctional protein deficiency or long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.^[5]

HADHA
Identifiers
Aliases	HADHA, hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit, ECHA, GBP, HADH, LCEH, LCHAD, MTPA, TP-ALPHA, hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit alpha
External IDs	OMIM: 600890; MGI: 2135593; HomoloGene: 152; GeneCards: HADHA; OMA:HADHA - orthologs
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2p23.3 Start 26,190,635 bp[1] End 26,244,672 bp[1]
Gene location (Mouse) Chr. Chromosome 5 (mouse)[2] Band 5|5 B1 Start 30,323,302 bp[2] End 30,360,160 bp[2]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in jejunal mucosa gastrocnemius muscle left ventricle apex of heart duodenum Skeletal muscle tissue of rectus abdominis right auricle of heart mucosa of transverse colon muscle of thigh rectum Top expressed in myocardium of ventricle right ventricle cardiac muscles brown adipose tissue muscle of thigh genital tubercle extraocular muscle soleus muscle epithelium of small intestine digastric muscle More reference expression data BioGPS n/a
Gene ontology Molecular function fatty-acyl-CoA binding acetyl-CoA C-acyltransferase activity protein-containing complex binding NAD binding enoyl-CoA hydratase activity acetyl-CoA C-acetyltransferase activity long-chain-3-hydroxyacyl-CoA dehydrogenase activity protein binding catalytic activity lyase activity oxidoreductase activity long-chain-enoyl-CoA hydratase activity 3-hydroxyacyl-CoA dehydrogenase activity Cellular component mitochondrion mitochondrial inner membrane mitochondrial nucleoid mitochondrial fatty acid beta-oxidation multienzyme complex extracellular matrix Biological process lipid metabolism fatty acid metabolic process response to insulin fatty acid beta-oxidation metabolism cardiolipin acyl-chain remodeling Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 3030 97212 Ensembl ENSG00000084754 ENSMUSG00000025745 UniProt P40939 Q8BMS1 RefSeq (mRNA) NM_000182 NM_178878 RefSeq (protein) NP_000173 NP_849209 Location (UCSC) Chr 2: 26.19 – 26.24 Mb Chr 5: 30.32 – 30.36 Mb PubMed search [3] [4]
Wikidata
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Structure

HADHA is an 82.9 kDa protein composed of 763 amino acids.^[6][7]

The mitochondrial membrane-bound heterocomplex is composed of four alpha and four beta subunits, with the alpha subunit catalyzing the 3-hydroxyacyl-CoA dehydrogenase and enoyl-CoA hydratase activities. The genes of the alpha and beta subunits of the mitochondrial trifunctional protein are located adjacent to each other in the human genome in a head-to-head orientation.^[5]

Function

This gene encodes the alpha subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial beta-oxidation of long chain fatty acids.^[5] The enzyme converts medium- and long-chain 2-enoyl-CoA compounds into the following 3-ketoacyl-CoA when NAD is solely present, and acetyl-CoA when NAD and CoASH are present.^[8] The alpha subunit catalyzes this reaction, and is attached to HADHB, which catalyzes the last step of the reaction.^[9]

Clinical significance

Mutations in this gene result in trifunctional protein deficiency or long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.^[5]

The most common form of the mutation is G1528C, in which the guanine at the 1528th position is changed to a cytosine. The gene mutation creates a protein deficiency that is associated with impaired oxidation of long-chain fatty acids that can lead to sudden infant death.^[10] Clinical manifestations of this deficiency can include myopathy, cardiomyopathy, episodes of coma, and hypoglycemia.^[11] Long-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency is associated with some pregnancy-specific disorders, including preeclampsia, HELLP syndrome (hemolysis, elevated liver enzymes, low platelets), hyperemesis gravidarum,^[12][13] acute fatty liver of pregnancy,^[14] and maternal floor infarct of the placenta.^[12][13]

From a clinical perspective, HADHA might also be a useful marker to predict resistance to certain types of chemotherapy in patients with lung cancer.^[15]

Interactions

HADHA has been shown to have 142 binary protein-protein interactions including 117 co-complex interactions. HADHA appears to interact with GABARAP, MAP1LC3B, TRAF6, GABARAPL2, GABARAPL1, GAST, BCAR3, EPB41, TNFRSF1A, HLA-B, NFKB2, MAP3K1, IKBKE, PRKAB1, RIPK3, CD74, NR4A1, cdsA, mtaD, ATXN2L, ABCF2, and MAPK3.^[16]