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Hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit
External IDs OMIM600890 HomoloGene152 GeneCards: HADHA Gene
EC number,
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:
30.12 – 30.16 Mb
PubMed search [1] [2]

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.[1]


HADHA is a 82.9 kDa protein composed of 763 amino acids.[2][3]

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. [1]


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. [1]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.[4] The alpha subunit catalyzes this reaction, and is attached to HADHB, which catalyzes the last step of the reaction.[5]

Clinical significance[edit]

Mutations in this gene result in trifunctional protein deficiency or long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.[1]

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.[6] 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, acute fatty liver of pregnancy, and maternal floor infarct of the placenta.[7][8] Additionally, it has been correlated with Acute fatty liver of pregnancy (AFLP) disease.[9]

From a clinical perspective, HADHA might also be a useful marker to predict resistance to certain types of chemotherapy in patients with lung cancer.[10]


  1. ^ a b c d "Entrez Gene: Hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit". 
  2. ^ Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS et al. (Oct 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. doi:10.1161/CIRCRESAHA.113.301151. PMC 4076475. PMID 23965338. 
  3. ^ "hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). 
  4. ^ Carpenter K, Pollitt RJ, Middleton B (Mar 1992). "Human liver long-chain 3-hydroxyacyl-coenzyme A dehydrogenase is a multifunctional membrane-bound beta-oxidation enzyme of mitochondria". Biochemical and Biophysical Research Communications 183 (2): 443–8. doi:10.1016/0006-291x(92)90501-b. PMID 1550553. 
  5. ^ Voet DJ, Voet JG, Pratt CW (2010). "Chapter 18, Mitochondrial ATP synthesis". Principles of Biochemistry (4th ed.). Wiley. p. 669. ISBN 978-0-470-23396-2. 
  6. ^ IJlst, L; Ruiter, JP; Hoovers, JM; Jakobs, ME; Wanders, RJ (15 August 1996). "Common missense mutation G1528C in long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency. Characterization and expression of the mutant protein, mutation analysis on genomic DNA and chromosomal localization of the mitochondrial trifunctional protein alpha subunit gene.". The Journal of clinical investigation 98 (4): 1028–33. doi:10.1172/jci118863. PMID 8770876. 
  7. ^ Rakheja, D; Bennett, MJ; Rogers, BB (July 2002). "Long-chain L-3-hydroxyacyl-coenzyme a dehydrogenase deficiency: a molecular and biochemical review.". Laboratory investigation; a journal of technical methods and pathology 82 (7): 815–24. doi:10.1097/01.lab.0000021175.50201.46. PMID 12118083. 
  8. ^ Griffin, AC; Strauss, AW; Bennett, MJ; Ernst, LM (September–October 2012). "Mutations in long-chain 3-hydroxyacyl coenzyme a dehydrogenase are associated with placental maternal floor infarction/massive perivillous fibrin deposition.". Pediatric and developmental pathology : the official journal of the Society for Pediatric Pathology and the Paediatric Pathology Society 15 (5): 368–74. doi:10.2350/12-05-1198-oa.1. PMID 22746996. 
  9. ^ Ibdah, JA; Yang, Z; Bennett, MJ (September–October 2000). "Liver disease in pregnancy and fetal fatty acid oxidation defects.". Molecular genetics and metabolism 71 (1-2): 182–9. PMID 11001809. 
  10. ^ Kageyama, T; Nagashio, R; Ryuge, S; Matsumoto, T; Iyoda, A; Satoh, Y; Masuda, N; Jiang, SX; Saegusa, M; Sato, Y (2011). "HADHA is a potential predictor of response to platinum-based chemotherapy for lung cancer.". Asian Pacific journal of cancer prevention : APJCP 12 (12): 3457–63. PMID 22471497. 

Further Reading[edit]

  • Rakheja D, Bennett MJ, Rogers BB (Jul 2002). "Long-chain L-3-hydroxyacyl-coenzyme a dehydrogenase deficiency: a molecular and biochemical review". Laboratory Investigation; A Journal of Technical Methods and Pathology 82 (7). PMID 12118083. 
  • Isaacs JD, Sims HF, Powell CK, Bennett MJ, Hale DE, Treem WR et al. (Sep 1996). "Maternal acute fatty liver of pregnancy associated with fetal trifunctional protein deficiency: molecular characterization of a novel maternal mutant allele". Pediatric Research 40 (3). doi:10.1203/00006450-199609000-00005. PMID 8865274. 
  • Gillingham MB, Matern D, Harding CO (Oct 2009). "Effect of feeding, exercise and genotype on plasma 3-hydroxyacylcarnitines in children with lchad deficiency". Topics in Clinical Nutrition 24 (4). doi:10.1097/TIN.0b013e3181c62182. PMID 20589231. 
  • Milewska M, McRedmond J, Byrne PC (Nov 2009). "Identification of novel spartin-interactors shows spartin is a multifunctional protein". Journal of Neurochemistry 111 (4). doi:10.1111/j.1471-4159.2009.06382.x. PMID 19765186. 
  • Weekes J, Morrison K, Mullen A, Wait R, Barton P, Dunn MJ (Feb 2003). "Hyperubiquitination of proteins in dilated cardiomyopathy". Proteomics 3 (2). doi:10.1002/pmic.200390029. PMID 12601813. 
  • Bogenhagen DF, Rousseau D, Burke S (Feb 2008). "The layered structure of human mitochondrial DNA nucleoids". The Journal of Biological Chemistry 283 (6). doi:10.1074/jbc.M708444200. PMID 18063578. 
  • Zhang QX, Baldwin GS (Oct 1994). "Structures of the human cDNA and gene encoding the 78 kDa gastrin-binding protein and of a related pseudogene". Biochimica Et Biophysica Acta 1219 (2). PMID 7918661. 
  • IJlst L, Oostheim W, Ruiter JP, Wanders RJ (Jul 1997). "Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of two new mutations". Journal of Inherited Metabolic Disease 20 (3). PMID 9266371. 
  • Yagi M, Lee T, Awano H, Tsuji M, Tajima G, Kobayashi H et al. (Dec 2011). "A patient with mitochondrial trifunctional protein deficiency due to the mutations in the HADHB gene showed recurrent myalgia since early childhood and was diagnosed in adolescence". Molecular Genetics and Metabolism 104 (4). doi:10.1016/j.ymgme.2011.09.025. PMID 22000755. 

This article incorporates text from the United States National Library of Medicine, which is in the public domain.