HADHA explained

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.^[1]

Structure

HADHA is an 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]

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.^[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

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] Clinical manifestations of this deficiency can include myopathy, cardiomyopathy, episodes of coma, and hypoglycemia.^[7] 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,^{[8] [9]} acute fatty liver of pregnancy,^[10] and maternal floor infarct of the placenta.^{[8] [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.^[11]

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.^[12]

Further reading

• Rakheja D, Bennett MJ, Rogers BB . Long-chain L-3-hydroxyacyl-coenzyme a dehydrogenase deficiency: a molecular and biochemical review . Laboratory Investigation . 82 . 7 . Jul 2002 . 12118083 . 10.1097/01.lab.0000021175.50201.46 . 815–24. free .
• Isaacs JD, Sims HF, Powell CK, Bennett MJ, Hale DE, Treem WR, Strauss AW . Maternal acute fatty liver of pregnancy associated with fetal trifunctional protein deficiency: molecular characterization of a novel maternal mutant allele . Pediatric Research . 40 . 3 . Sep 1996 . 8865274 . 10.1203/00006450-199609000-00005 . 393–8. free .
• Gillingham MB, Matern D, Harding CO . Effect of feeding, exercise and genotype on plasma 3-hydroxyacylcarnitines in children with lchad deficiency . Topics in Clinical Nutrition . 24 . 4 . Oct 2009 . 20589231 . 10.1097/TIN.0b013e3181c62182 . 359–365 . 2892921.
• Milewska M, McRedmond J, Byrne PC . Identification of novel spartin-interactors shows spartin is a multifunctional protein . Journal of Neurochemistry . 111 . 4 . Nov 2009 . 19765186 . 10.1111/j.1471-4159.2009.06382.x . 1022–30. 205621232 .
• Weekes J, Morrison K, Mullen A, Wait R, Barton P, Dunn MJ . Hyperubiquitination of proteins in dilated cardiomyopathy . Proteomics . 3 . 2 . Feb 2003 . 12601813 . 10.1002/pmic.200390029 . 208–16. 19874662 .
• Bogenhagen DF, Rousseau D, Burke S . The layered structure of human mitochondrial DNA nucleoids . Journal of Biological Chemistry . 283 . 6 . Feb 2008 . 18063578 . 10.1074/jbc.M708444200 . 3665–75. free .
• Zhang QX, Baldwin GS . Structures of the human cDNA and gene encoding the 78 kDa gastrin-binding protein and of a related pseudogene . Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression . 1219 . 2 . Oct 1994 . 7918661 . 567–75 . 10.1016/0167-4781(94)90091-4.
• IJlst L, Oostheim W, Ruiter JP, Wanders RJ . Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of two new mutations . Journal of Inherited Metabolic Disease . 20 . 3 . Jul 1997 . 9266371 . 10.1023/A:1005310903004 . 420–2. 23046057 .
• Yagi M, Lee T, Awano H, Tsuji M, Tajima G, Kobayashi H, Hasegawa Y, Yamaguchi S, Takeshima Y, Matsuo M . 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 . Dec 2011 . 22000755 . 10.1016/j.ymgme.2011.09.025 . 556–9.

External links

• PDBe-KB provides an overview of all the structure information available in the PDB for Human Trifunctional enzyme subunit alpha, mitochondrial (HADHA)

Notes and References

1. Web site: 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, Deng N, Kim AK, Choi JH, Zelaya I, Liem D, Meyer D, Odeberg J, Fang C, Lu HJ, Xu T, Weiss J, Duan H, Uhlen M, Yates JR, Apweiler R, Ge J, Hermjakob H, Ping P . Integration of cardiac proteome biology and medicine by a specialized knowledgebase . Circulation Research . 113 . 9 . 1043–53 . Oct 2013 . 23965338 . 4076475 . 10.1161/CIRCRESAHA.113.301151 .
3. Web site: hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit . Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) . 2015-03-18 . 2016-03-05 . https://web.archive.org/web/20160305175422/http://heartproteome.org/copa/proteininfo.aspx?qtype=protein%20id&qvalue=p40939 . dead .
4. Carpenter K, Pollitt RJ, Middleton B . 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 . Mar 1992 . 1550553 . 10.1016/0006-291x(92)90501-b.
5. Book: Principles of Biochemistry . Chapter 18, Mitochondrial ATP synthesis . Donald J. . Voet . Judith G. . Voet . Charlotte W. . Pratt . Wiley . 2010 . 978-0-470-23396-2 . 669 . 4th . vanc .
6. IJlst L, Ruiter JP, Hoovers JM, Jakobs ME, Wanders RJ . 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 . August 1996 . 8770876 . 507519 . 10.1172/jci118863 .
7. Rocchiccioli F, Wanders RJ, Aubourg P, Vianey-Liaud C, Ijlst L, Fabre M, Cartier N, Bougneres PF . Deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase: a cause of lethal myopathy and cardiomyopathy in early childhood . Pediatric Research . 28 . 6 . 657–62 . December 1990 . 2284166 . 10.1203/00006450-199012000-00023 . free .
8. Rakheja D, Bennett MJ, Rogers BB . 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 . July 2002 . 12118083 . 10.1097/01.lab.0000021175.50201.46 . free .
9. Griffin AC, Strauss AW, Bennett MJ, Ernst LM . Mutations in long-chain 3-hydroxyacyl coenzyme a dehydrogenase are associated with placental maternal floor infarction/massive perivillous fibrin deposition . Pediatric and Developmental Pathology . 15 . 5 . 368–74 . September–October 2012 . 22746996 . 10.2350/12-05-1198-oa.1 . 38407420 .
10. Ibdah JA, Yang Z, Bennett MJ . Liver disease in pregnancy and fetal fatty acid oxidation defects . Molecular Genetics and Metabolism . 71 . 1–2 . 182–9 . September–October 2000 . 11001809 . 10.1006/mgme.2000.3065 .
11. Kageyama T, Nagashio R, Ryuge S, Matsumoto T, Iyoda A, Satoh Y, Masuda N, Jiang SX, Saegusa M, Sato Y . HADHA is a potential predictor of response to platinum-based chemotherapy for lung cancer . Asian Pacific Journal of Cancer Prevention . 12 . 12 . 3457–63 . 2011 . 22471497 .
12. Web site: 142 binary interactions found for search term HADHA . IntAct Molecular Interaction Database . EMBL-EBI . 2018-08-25 .