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
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 30,118,304 bp[2] End 30,155,162 bp[2]
Gene ontology Molecular function • fatty-acyl-CoA binding • acetyl-CoA C-acyltransferase activity • GO:0032403 macromolecular complex binding • NAD binding • enoyl-CoA hydratase activity • acetyl-CoA C-acetyltransferase activity • long-chain-3-hydroxyacyl-CoA dehydrogenase activity • GO:0001948 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 • oxidation-reduction process • response to drug 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: 30.12 – 30.16 Mb
PubMed search	[3]	[4]
Wikidata
View/Edit Human View/Edit Mouse

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, acute fatty liver of pregnancy, and maternal floor infarct of the placenta.[12][13] Additionally, it has been correlated with Acute fatty liver of pregnancy (AFLP) disease.[14]

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]

References

1. GRCh38: Ensembl release 89: ENSG00000084754 - Ensembl, May 2017
2. GRCm38: Ensembl release 89: ENSMUSG00000025745 - Ensembl, May 2017
3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
5. "Entrez Gene: Hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit".
6. 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 (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.
7. "hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB).
8. 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.
9. 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.
10. IJlst L, Ruiter JP, Hoovers JM, Jakobs ME, Wanders RJ (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. PMC 507519. PMID 8770876.
11. Rocchiccioli F, Wanders RJ, Aubourg P, Vianey-Liaud C, Ijlst L, Fabre M, Cartier N, Bougneres PF (December 1990). "Deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase: a cause of lethal myopathy and cardiomyopathy in early childhood". Pediatric Research. 28 (6): 657–62. doi:10.1203/00006450-199012000-00023. PMID 2284166.
12. 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.
13. 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. 15 (5): 368–74. doi:10.2350/12-05-1198-oa.1. PMID 22746996.
14. 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. doi:10.1006/mgme.2000.3065. PMID 11001809.
15. 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. 12 (12): 3457–63. PMID 22471497.
16. "142 binary interactions found for search term HADHA". IntAct Molecular Interaction Database. EMBL-EBI. Retrieved 2018-08-25.

Further reading

• Rakheja D, Bennett MJ, Rogers BB (Jul 2002). "Long-chain L-3-hydroxyacyl-coenzyme a dehydrogenase deficiency: a molecular and biochemical review". Laboratory Investigation. 82 (7): 815–24. doi:10.1097/01.lab.0000021175.50201.46. PMID 12118083.
• Isaacs JD, Sims HF, Powell CK, Bennett MJ, Hale DE, Treem WR, Strauss AW (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): 393–8. 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): 359–365. doi:10.1097/TIN.0b013e3181c62182. PMC 2892921. 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): 1022–30. 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): 208–16. doi:10.1002/pmic.200390029. PMID 12601813.
• Bogenhagen DF, Rousseau D, Burke S (Feb 2008). "The layered structure of human mitochondrial DNA nucleoids". Journal of Biological Chemistry. 283 (6): 3665–75. 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 (BBA) - Gene Structure and Expression. 1219 (2): 567–75. doi:10.1016/0167-4781(94)90091-4. 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): 420–2. doi:10.1023/A:1005310903004. PMID 9266371.
• Yagi M, Lee T, Awano H, Tsuji M, Tajima G, Kobayashi H, Hasegawa Y, Yamaguchi S, Takeshima Y, Matsuo M (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): 556–9. doi:10.1016/j.ymgme.2011.09.025. PMID 22000755.

External links

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

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