Biology:HADHA
 Generic protein structure example |
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]
References
- ↑ 1.0 1.1 1.2 1.3 "Entrez Gene: Hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit". https://www.ncbi.nlm.nih.gov/gene/3030.
- ↑ "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–53. Oct 2013. doi:10.1161/CIRCRESAHA.113.301151. PMID 23965338.
- ↑ "hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P40939.
- ↑ "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. doi:10.1016/0006-291x(92)90501-b. PMID 1550553.
- ↑ Voet, Donald J.; Voet, Judith G.; Pratt, Charlotte W. (2010). "Chapter 18, Mitochondrial ATP synthesis". Principles of Biochemistry (4th ed.). Wiley. p. 669. ISBN 978-0-470-23396-2.
- ↑ "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. doi:10.1172/jci118863. PMID 8770876.
- ↑ "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. doi:10.1203/00006450-199012000-00023. PMID 2284166.
- ↑ 8.0 8.1 "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. doi:10.1097/01.lab.0000021175.50201.46. PMID 12118083.
- ↑ 9.0 9.1 "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. doi:10.2350/12-05-1198-oa.1. PMID 22746996.
- ↑ "Liver disease in pregnancy and fetal fatty acid oxidation defects". Molecular Genetics and Metabolism 71 (1–2): 182–9. September–October 2000. doi:10.1006/mgme.2000.3065. PMID 11001809.
- ↑ "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. PMID 22471497.
- ↑ "142 binary interactions found for search term HADHA". IntAct Molecular Interaction Database. EMBL-EBI. https://www.ebi.ac.uk/intact/interactions?conversationContext=3&query=HADHA.
Further reading
- "Long-chain L-3-hydroxyacyl-coenzyme a dehydrogenase deficiency: a molecular and biochemical review". Laboratory Investigation 82 (7): 815–24. Jul 2002. doi:10.1097/01.lab.0000021175.50201.46. PMID 12118083.
- "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. Sep 1996. doi:10.1203/00006450-199609000-00005. PMID 8865274.
- "Effect of feeding, exercise and genotype on plasma 3-hydroxyacylcarnitines in children with lchad deficiency". Topics in Clinical Nutrition 24 (4): 359–365. Oct 2009. doi:10.1097/TIN.0b013e3181c62182. PMID 20589231.
- "Identification of novel spartin-interactors shows spartin is a multifunctional protein". Journal of Neurochemistry 111 (4): 1022–30. Nov 2009. doi:10.1111/j.1471-4159.2009.06382.x. PMID 19765186.
- "Hyperubiquitination of proteins in dilated cardiomyopathy". Proteomics 3 (2): 208–16. Feb 2003. doi:10.1002/pmic.200390029. PMID 12601813.
- "The layered structure of human mitochondrial DNA nucleoids". Journal of Biological Chemistry 283 (6): 3665–75. Feb 2008. doi:10.1074/jbc.M708444200. PMID 18063578.
- "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. Oct 1994. doi:10.1016/0167-4781(94)90091-4. PMID 7918661.
- "Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of two new mutations". Journal of Inherited Metabolic Disease 20 (3): 420–2. Jul 1997. doi:10.1023/A:1005310903004. PMID 9266371. http://dare.uva.nl/personal/pure/en/publications/molecular-basis-of-longchain-3hydroxyacylcoa-dehydrogenase-deficiency-identification-of-two-new-mutations(cf89b956-8a1f-4fbf-b408-b09b1dce499e).html.
- "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. Dec 2011. 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.
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