HADHA: Difference between revisions

'''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 [[Mitochondrial trifunctional protein deficiency|trifunctional protein deficiency]] or [[long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency]].<ref name="entrez">{{cite web | url=https://www.ncbi.nlm.nih.gov/gene/3030|title = Entrez Gene: Hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit | url = https://www.ncbi.nlm.nih.gov/gene/3030 }}</ref>

This gene encodes the alpha subunit of the mitochondrial trifunctional protein, which catalyzes the last three steps of mitochondrial [[Beta oxidation|beta-oxidation]] of long chain fatty acids.<ref name="entrez"/> 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.<ref>{{cite journal | vauthors = Carpenter K, Pollitt RJ, Middleton B | title = Human liver long-chain 3-hydroxyacyl-coenzyme A dehydrogenase is a multifunctional membrane-bound beta-oxidation enzyme of mitochondria | journal = Biochemical and Biophysical Research Communications | volume = 183 | issue = 2 | pages = 443–8 | date = Mar 1992 | pmid = 1550553 | doi=10.1016/0006-291x(92)90501-b}}</ref> The alpha subunit catalyzes this reaction, and is attached to [[HADHB]], which catalyzes the last step of the reaction.<ref name="BioChem">{{cite book | title = Principles of Biochemistry | chapter = Chapter 18, Mitochondrial ATP synthesis | first1 = Donald J. | last1 = Voet | first2 = Judith G. | last2 = Voet | first3 = Charlotte W. | last3 = Pratt | publisher = Wiley | year = 2010 | isbn = 978-0-470-23396-2 | page = 669 | edition = 4th | name-list-format = vanc }}</ref>

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 [[Fatty acid|long-chain fatty acids]] that can lead to sudden infant death.<ref>{{cite journal | vauthors = IJlst L, Ruiter JP, Hoovers JM, Jakobs ME, Wanders RJ | title = 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 | journal = The Journal of Clinical Investigation | volume = 98 | issue = 4 | pages = 1028–33 | date = Aug 1996 | pmid = 8770876 | doi = 10.1172/jci118863 | pmc=507519}}</ref> Clinical manifestations of this deficiency can include [[myopathy]], [[cardiomyopathy]], episodes of [[coma]], and [[hypoglycemia]].<ref>{{Cite journal|last=Rocchiccioli|first=F.|last2=Wanders|first2=R. J.|last3=Aubourg|first3=P.|last4=Vianey-Liaud|first4=C.|last5=Ijlst|first5=L.|last6=Fabre|first6=M.|last7=Cartier|first7=N.|last8=Bougneres|first8=P. F.|date=1990-12|title=Deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase: a cause of lethal myopathy and cardiomyopathy in early childhood|url=https://www.ncbi.nlm.nih.gov/pubmed/2284166|journal=Pediatric Research|volume=28|issue=6|pages=657–662|doi=10.1203/00006450-199012000-00023|issn=0031-3998|pmid=2284166}}</ref> Long-chain L-3-hydroxyacyl-coenzyme A dehydrogenase deficiency is associated with some pregnancy-specific disorders, including [[Pre-eclampsia|preeclampsia]], [[HELLP syndrome]] (hemolysis, elevated liver enzymes, low platelets), [[hyperemesis gravidarum]], acute fatty liver of pregnancy, and maternal floor infarct of the placenta.<ref>{{cite journal | vauthors = Rakheja D, Bennett MJ, Rogers BB | title = Long-chain L-3-hydroxyacyl-coenzyme a dehydrogenase deficiency: a molecular and biochemical review | journal = Laboratory Investigation | volume = 82 | issue = 7 | pages = 815–24 | date = Jul 2002 | pmid = 12118083 | doi = 10.1097/01.lab.0000021175.50201.46 }}</ref><ref>{{cite journal | vauthors = Griffin AC, Strauss AW, Bennett MJ, Ernst LM | title = Mutations in long-chain 3-hydroxyacyl coenzyme a dehydrogenase are associated with placental maternal floor infarction/massive perivillous fibrin deposition | journal = Pediatric and Developmental Pathology | volume = 15 | issue = 5 | pages = 368–74 | date = September–October 2012 | pmid = 22746996 | doi = 10.2350/12-05-1198-oa.1 }}</ref> Additionally, it has been correlated with [[Acute fatty liver of pregnancy]] (AFLP) disease.<ref>{{cite journal | vauthors = Ibdah JA, Yang Z, Bennett MJ | title = Liver disease in pregnancy and fetal fatty acid oxidation defects | journal = Molecular Genetics and Metabolism | volume = 71 | issue = 1–2 | pages = 182–9 | date = September–October 2000 | pmid = 11001809 | doi = 10.1006/mgme.2000.3065 }}</ref>

From a clinical perspective, HADHA might also be a useful marker to predict resistance to certain types of [[chemotherapy]] in patients with [[lung cancer]].<ref>{{cite journal | vauthors = Kageyama T, Nagashio R, Ryuge S, Matsumoto T, Iyoda A, Satoh Y, Masuda N, Jiang SX, Saegusa M, Sato Y | title = HADHA is a potential predictor of response to platinum-based chemotherapy for lung cancer | journal = Asian Pacific Journal of Cancer Prevention | volume = 12 | issue = 12 | pages = 3457–63 | date = 2011 | pmid = 22471497 }}</ref>