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{{Short description|Protein-coding gene in the species Homo sapiens}}
{{Infobox_gene}}
'''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}}</ref>
'''HADHA''' is a gene associated with [[long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency]].▼
==
HADHA is an 82.9 kDa protein composed of 763 amino acids.<ref name=COPaKB>{{cite journal | vauthors = 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 | title = Integration of cardiac proteome biology and medicine by a specialized knowledgebase | journal = Circulation Research | volume = 113 | issue = 9 | pages = 1043–53 | date = Oct 2013 | pmid = 23965338 | pmc = 4076475 | doi = 10.1161/CIRCRESAHA.113.301151 }}</ref><ref name="url_COPaKB">{{cite web | url = http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P40939 | work = Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) | title = hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), alpha subunit | access-date = 2015-03-18 | archive-date = 2016-03-05 | archive-url = https://web.archive.org/web/20160305175422/http://heartproteome.org/copa/proteininfo.aspx?qtype=protein%20id&qvalue=p40939 | url-status = dead }}</ref>
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.<ref name="entrez"/>
== Function ==
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-style = vanc }}</ref>
== Clinical significance ==
▲
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 = August 1996 | pmid = 8770876 | pmc = 507519 | doi = 10.1172/jci118863 }}</ref> Clinical manifestations of this deficiency can include [[myopathy]], [[cardiomyopathy]], episodes of [[coma]], and [[hypoglycemia]].<ref>{{cite journal | vauthors = Rocchiccioli F, Wanders RJ, Aubourg P, Vianey-Liaud C, Ijlst L, Fabre M, Cartier N, Bougneres PF | title = Deficiency of long-chain 3-hydroxyacyl-CoA dehydrogenase: a cause of lethal myopathy and cardiomyopathy in early childhood | journal = Pediatric Research | volume = 28 | issue = 6 | pages = 657–62 | date = December 1990 | pmid = 2284166 | doi = 10.1203/00006450-199012000-00023 | doi-access = free }}</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]],<ref name=rakheja2002>{{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; A Journal of Technical Methods and Pathology | volume = 82 | issue = 7 | pages = 815–24 | date = July 2002 | pmid = 12118083 | doi = 10.1097/01.lab.0000021175.50201.46 | doi-access = free }}</ref><ref name=griffin2012>{{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 | s2cid = 38407420 }}</ref> [[acute fatty liver of pregnancy]],<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> and maternal floor infarct of the placenta.<ref name=rakheja2002/><ref name=griffin2012/>
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>
== Interactions ==
HADHA has been shown to have 142 binary [[Protein–protein interaction|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]].<ref>{{Cite web | url = https://www.ebi.ac.uk/intact/interactions?conversationContext=3&query=HADHA | title = 142 binary interactions found for search term HADHA | work = IntAct Molecular Interaction Database | publisher = EMBL-EBI | access-date = 2018-08-25 }}</ref>
== References ==
{{reflist|32em}}
== Further reading ==
{{refbegin|32em}}
* {{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 | date = Jul 2002 | pmid = 12118083 | doi=10.1097/01.lab.0000021175.50201.46 | pages=815–24| doi-access = free }}
* {{cite journal | vauthors = Isaacs JD, Sims HF, Powell CK, Bennett MJ, Hale DE, Treem WR, Strauss AW | title = Maternal acute fatty liver of pregnancy associated with fetal trifunctional protein deficiency: molecular characterization of a novel maternal mutant allele | journal = Pediatric Research | volume = 40 | issue = 3 | date = Sep 1996 | pmid = 8865274 | doi = 10.1203/00006450-199609000-00005 | pages=393–8| doi-access = free }}
* {{cite journal | vauthors = Gillingham MB, Matern D, Harding CO | title = Effect of feeding, exercise and genotype on plasma 3-hydroxyacylcarnitines in children with lchad deficiency | journal = Topics in Clinical Nutrition | volume = 24 | issue = 4 | date = Oct 2009 | pmid = 20589231 | doi = 10.1097/TIN.0b013e3181c62182 | pages=359–365 | pmc=2892921}}
* {{cite journal | vauthors = Milewska M, McRedmond J, Byrne PC | title = Identification of novel spartin-interactors shows spartin is a multifunctional protein | journal = Journal of Neurochemistry | volume = 111 | issue = 4 | date = Nov 2009 | pmid = 19765186 | doi = 10.1111/j.1471-4159.2009.06382.x | pages=1022–30| s2cid = 205621232 }}
* {{cite journal | vauthors = Weekes J, Morrison K, Mullen A, Wait R, Barton P, Dunn MJ | title = Hyperubiquitination of proteins in dilated cardiomyopathy | journal = Proteomics | volume = 3 | issue = 2 | date = Feb 2003 | pmid = 12601813 | doi = 10.1002/pmic.200390029 | pages=208–16| s2cid = 19874662 }}
* {{cite journal | vauthors = Bogenhagen DF, Rousseau D, Burke S | title = The layered structure of human mitochondrial DNA nucleoids | journal = Journal of Biological Chemistry | volume = 283 | issue = 6 | date = Feb 2008 | pmid = 18063578 | doi = 10.1074/jbc.M708444200 | pages=3665–75| doi-access = free }}
* {{cite journal | vauthors = Zhang QX, Baldwin GS | title = Structures of the human cDNA and gene encoding the 78 kDa gastrin-binding protein and of a related pseudogene | journal = Biochimica et Biophysica Acta (BBA) - Gene Structure and Expression | volume = 1219 | issue = 2 | date = Oct 1994 | pmid = 7918661 | pages=567–75 | doi=10.1016/0167-4781(94)90091-4}}
* {{cite journal | vauthors = IJlst L, Oostheim W, Ruiter JP, Wanders RJ | title = Molecular basis of long-chain 3-hydroxyacyl-CoA dehydrogenase deficiency: identification of two new mutations | journal = Journal of Inherited Metabolic Disease | volume = 20 | issue = 3 | date = Jul 1997 | pmid = 9266371 | doi=10.1023/A:1005310903004 | pages=420–2| s2cid = 23046057 | url = 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 }}
* {{cite journal | vauthors = Yagi M, Lee T, Awano H, Tsuji M, Tajima G, Kobayashi H, Hasegawa Y, Yamaguchi S, Takeshima Y, Matsuo M | title = 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 | journal = Molecular Genetics and Metabolism | volume = 104 | issue = 4 | date = Dec 2011 | pmid = 22000755 | doi = 10.1016/j.ymgme.2011.09.025 | pages=556–9}}
{{refend}}
== External links ==
* [https://www.ebi.ac.uk/pdbe/pdbe-kb/proteins/P40939 PDBe-KB] provides an overview of all the structure information available in the PDB for Human Trifunctional enzyme subunit alpha, mitochondrial (HADHA)
{{NLM content}}
{{Multienzyme complexes}}
{{Lipid metabolism enzymes}}
{{Alcohol oxidoreductases}}
{{Enzymes}}
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[[Category:EC 1.1.1]]
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