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 = http://www.ncbi.nlm.nih.gov/gene/3030 }}</ref>

HADHA is aan 82.9 kDa protein composed of 763 amino acids.<ref name=COPaKB>{{vcite2cite 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 = 1043-531043–53 | 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"/>

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>{{vcite2cite 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 = 443-8443–8 | 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-formatstyle = vanc }}</ref>

Mutations in this gene result in trifunctional protein deficiency or [[long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency]]. .<ref name="entrez"/>

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 |last1 vauthors = IJlst|first1= L|last2=, Ruiter|first2= JP|last3=, Hoovers|first3= JM|last4=, Jakobs|first4= ME|last5=, Wanders|first5= 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 clinicalClinical Investigation investigation| volume = 98 | issue = 4 | pages = 1028–33 | date =15 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 =98 28 | issue =4 6 | pages =1028-33 657–62 | date = December 1990 | pmid =8770876 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]], acute fatty liver of pregnancy, and maternal floor infarct of the placenta.<ref name=rakheja2002>{{cite journal |last1 vauthors = Rakheja|first1= D|last2=, Bennett|first2= MJ|last3=, Rogers|first3= BB | title = Long-chain L-3-hydroxyacyl-coenzyme a dehydrogenase deficiency: a molecular and biochemical review. | journal = Laboratory investigationInvestigation; aA journalJournal of technicalTechnical methodsMethods and pathology|date=JulyPathology 2002| volume = 82 | issue = 7 | pages =815-24 815–24 | date = July 2002 | pmid = 12118083 | doi = 10.1097/01.lab.0000021175.50201.46 | doi-access = free }}</ref> <ref name=griffin2012>{{cite journal |last1 vauthors = Griffin|first1= AC|last2=, Strauss|first2= AW|last3=, Bennett|first3= MJ|last4=, Ernst|first4= 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 developmentalDevelopmental pathologyPathology :| thevolume official= journal15 of| theissue Society= for5 Pediatric| Pathologypages and= the368–74 Paediatric Pathology Society| date =NaN September–October 2012 |volume pmid =15 22746996 |issue=5|pages doi =368 10.2350/12-7405-1198-oa.1 |pmid s2cid =22746996 38407420 }}</ref> Additionally, it has been correlated with Acute[[acute fatty liver of pregnancy (AFLP) disease. ]],<ref>{{cite journal |last1 vauthors = Ibdah|first1= JA|last2=, Yang|first2= Z|last3=, Bennett|first3= MJ | title = Liver disease in pregnancy and fetal fatty acid oxidation defects. | journal = Molecular geneticsGenetics and metabolism|date=NaNMetabolism | volume = 71 | issue =1-2 1–2 | pages =182-9 182–9 | 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 |last1 vauthors = Kageyama|first1= T|last2=, Nagashio|first2= R|last3=, Ryuge|first3= S|last4=, Matsumoto|first4= T|last5=, Iyoda|first5= A|last6=, Satoh|first6= Y|last7=, Masuda|first7= N|last8=, Jiang|first8= SX|last9=, Saegusa|first9= M|last10=, Sato|first10= Y | title = HADHA is a potential predictor of response to platinum-based chemotherapy for lung cancer. | journal = Asian Pacific journalJournal of cancerCancer preventionPrevention : APJCP|date=2011| volume = 12 | issue = 12 | pages =3457-63 3457–63 | date = 2011 | pmid = 22471497 }}</ref>

== ReferencesInteractions ==

== Further ReadingReferences ==

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* {{vcite2cite journal | vauthors = MilewskaRakheja MD, McRedmondBennett JMJ, ByrneRogers PCBB | title = IdentificationLong-chain of novel spartinL-interactors3-hydroxyacyl-coenzyme showsa spartindehydrogenase isdeficiency: a multifunctionalmolecular proteinand biochemical review | journal = JournalLaboratory of NeurochemistryInvestigation | volume = 11182 | issue = 47 | date = NovJul 20092002 | pmid = 1976518612118083 | doi = 10.11111097/j01.1471-4159lab.20090000021175.0638250201.x46 | pages=815–24| doi-access = free }}

* {{vcite2cite journal | vauthors = WeekesIsaacs JJD, MorrisonSims KHF, MullenPowell ACK, WaitBennett RMJ, BartonHale PDE, DunnTreem MJWR, Strauss AW | title = HyperubiquitinationMaternal acute fatty liver of proteinspregnancy inassociated dilatedwith cardiomyopathyfetal trifunctional protein deficiency: molecular characterization of a novel maternal mutant allele | journal = ProteomicsPediatric Research | volume = 340 | issue = 23 | date = FebSep 20031996 | pmid = 126018138865274 | doi = 10.10021203/pmic.20039002900006450-199609000-00005 | pages=393–8| doi-access = free }}

* {{vcite2cite journal | vauthors = BogenhagenGillingham DFMB, RousseauMatern D, BurkeHarding SCO | title = TheEffect layeredof structurefeeding, ofexercise humanand mitochondrialgenotype DNAon nucleoidsplasma 3-hydroxyacylcarnitines in children with lchad deficiency | journal = TheTopics Journalin of BiologicalClinical ChemistryNutrition | volume = 28324 | issue = 64 | date = FebOct 20082009 | pmid = 1806357820589231 | doi = 10.10741097/jbcTIN.M7084442000b013e3181c62182 | pages=359–365 | pmc=2892921}}

* {{vcite2cite journal | vauthors = ZhangMilewska QXM, BaldwinMcRedmond GSJ, Byrne PC | title = StructuresIdentification of thenovel humanspartin-interactors cDNAshows andspartin geneis encodinga themultifunctional 78protein kDa| gastrin-bindingjournal protein= andJournal of a related pseudogeneNeurochemistry | journalvolume = Biochimica111 Et| Biophysicaissue = Acta4 | volumedate = 1219Nov 2009 | issuepmid = 219765186 | datedoi = Oct10.1111/j.1471-4159.2009.06382.x 1994| pages=1022–30| pmids2cid = 7918661205621232 }}

* {{vcite2cite journal | vauthors = IJlstWeekes LJ, OostheimMorrison WK, RuiterMullen JPA, WandersWait RJR, Barton P, Dunn MJ | title = Molecular basisHyperubiquitination of long-chainproteins 3-hydroxyacyl-CoAin dehydrogenasedilated deficiency:cardiomyopathy identification| ofjournal two new= mutationsProteomics | journalvolume = Journal3 of| Inheritedissue Metabolic= Disease2 | volumedate = 20Feb 2003 | issuepmid = 312601813 | datedoi = Jul10.1002/pmic.200390029 1997| pages=208–16| pmids2cid = 926637119874662 }}

* {{vcite2cite journal | vauthors = YagiBogenhagen MDF, LeeRousseau TD, Awano H, Tsuji M, Tajima G, Kobayashi H, Hasegawa Y, YamaguchiBurke S, Takeshima Y, Matsuo M | title = AThe patientlayered withstructure mitochondrialof trifunctionalhuman protein deficiency due to the mutations in the HADHB gene showed recurrent myalgia since early childhood and was diagnosedmitochondrial inDNA adolescencenucleoids | journal = MolecularJournal Geneticsof andBiological MetabolismChemistry | volume = 104283 | issue = 46 | date = DecFeb 20112008 | pmid = 2200075518063578 | doi = 10.10161074/jjbc.ymgme.2011.09.025M708444200 | pages=3665–75| doi-access = free }}