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HADHA

January 01, 1970

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
AliasesHADHA, 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 IDsOMIM: 600890; MGI: 2135593; HomoloGene: 152; GeneCards: HADHA; OMA:HADHA - orthologs
Orthologs
SpeciesHumanMouse
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 MbChr 5: 30.32 – 30.36 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Structure edit

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 edit

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 edit

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,[12][13] acute fatty liver of pregnancy,[14] and maternal floor infarct of the placenta.[12][13]

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 edit

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 edit

  1. ^ a b c GRCh38: Ensembl release 89: ENSG00000084754 – Ensembl, May 2017
  2. ^ a b c 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. ^ a b c d "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. ^ . Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 2016-03-05. Retrieved 2015-03-18.
  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. ^ a b 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. ^ a b 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. S2CID 38407420.
  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 edit

  • 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. S2CID 205621232.
  • 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. S2CID 19874662.
  • 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. S2CID 23046057.
  • 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 edit

  • 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.


January 01, 1970
hadha, trifunctional, enzyme, subunit, alpha, mitochondrial, also, known, hydroxyacyl, dehydrogenase, ketoacyl, thiolase, enoyl, hydratase, trifunctional, protein, alpha, subunit, protein, that, humans, encoded, gene, mutations, have, been, associated, with, t. 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 HADHAIdentifiersAliasesHADHA 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 alphaExternal IDsOMIM 600890 MGI 2135593 HomoloGene 152 GeneCards HADHA OMA HADHA orthologsGene location Human Chr Chromosome 2 human 1 Band2p23 3Start26 190 635 bp 1 End26 244 672 bp 1 Gene location Mouse Chr Chromosome 5 mouse 2 Band5 5 B1Start30 323 302 bp 2 End30 360 160 bp 2 RNA expression patternBgeeHumanMouse ortholog Top expressed injejunal mucosagastrocnemius muscleleft ventricleduodenumrectumthoracic diaphragmmonocytedeltoid muscleright adrenal glandright ventricleTop expressed inmyocardium of ventricleright ventriclecardiac musclesbrown adipose tissueextraocular musclesoleus muscledigastric muscleleft ventricleintercostal muscleesophagusMore reference expression dataBioGPSn aGene ontologyMolecular functionfatty acyl CoA binding acetyl CoA C acyltransferase activity protein containing complex binding NAD binding enoyl CoA hydratase activity acetyl CoA C acetyltransferase activity long chain 3 hydroxyacyl CoA dehydrogenase activity protein binding catalytic activity lyase activity oxidoreductase activity long chain enoyl CoA hydratase activity 3 hydroxyacyl CoA dehydrogenase activityCellular componentmitochondrion mitochondrial inner membrane mitochondrial nucleoid mitochondrial fatty acid beta oxidation multienzyme complex extracellular matrixBiological processlipid metabolism fatty acid metabolic process response to insulin fatty acid beta oxidation metabolism cardiolipin acyl chain remodelingSources Amigo QuickGOOrthologsSpeciesHumanMouseEntrez303097212EnsemblENSG00000084754ENSMUSG00000025745UniProtP40939Q8BMS1RefSeq mRNA NM 000182NM 178878RefSeq protein NP 000173NP 849209Location UCSC Chr 2 26 19 26 24 MbChr 5 30 32 30 36 MbPubMed search 3 4 WikidataView Edit HumanView Edit Mouse Contents 1 Structure 2 Function 3 Clinical significance 4 Interactions 5 References 6 Further reading 7 External linksStructure editHADHA 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 editThis 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 editMutations 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 12 13 acute fatty liver of pregnancy 14 and maternal floor infarct of the placenta 12 13 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 editHADHA 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 edit a b c GRCh38 Ensembl release 89 ENSG00000084754 Ensembl May 2017 a b c GRCm38 Ensembl release 89 ENSMUSG00000025745 Ensembl May 2017 Human PubMed Reference National Center for Biotechnology Information U S National Library of Medicine Mouse PubMed Reference National Center for Biotechnology Information U S National Library of Medicine a b c d Entrez Gene Hydroxyacyl CoA dehydrogenase 3 ketoacyl CoA thiolase enoyl CoA hydratase trifunctional protein alpha subunit 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 hydroxyacyl CoA dehydrogenase 3 ketoacyl CoA thiolase enoyl CoA hydratase trifunctional protein alpha subunit Cardiac Organellar Protein Atlas Knowledgebase COPaKB Archived from the original on 2016 03 05 Retrieved 2015 03 18 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 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 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 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 a b 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 a b 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 S2CID 38407420 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 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 142 binary interactions found for search term HADHA IntAct Molecular Interaction Database EMBL EBI Retrieved 2018 08 25 Further reading editRakheja 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 S2CID 205621232 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 S2CID 19874662 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 S2CID 23046057 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 editPDBe 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 Portal nbsp Biology Retrieved from https en wikipedia org w index php title HADHA amp oldid 1160444792, wikipedia, wiki, book, books, library,

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