HADHB explained

Trifunctional enzyme subunit beta, mitochondrial (TP-beta) also known as 3-ketoacyl-CoA thiolase, acetyl-CoA acyltransferase, or beta-ketothiolase is an enzyme that in humans is encoded by the HADHB gene.^[1]

HADHB is a subunit of the mitochondrial trifunctional protein and has thiolase activity.

Structure

The HADHB gene is located on chromosome 2, with its specific location being 2p23. The gene contains 17 exons. HADHB encodes a 51.2 kDa protein that is composed of 474 amino acids; 124 peptides have been observed through mass spectrometry data.^[2]

Function

This gene encodes the beta subunit of the mitochondrial trifunctional protein, a catalyst of mitochondrial beta-oxidation of long chain fatty acids. The HADHB protein catalyzes the final step of beta-oxidation, in which 3-ketoacyl CoA is cleaved by the thiol group of another molecule of Coenzyme A. The thiol is inserted between C-2 and C-3, which yields an acetyl CoA molecule and an acyl CoA molecule, which is two carbons shorter.

The encoded protein can also bind RNA and decreases the stability of some mRNAs. 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.

Clinical significance

Mutations in this gene, along with mutations in HADHA, result in trifunctional protein deficiency.^[1] Mutations in either gene have similar clinical presentations.^[3] Trifunctional protein deficiency is characterized by decreased activity of long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD), long-chain enoyl-CoA hydratase, and long-chain thiolase. This deficiency can be classified into 3 main clinical phenotypes: neonatal onset of a severe, lethal condition resulting in sudden infant death syndrome (SIDS),^[4] infantile onset of a hepatic Reye-like syndrome, and late-adolescent onset of primarily a skeletal myopathy.^[5] Additionally, some presents showed symptoms associated with myopathy, recurrent and episodic rhabdomyolysis, and sensorimotor axonal neuropathy.^[6] In some cases, symptoms of the deficiency can present as dilated cardiomyopathy, congestive heart failure, and respiratory failure. The deficiency has presented as hydrops fetalis and HELLP syndrome in fetuses.^[7] A compound heterozygous mutation of the HADHB gene can cause axonal Charcot-Marie-tooth disease, which is a neurological disorder, which shows that mutations in this gene can result in deficiencies that present in new forms not currently described.^[8]

Interactions

HADHB is a functional molecular target of ERα in the mitochondria, and the interaction may play an important role in the estrogen-mediated lipid metabolism in animals and humans.^[9] Additionally, HADHB has been shown to bind to the distal 3' untranslated region of renin mRNA, thereby regulating renin protein expression.^[10] HADHB and cold-inducible RBP (CIRBP) were shown to be regulated after ischemia, positively regulating biogenesis of miR-329 and miR-495.^[11]

Further reading

• Wang R, Yang Z, Zhu JM, Wang JL, Yang HX, Wang Q, Zhai GR, Li Z, Yu M . [Screening for G1528C mutation in mitochondrial trifunctional protein gene in pregnant women with severe preeclampsia and new born infant] . Zhonghua Fu Chan Ke Za Zhi . 41 . 10 . 672–675 . October 2006 . 17199921 .
• Aboulaich N, Vainonen JP, Strålfors P, Vener AV . Vectorial proteomics reveal targeting, phosphorylation and specific fragmentation of polymerase I and transcript release factor (PTRF) at the surface of caveolae in human adipocytes . The Biochemical Journal . 383 . Pt 2 . 237–248 . October 2004 . 15242332 . 1134064 . 10.1042/BJ20040647 .
• Adams DJ, Beveridge DJ, van der Weyden L, Mangs H, Leedman PJ, Morris BJ . HADHB, HuR, and CP1 bind to the distal 3'-untranslated region of human renin mRNA and differentially modulate renin expression . The Journal of Biological Chemistry . 278 . 45 . 44894–44903 . November 2003 . 12933794 . 10.1074/jbc.M307782200 . free .
• Spiekerkoetter U, Khuchua Z, Yue Z, Bennett MJ, Strauss AW . General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover . Pediatric Research . 55 . 2 . 190–196 . February 2004 . 14630990 . 10.1203/01.PDR.0000103931.80055.06 . free .
• Kimura K, Wakamatsu A, Suzuki Y, Ota T, Nishikawa T, Yamashita R, Yamamoto J, Sekine M, Tsuritani K, Wakaguri H, Ishii S, Sugiyama T, Saito K, Isono Y, Irie R, Kushida N, Yoneyama T, Otsuka R, Kanda K, Yokoi T, Kondo H, Wagatsuma M, Murakawa K, Ishida S, Ishibashi T, Takahashi-Fujii A, Tanase T, Nagai K, Kikuchi H, Nakai K, Isogai T, Sugano S . Diversification of transcriptional modulation: large-scale identification and characterization of putative alternative promoters of human genes . Genome Research . 16 . 1 . 55–65 . January 2006 . 16344560 . 1356129 . 10.1101/gr.4039406 .
• Bogenhagen DF, Rousseau D, Burke S . The layered structure of human mitochondrial DNA nucleoids . The Journal of Biological Chemistry . 283 . 6 . 3665–3675 . February 2008 . 18063578 . 10.1074/jbc.M708444200 . free .
• Middleton B . The mitochondrial long-chain trifunctional enzyme: 2-enoyl-CoA hydratase, 3-hydroxyacyl-CoA dehydrogenase and 3-oxoacyl-CoA thiolase . Biochemical Society Transactions . 22 . 2 . 427–431 . May 1994 . 7958339 . 10.1042/bst0220427 .
• Zhao Y, Meng XM, Wei YJ, Zhao XW, Liu DQ, Cao HQ, Liew CC, Ding JF . Cloning and characterization of a novel cardiac-specific kinase that interacts specifically with cardiac troponin I . Journal of Molecular Medicine . 81 . 5 . 297–304 . May 2003 . 12721663 . 10.1007/s00109-003-0427-x . 13468188 .
• Behrends C, Sowa ME, Gygi SP, Harper JW . Network organization of the human autophagy system . Nature . 466 . 7302 . 68–76 . July 2010 . 20562859 . 2901998 . 10.1038/nature09204 . 2010Natur.466...68B .
• Purevsuren J, Fukao T, Hasegawa Y, Kobayashi H, Li H, Mushimoto Y, Fukuda S, Yamaguchi S . Clinical and molecular aspects of Japanese patients with mitochondrial trifunctional protein deficiency . Molecular Genetics and Metabolism . 98 . 4 . 372–377 . December 2009 . 19699128 . 10.1016/j.ymgme.2009.07.011 .
• Spiekerkoetter U, Sun B, Khuchua Z, Bennett MJ, Strauss AW . Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations . Human Mutation . 21 . 6 . 598–607 . June 2003 . 12754706 . 10.1002/humu.10211 . 85671653 . free .
• Fould B, Garlatti V, Neumann E, Fenel D, Gaboriaud C, Arlaud GJ . Structural and functional characterization of the recombinant human mitochondrial trifunctional protein . Biochemistry . 49 . 39 . 8608–8617 . October 2010 . 20825197 . 10.1021/bi100742w .
• Ibdah JA, Tein I, Dionisi-Vici C, Bennett MJ, IJlst L, Gibson B, Wanders RJ, Strauss AW . Mild trifunctional protein deficiency is associated with progressive neuropathy and myopathy and suggests a novel genotype-phenotype correlation . The Journal of Clinical Investigation . 102 . 6 . 1193–1199 . September 1998 . 9739053 . 509102 . 10.1172/JCI2091 .
• Gevaert K, Goethals M, Martens L, Van Damme J, Staes A, Thomas GR, Vandekerckhove J . Exploring proteomes and analyzing protein processing by mass spectrometric identification of sorted N-terminal peptides . Nature Biotechnology . 21 . 5 . 566–569 . May 2003 . 12665801 . 10.1038/nbt810 . 23783563 .
• Hendrickson SL, Lautenberger JA, Chinn LW, Malasky M, Sezgin E, Kingsley LA, Goedert JJ, Kirk GD, Gomperts ED, Buchbinder SP, Troyer JL, O'Brien SJ . Genetic variants in nuclear-encoded mitochondrial genes influence AIDS progression . PLOS ONE . 5 . 9 . e12862 . September 2010 . 20877624 . 2943476 . 10.1371/journal.pone.0012862 . free . 2010PLoSO...512862H .
• Frackowiak J, Mazur-Kolecka B, Kaczmarski W, Dickson D . Deposition of Alzheimer's vascular amyloid-beta is associated with decreased expression of brain L-3-hydroxyacyl-coenzyme A dehydrogenase (ERAB) . Brain Research . 907 . 1–2 . 44–53 . July 2001 . 11430884 . 10.1016/S0006-8993(01)02497-0 . 22800813 .

Notes and References

1. Web site: Entrez Gene: hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (trifunctional protein).
2. Web site: Trifunctional enzyme subunit beta, mitochondrial . Cardiac Organellar Protein Atlas Knowledgebase (COPaKB) . 23 March 2015 . https://web.archive.org/web/20160304110706/http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P55084 . 4 March 2016 .
3. Spiekerkoetter U, Khuchua Z, Yue Z, Bennett MJ, Strauss AW . General mitochondrial trifunctional protein (TFP) deficiency as a result of either alpha- or beta-subunit mutations exhibits similar phenotypes because mutations in either subunit alter TFP complex expression and subunit turnover . Pediatric Research . 55 . 2 . 190–196 . February 2004 . 14630990 . 10.1203/01.pdr.0000103931.80055.06 . free .
4. Sonta SI, Sandberg AA . Chromosomes and causation of human cancer and leukemia: XXVIII. Value of detailed chromosome studies on large numbers of cells in CML . American Journal of Hematology . 3 . 2 . 121–126 . 1977 . 272120 . 10.1002/ajh.2830030202 . 13141165 .
5. Spiekerkoetter U, Sun B, Khuchua Z, Bennett MJ, Strauss AW . Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations . Human Mutation . 21 . 6 . 598–607 . June 2003 . 12754706 . 10.1002/humu.10211 . 85671653 . free .
6. den Boer ME, Dionisi-Vici C, Chakrapani A, van Thuijl AO, Wanders RJ, Wijburg FA . Mitochondrial trifunctional protein deficiency: a severe fatty acid oxidation disorder with cardiac and neurologic involvement . The Journal of Pediatrics . 142 . 6 . 684–689 . June 2003 . 12838198 . 10.1067/mpd.2003.231 .
7. Jackson S, Kler RS, Bartlett K, Briggs H, Bindoff LA, Pourfarzam M, Gardner-Medwin D, Turnbull DM . Combined enzyme defect of mitochondrial fatty acid oxidation . The Journal of Clinical Investigation . 90 . 4 . 1219–1225 . October 1992 . 1401059 . 443162 . 10.1172/jci115983 .
8. Hong YB, Lee JH, Park JM, Choi YR, Hyun YS, Yoon BR, Yoo JH, Koo H, Jung SC, Chung KW, Choi BO . A compound heterozygous mutation in HADHB gene causes an axonal Charcot-Marie-tooth disease . BMC Medical Genetics . 14 . 125 . December 2013 . 24314034 . 4029087 . 10.1186/1471-2350-14-125 . free .
9. Zhou Z, Zhou J, Du Y . Estrogen receptor alpha interacts with mitochondrial protein HADHB and affects beta-oxidation activity . Molecular & Cellular Proteomics . 11 . 7 . M111.011056 . July 2012 . 22375075 . 3394935 . 10.1074/mcp.m111.011056 . free .
10. Adams DJ, Beveridge DJ, van der Weyden L, Mangs H, Leedman PJ, Morris BJ . HADHB, HuR, and CP1 bind to the distal 3'-untranslated region of human renin mRNA and differentially modulate renin expression . The Journal of Biological Chemistry . 278 . 45 . 44894–44903 . November 2003 . 12933794 . 10.1074/jbc.m307782200 . free .
11. Downie Ruiz Velasco A, Welten SM, Goossens EA, Quax PH, Rappsilber J, Michlewski G, Nossent AY . Posttranscriptional Regulation of 14q32 MicroRNAs by the CIRBP and HADHB during Vascular Regeneration after Ischemia . Molecular Therapy. Nucleic Acids . 14 . 329–338 . March 2019 . 30665182 . 6350214 . 10.1016/j.omtn.2018.11.017 .