HADHB

Last updated

HADHB
4c2j.jpg
Identifiers
Aliases HADHB , ECHB, MSTP029, MTPB, TP-BETA, hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase (trifunctional protein), beta subunit, hydroxyacyl-CoA dehydrogenase trifunctional multienzyme complex subunit beta
External IDs OMIM: 143450; MGI: 2136381; HomoloGene: 153; GeneCards: HADHB; OMA:HADHB - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000183
NM_001281512
NM_001281513

NM_145558
NM_001289798
NM_001289799

RefSeq (protein)

NP_000174
NP_001268441
NP_001268442

NP_001276727
NP_001276728
NP_663533

Location (UCSC) Chr 2: 26.24 – 26.29 Mb Chr 5: 30.36 – 30.39 Mb
PubMed search [3] [4]
Wikidata
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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. [5]

Contents

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. [5] 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. [6] [7]

Function

Enzymatic activity of HADHB in beta-oxidation Beta-ketothiolase.png
Enzymatic activity of HADHB in beta-oxidation

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. [5]

Clinical significance

Mutations in this gene, along with mutations in HADHA, result in trifunctional protein deficiency. [5] Mutations in either gene have similar clinical presentations. [8] 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), [9] infantile onset of a hepatic Reye-like syndrome, and late-adolescent onset of primarily a skeletal myopathy. [10] Additionally, some presents showed symptoms associated with myopathy, recurrent and episodic rhabdomyolysis, and sensorimotor axonal neuropathy. [11] 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. [12] 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. [13]

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. [14] Additionally, HADHB has been shown to bind to the distal 3’ untranslated region of renin mRNA, thereby regulating renin protein expression. [15] HADHB and cold-inducible RBP (CIRBP) were shown to be regulated after ischemia, positively regulating biogenesis of miR-329 and miR-495. [16]

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000138029 Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000059447 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. 1 2 3 4 "Entrez Gene: hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (trifunctional protein)".
  6. ]Zong NC, Li H, Li H, Lam MP, Jimenez RC, Kim CS, et al. (October 2013). "Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research. 113 (9): 1043–1053. doi:10.1161/CIRCRESAHA.113.301151. PMC   4076475 . PMID   23965338.
  7. "Trifunctional enzyme subunit beta, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). Archived from the original on 4 March 2016. Retrieved 23 March 2015.
  8. Spiekerkoetter U, Khuchua Z, Yue Z, Bennett MJ, Strauss AW (February 2004). "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. doi: 10.1203/01.pdr.0000103931.80055.06 . PMID   14630990.
  9. Sonta SI, Sandberg AA (1977). "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. doi:10.1002/ajh.2830030202. PMID   272120. S2CID   13141165.
  10. Spiekerkoetter U, Sun B, Khuchua Z, Bennett MJ, Strauss AW (June 2003). "Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations". Human Mutation. 21 (6): 598–607. doi: 10.1002/humu.10211 . PMID   12754706. S2CID   85671653.
  11. den Boer ME, Dionisi-Vici C, Chakrapani A, van Thuijl AO, Wanders RJ, Wijburg FA (June 2003). "Mitochondrial trifunctional protein deficiency: a severe fatty acid oxidation disorder with cardiac and neurologic involvement". The Journal of Pediatrics. 142 (6): 684–689. doi:10.1067/mpd.2003.231. PMID   12838198.
  12. Jackson S, Kler RS, Bartlett K, Briggs H, Bindoff LA, Pourfarzam M, et al. (October 1992). "Combined enzyme defect of mitochondrial fatty acid oxidation". The Journal of Clinical Investigation. 90 (4): 1219–1225. doi:10.1172/jci115983. PMC   443162 . PMID   1401059.
  13. Hong YB, Lee JH, Park JM, Choi YR, Hyun YS, Yoon BR, et al. (December 2013). "A compound heterozygous mutation in HADHB gene causes an axonal Charcot-Marie-tooth disease". BMC Medical Genetics. 14 125. doi: 10.1186/1471-2350-14-125 . PMC   4029087 . PMID   24314034.
  14. Zhou Z, Zhou J, Du Y (July 2012). "Estrogen receptor alpha interacts with mitochondrial protein HADHB and affects beta-oxidation activity". Molecular & Cellular Proteomics. 11 (7): M111.011056. doi: 10.1074/mcp.m111.011056 . PMC   3394935 . PMID   22375075.
  15. Adams DJ, Beveridge DJ, van der Weyden L, Mangs H, Leedman PJ, Morris BJ (November 2003). "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. doi: 10.1074/jbc.m307782200 . PMID   12933794.
  16. Downie Ruiz Velasco A, Welten SM, Goossens EA, Quax PH, Rappsilber J, Michlewski G, et al. (March 2019). "Posttranscriptional Regulation of 14q32 MicroRNAs by the CIRBP and HADHB during Vascular Regeneration after Ischemia". Molecular Therapy. Nucleic Acids. 14: 329–338. doi:10.1016/j.omtn.2018.11.017. PMC   6350214 . PMID   30665182.

Further reading

This article incorporates text from the United States National Library of Medicine, which is in the public domain.