Biology:HADHB

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Short description: Protein-coding gene in the species Homo sapiens


A representation of the 3D structure of the protein myoglobin showing turquoise α-helices.
Generic protein structure example

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.[1] 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][3]

Function

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.[1]

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.[4] 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),[5] infantile onset of a hepatic Reye-like syndrome, and late-adolescent onset of primarily a skeletal myopathy.[6] Additionally, some presents showed symptoms associated with myopathy, recurrent and episodic rhabdomyolysis, and sensorimotor axonal neuropathy.[7] 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.[8] 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.[9]

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.[10] Additionally, HADHB has been shown to bind to the distal 3' untranslated region of renin mRNA, thereby regulating renin protein expression.[11] HADHB and cold-inducible RBP (CIRBP) were shown to be regulated after ischemia, positively regulating biogenesis of miR-329 and miR-495.[12]

References

  1. ↑ 1.0 1.1 1.2 1.3 "Entrez Gene: hydroxyacyl-Coenzyme A dehydrogenase/3-ketoacyl-Coenzyme A thiolase/enoyl-Coenzyme A hydratase (trifunctional protein)". https://www.ncbi.nlm.nih.gov/gene?Db=gene&Cmd=ShowDetailView&TermToSearch=3032. 
  2. ↑ ]"Integration of cardiac proteome biology and medicine by a specialized knowledgebase". Circulation Research 113 (9): 1043–1053. October 2013. doi:10.1161/CIRCRESAHA.113.301151. PMID 23965338. 
  3. ↑ "Trifunctional enzyme subunit beta, mitochondrial". Cardiac Organellar Protein Atlas Knowledgebase (COPaKB). http://www.heartproteome.org/copa/ProteinInfo.aspx?QType=Protein%20ID&QValue=P55084. 
  4. ↑ "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. doi:10.1203/01.pdr.0000103931.80055.06. PMID 14630990. 
  5. ↑ "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. doi:10.1002/ajh.2830030202. PMID 272120. 
  6. ↑ "Molecular and phenotypic heterogeneity in mitochondrial trifunctional protein deficiency due to beta-subunit mutations". Human Mutation 21 (6): 598–607. June 2003. doi:10.1002/humu.10211. PMID 12754706. 
  7. ↑ "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. doi:10.1067/mpd.2003.231. PMID 12838198. 
  8. ↑ "Combined enzyme defect of mitochondrial fatty acid oxidation". The Journal of Clinical Investigation 90 (4): 1219–1225. October 1992. doi:10.1172/jci115983. PMID 1401059. 
  9. ↑ "A compound heterozygous mutation in HADHB gene causes an axonal Charcot-Marie-tooth disease". BMC Medical Genetics 14. December 2013. doi:10.1186/1471-2350-14-125. PMID 24314034. 
  10. ↑ "Estrogen receptor alpha interacts with mitochondrial protein HADHB and affects beta-oxidation activity". Molecular & Cellular Proteomics 11 (7). July 2012. doi:10.1074/mcp.m111.011056. PMID 22375075. 
  11. ↑ "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. doi:10.1074/jbc.m307782200. PMID 12933794. 
  12. ↑ "Posttranscriptional Regulation of 14q32 MicroRNAs by the CIRBP and HADHB during Vascular Regeneration after Ischemia". Molecular Therapy. Nucleic Acids 14: 329–338. March 2019. doi:10.1016/j.omtn.2018.11.017. PMID 30665182. 

Further reading

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



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