Biology:ACADSB
 Generic protein structure example |
ACADSB is a human gene that encodes short/branched chain specific acyl-CoA dehydrogenase (SBCAD), an enzyme in the acyl CoA dehydrogenase family.
It can cause short/branched-chain acyl-CoA dehydrogenase deficiency.[1]
Structure
The human ACADSB gene is located on chromosome 10; its exact localization has been identified as 10q25-q26.[2] The open reading frame (ORF) encodes a precursor protein that contains 431 amino acids; post-translational processing results in a mature protein with 399 amino acids. The cDNA is significantly similar to the cDNA of other members of the acyl-CoA dehydrogenase family; its structure is closest to that of short chain acyl-CoA dehydrogenase.[3] The structure of the catalytic pocket has also been studied; position 104 at the bottom of the substrate-binding pocket has been identified as important in determining the length of the primary carbon chain that can be accommodated. Altering residues at positions 105 and 177 have been demonstrated to affect the rate of the dehydrogenation reactions.[4]
Function
Short/branched chain acyl-CoA dehydrogenase (ACADSB) is a member of the acyl-CoA dehydrogenase family of enzymes that catalyze the dehydrogenation of acyl-CoA derivatives in the metabolism of fatty acids or branch chained amino acids. Substrate specificity is the primary characteristic used to define members of this gene family. The ACADSB gene product has the greatest activity towards the short branched chain acyl-CoA derivative, (S)-2-methylbutyryl-CoA, but also reacts significantly with other 2-methyl branched chain substrates and with short straight chain acyl-CoAs.[5] The encoded protein is also involved in L-leucine catabolism.[6]
Clinical significance
Mutations in the ACADSB gene have been associated with 2-Methylbutyryl-CoA dehydrogenase deficiency (SBCADD, also known as MBD) deficiency, an autosomal recessive metabolic disorder of impaired isoleucine degradation.[7] Many mutations across the gene's 10 exons have been identified, with the mutations causing exon skipping and other transcriptional and translational errors. The disorder may be detected by MS/MS-based routine newborn screening due to the heightened presence of 2-methylbutyrylcarnitine in tissue samples.[8][9] The disorder may also be identified using urinary organic acid analysis, by detecting the presence of 2-methylbutyryl glycinuria.[6] While many individuals with a mutation in this gene may be asymptomatic, some patients have been reported to have symptoms in early infancy. Infants may experience apneic episodes, generalized muscle atrophy, hypotonia, lethargy, seizures, and delayed motor development. Patients may also experience metabolic symptoms such as hypothermia and hypoglycemia.[10] Finally, genetic polymorphisms of the ACADSB gene may also be involved in the development of hypertension in the Japanese population.[11]
References
- ↑ "Isolated 2-methylbutyrylglycinuria caused by short/branched-chain acyl-CoA dehydrogenase deficiency: identification of a new enzyme defect, resolution of its molecular basis, and evidence for distinct acyl-CoA dehydrogenases in isoleucine and valine metabolism". American Journal of Human Genetics 67 (5): 1095–103. Nov 2000. doi:10.1086/303105. PMID 11013134.
- ↑ "Localization of short/branched chain acyl-CoA dehydrogenase (ACADSB) to human chromosome 10". Genomics 25 (3): 743–5. Feb 1995. doi:10.1016/0888-7543(95)80023-f. PMID 7759115.
- ↑ "Isolation and expression of a cDNA encoding the precursor for a novel member (ACADSB) of the acyl-CoA dehydrogenase gene family". Genomics 24 (2): 280–7. Nov 1994. doi:10.1006/geno.1994.1617. PMID 7698750.
- ↑ "A novel approach to the characterization of substrate specificity in short/branched chain Acyl-CoA dehydrogenase". The Journal of Biological Chemistry 278 (39): 37974–86. Sep 2003. doi:10.1074/jbc.M306882200. PMID 12855692.
- ↑ "Entrez Gene: acyl-CoA dehydrogenase, short/branched chain". https://www.ncbi.nlm.nih.gov/gene/36.
- ↑ 6.0 6.1 "Isolated 2-methylbutyrylglycinuria caused by short/branched-chain acyl-CoA dehydrogenase deficiency: identification of a new enzyme defect, resolution of its molecular basis, and evidence for distinct acyl-CoA dehydrogenases in isoleucine and valine metabolism". American Journal of Human Genetics 67 (5): 1095–103. Nov 2000. doi:10.1086/303105. PMID 11013134.
- ↑ "2-Methylbutyryl-coenzyme A dehydrogenase deficiency: functional and molecular studies on a defect in isoleucine catabolism". Molecular Genetics and Metabolism 93 (1): 30–5. Jan 2008. doi:10.1016/j.ymgme.2007.09.002. PMID 17945527.
- ↑ "Short/branched-chain acyl-CoA dehydrogenase deficiency due to an IVS3+3A>G mutation that causes exon skipping". Human Genetics 118 (6): 680–90. Feb 2006. doi:10.1007/s00439-005-0070-4. PMID 16317551.
- ↑ "Characterization of new ACADSB gene sequence mutations and clinical implications in patients with 2-methylbutyrylglycinuria identified by newborn screening". Molecular Genetics and Metabolism 100 (4): 333–8. Aug 2010. doi:10.1016/j.ymgme.2010.04.014. PMID 20547083.
- ↑ "2-Methylbutyryl-coenzyme A dehydrogenase deficiency: a new inborn error of L-isoleucine metabolism". Pediatric Research 47 (6): 830–3. Jun 2000. doi:10.1203/00006450-200006000-00025. PMID 10832746.
- ↑ "Association of genetic polymorphisms of ACADSB and COMT with human hypertension". Journal of Hypertension 25 (1): 103–10. Jan 2007. doi:10.1097/HJH.0b013e3280103a40. PMID 17143180.
External links
- Human ACADSB genome location and ACADSB gene details page in the UCSC Genome Browser.
- Overview of all the structural information available in the PDB for UniProt: P45954 (Short/branched chain specific acyl-CoA dehydrogenase, mitochondrial) at the PDBe-KB.
This article incorporates text from the United States National Library of Medicine, which is in the public domain.
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