ACADSB explained

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. 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]

Notes and References

  1. Andresen BS, Christensen E, Corydon TJ, Bross P, Pilgaard B, Wanders RJ, Ruiter JP, Simonsen H, Winter V, Knudsen I, Schroeder LD, Gregersen N, Skovby F . 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 . 11013134 . 1288551 . 10.1086/303105 .
  2. Arden KC, Viars CS, Fu K, Rozen R . Localization of short/branched chain acyl-CoA dehydrogenase (ACADSB) to human chromosome 10 . Genomics . 25 . 3 . 743–5 . Feb 1995 . 7759115 . 10.1016/0888-7543(95)80023-f.
  3. Rozen R, Vockley J, Zhou L, Milos R, Willard J, Fu K, Vicanek C, Low-Nang L, Torban E, Fournier B . 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 . 7698750 . 10.1006/geno.1994.1617 .
  4. He M, Burghardt TP, Vockley J . 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 . 12855692 . 10.1074/jbc.M306882200 . free .
  5. Web site: Entrez Gene: acyl-CoA dehydrogenase, short/branched chain .
  6. Andresen BS, Christensen E, Corydon TJ, Bross P, Pilgaard B, Wanders RJ, Ruiter JP, Simonsen H, Winter V, Knudsen I, Schroeder LD, Gregersen N, Skovby F . 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 . 11013134 . 10.1086/303105 . 1288551.
  7. Sass JO, Ensenauer R, Röschinger W, Reich H, Steuerwald U, Schirrmacher O, Engel K, Häberle J, Andresen BS, Mégarbané A, Lehnert W, Zschocke J . 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 . 17945527 . 10.1016/j.ymgme.2007.09.002 .
  8. Madsen PP, Kibaek M, Roca X, Sachidanandam R, Krainer AR, Christensen E, Steiner RD, Gibson KM, Corydon TJ, Knudsen I, Wanders RJ, Ruiter JP, Gregersen N, Andresen BS . 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 . 16317551 . 10.1007/s00439-005-0070-4 . 22861705 .
  9. Alfardan J, Mohsen AW, Copeland S, Ellison J, Keppen-Davis L, Rohrbach M, Powell BR, Gillis J, Matern D, Kant J, Vockley J . 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 . 20547083 . 10.1016/j.ymgme.2010.04.014 . 2906669.
  10. Gibson KM, Burlingame TG, Hogema B, Jakobs C, Schutgens RB, Millington D, Roe CR, Roe DS, Sweetman L, Steiner RD, Linck L, Pohowalla P, Sacks M, Kiss D, Rinaldo P, Vockley J . 2-Methylbutyryl-coenzyme A dehydrogenase deficiency: a new inborn error of L-isoleucine metabolism . Pediatric Research . 47 . 6 . 830–3 . Jun 2000 . 10832746 . 10.1203/00006450-200006000-00025. free .
  11. Kamide K, Kokubo Y, Yang J, Matayoshi T, Inamoto N, Takiuchi S, Horio T, Miwa Y, Yoshii M, Tomoike H, Tanaka C, Banno M, Okuda T, Kawano Y, Miyata T . Association of genetic polymorphisms of ACADSB and COMT with human hypertension . Journal of Hypertension . 25 . 1 . 103–10 . Jan 2007 . 17143180 . 10.1097/HJH.0b013e3280103a40 . 40885244 .

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