ACADSB

Last updated
ACADSB
2jif.jpg
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases ACADSB , acyl-CoA dehydrogenase, short/branched chain, 2-MEBCAD, ACAD7, SBCAD, acyl-CoA dehydrogenase short/branched chain
External IDs OMIM: 600301 MGI: 1914135 HomoloGene: 1216 GeneCards: ACADSB
Orthologs
SpeciesHumanMouse
Entrez

36

66885

Ensembl

ENSG00000196177

ENSMUSG00000030861

UniProt

P45954

Q9DBL1

RefSeq (mRNA)

NM_001609
NM_001330174

NM_025826

RefSeq (protein)

NP_001317103
NP_001600

NP_080102

Location (UCSC) Chr 10: 123.01 – 123.06 Mb Chr 7: 131.01 – 131.05 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

ACADSB is a human gene that encodes short/branched chain specific acyl-CoA dehydrogenase (SBCAD), an enzyme in the acyl CoA dehydrogenase family.

Contents

It can cause short/branched-chain acyl-CoA dehydrogenase deficiency. [5]

Structure

The human ACADSB gene is located on chromosome 10; its exact localization has been identified as 10q25-q26. [6] 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. [7] 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. [8]

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. [9] The encoded protein is also involved in L-leucine catabolism. [10]

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. [11] 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. [12] [13] The disorder may also be identified using urinary organic acid analysis, by detecting the presence of 2-methylbutyryl glycinuria. [10] 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. [14] Finally, genetic polymorphisms of the ACADSB gene may also be involved in the development of hypertension in the Japanese population. [15]

Related Research Articles

Isovaleric acidemia Medical condition

Isovaleric acidemia is a rare autosomal recessive metabolic disorder which disrupts or prevents normal metabolism of the branched-chain amino acid leucine. It is a classical type of organic acidemia.

ACADVL

Very long-chain specific acyl-CoA dehydrogenase, mitochondrial (VLCAD) is an enzyme that in humans is encoded by the ACADVL gene.

ACADM

ACADM is a gene that provides instructions for making an enzyme called acyl-coenzyme A dehydrogenase that is important for breaking down (degrading) a certain group of fats called medium-chain fatty acids.

Short-chain acyl-coenzyme A dehydrogenase deficiency Medical condition

Short-chain acyl-coenzyme A dehydrogenase deficiency (SCADD), is an autosomal recessive fatty acid oxidation disorder which affects enzymes required to break down a certain group of fats called short chain fatty acids.

2-Methylbutyryl-CoA dehydrogenase deficiency, is an autosomal recessive metabolic disorder. It causes the body to be unable to process the amino acid isoleucine properly. Initial case reports identified individuals with developmental delay and epilepsy, however most cases identified through newborn screening have been asymptomatic.

Acyl-CoA dehydrogenases (ACADs) are a class of enzymes that function to catalyze the initial step in each cycle of fatty acid β-oxidation in the mitochondria of cells. Their action results in the introduction of a trans double-bond between C2 (α) and C3 (β) of the acyl-CoA thioester substrate. Flavin adenine dinucleotide (FAD) is a required co-factor in addition to the presence of an active site glutamate in order for the enzyme to function.

ACADS

Acyl-CoA dehydrogenase, C-2 to C-3 short chain is an enzyme that in humans is encoded by the ACADS gene. This gene encodes a tetrameric mitochondrial flavoprotein, which is a member of the acyl-CoA dehydrogenase family. This enzyme catalyzes the initial step of the mitochondrial fatty acid beta-oxidation pathway. The ACADS gene associated with short-chain acyl-coenzyme A dehydrogenase deficiency.

ACADL

Acyl-CoA dehydrogenase, long chain is a protein that in humans is encoded by the ACADL gene.

HADHA

Trifunctional enzyme subunit alpha, mitochondrial also known as hydroxyacyl-CoA dehydrogenase/3-ketoacyl-CoA thiolase/enoyl-CoA hydratase, alpha subunit is a protein that in humans is encoded by the HADHA gene. Mutations in HADHA have been associated with trifunctional protein deficiency or long-chain 3-hydroxyacyl-coenzyme A dehydrogenase deficiency.

HADHB

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.

Electron-transferring-flavoprotein dehydrogenase

Electron-transferring-flavoprotein dehydrogenase is an enzyme that transfers electrons from electron-transferring flavoprotein in the mitochondrial matrix, to the ubiquinone pool in the inner mitochondrial membrane. It is part of the electron transport chain. The enzyme is found in both prokaryotes and eukaryotes and contains a flavin and FE-S cluster. In humans, it is encoded by the ETFDH gene. Deficiency in ETF dehydrogenase causes the human genetic disease multiple acyl-CoA dehydrogenase deficiency.

HSD17B10

17-β-Hydroxysteroid dehydrogenase X (HSD10) also known as 3-hydroxyacyl-CoA dehydrogenase type-2 is a mitochondrial enzyme that in humans is encoded by the HSD17B10 gene. Several alternatively spliced transcript variants have been identified, but the full-length nature of only two transcript variants has been determined. Human HSD10 cDNA was cloned from brain (NM_004493), and the resulting protein, a homotetramer, was first characterized as a short chain 3-hydroxyacyl-CoA dehydrogenase (SCHAD). Active sites of this enzyme can accommodate different substrates; 17β-HSD10 is involved in the oxidation of isoleucine, branched-chain fatty acids, and xenobiotics as well as the metabolism of sex hormones and neuroactive steroids.

HSD17B4

D-bifunctional protein (DBP), also known as peroxisomal multifunctional enzyme type 2 (MFP-2), as well as 17β-hydroxysteroid dehydrogenase type IV is a protein that in humans is encoded by the HSD17B4 gene. It's an alcohol oxidoreductase, specifically 17β-Hydroxysteroid dehydrogenase. It is involved in fatty acid β-oxidation and steroid metabolism.

BCKDHA

A 2-oxoisovalerate dehydrogenase subunit alpha, mitochondrial is an enzyme that in humans is encoded by the BCKDHA gene.

ETFA

The human ETFA gene encodes the Electron-transfer-flavoprotein, alpha subunit, also known as ETF-α. Together with Electron-transfer-flavoprotein, beta subunit, encoded by the 'ETFB' gene, it forms the heterodimeric electron transfer flavoprotein (ETF). The native ETF protein contains one molecule of FAD and one molecule of AMP, respectively.

ETFB

The human ETFB gene encodes the Electron-transfer-flavoprotein, beta subunit, also known as ETF-β. Together with Electron-transfer-flavoprotein, alpha subunit, encoded by the 'ETFA' gene, it forms the heterodimeric Electron transfer flavoprotein (ETF). The native ETF protein contains one molecule of FAD and one molecule of AMP, respectively.

BCKDK

Branched chain ketoacid dehydrogenase kinase (BCKDK) is an enzyme encoded by the BCKDK gene on chromosome 16. This enzyme is part of the mitochondrial protein kinases family and it is a regulator of the valine, leucine, and isoleucine catabolic pathways. BCKDK is found in the mitochondrial matrix and the prevalence of it depends on the type of cell. Liver cells tend to have the lowest concentration of BCKDK, whereas skeletal muscle cells have the highest amount. Abnormal activity of this enzyme often leads to diseases such as maple syrup urine disease and cachexia.

ACAD8

Isobutyryl-CoA dehydrogenase, mitochondrial is an enzyme that in humans is encoded by the ACAD8 gene on chromosome 11.

ETFDH

Electron transfer flavoprotein-ubiquinone oxidoreductase, mitochondrial is an enzyme that in humans is encoded by the ETFDH gene. This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain.

ACAD9

Acyl-CoA dehydrogenase family member 9, mitochondrial is an enzyme that in humans is encoded by the ACAD9 gene. Mitochondrial Complex I Deficiency with varying clinical manifestations has been associated with mutations in ACAD9.

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000196177 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000030861 - 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. ↑ 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 (Nov 2000). "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. doi:10.1086/303105. PMC   1288551 . PMID   11013134.
  6. ↑ Arden KC, Viars CS, Fu K, Rozen R (Feb 1995). "Localization of short/branched chain acyl-CoA dehydrogenase (ACADSB) to human chromosome 10". Genomics. 25 (3): 743–5. doi:10.1016/0888-7543(95)80023-f. PMID   7759115.
  7. ↑ Rozen R, Vockley J, Zhou L, Milos R, Willard J, Fu K, Vicanek C, Low-Nang L, Torban E, Fournier B (Nov 1994). "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. doi:10.1006/geno.1994.1617. PMID   7698750.
  8. ↑ He M, Burghardt TP, Vockley J (Sep 2003). "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. doi: 10.1074/jbc.M306882200 . PMID   12855692.
  9. ↑ "Entrez Gene: acyl-CoA dehydrogenase, short/branched chain".
  10. 1 2 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 (Nov 2000). "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. doi:10.1086/303105. PMC   1288551 . PMID   11013134.
  11. ↑ Sass JO, Ensenauer R, Röschinger W, Reich H, Steuerwald U, Schirrmacher O, Engel K, Häberle J, Andresen BS, Mégarbané A, Lehnert W, Zschocke J (Jan 2008). "2-Methylbutyryl-coenzyme A dehydrogenase deficiency: functional and molecular studies on a defect in isoleucine catabolism". Molecular Genetics and Metabolism. 93 (1): 30–5. doi:10.1016/j.ymgme.2007.09.002. PMID   17945527.
  12. ↑ 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 (Feb 2006). "Short/branched-chain acyl-CoA dehydrogenase deficiency due to an IVS3+3A>G mutation that causes exon skipping". Human Genetics. 118 (6): 680–90. doi:10.1007/s00439-005-0070-4. PMID   16317551. S2CID   22861705.
  13. ↑ Alfardan J, Mohsen AW, Copeland S, Ellison J, Keppen-Davis L, Rohrbach M, Powell BR, Gillis J, Matern D, Kant J, Vockley J (Aug 2010). "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. doi:10.1016/j.ymgme.2010.04.014. PMC   2906669 . PMID   20547083.
  14. ↑ 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 (Jun 2000). "2-Methylbutyryl-coenzyme A dehydrogenase deficiency: a new inborn error of L-isoleucine metabolism". Pediatric Research. 47 (6): 830–3. doi: 10.1203/00006450-200006000-00025 . PMID   10832746.
  15. ↑ 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 (Jan 2007). "Association of genetic polymorphisms of ACADSB and COMT with human hypertension". Journal of Hypertension. 25 (1): 103–10. doi:10.1097/HJH.0b013e3280103a40. PMID   17143180. S2CID   40885244.

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