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Gene Review

ACADS  -  acyl-CoA dehydrogenase, C-2 to C-3 short...

Homo sapiens

Synonyms: ACAD3, Butyryl-CoA dehydrogenase, SCAD, Short-chain specific acyl-CoA dehydrogenase, mitochondrial
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Disease relevance of ACADS

  • Defects in the SCAD enzyme are associated with failure to thrive, often with neuromuscular dysfunction and elevated urinary excretion of ethylmalonic acid (EMA) [1].
  • Defects of short-chain acylcoenzyme A dehydrogenase (SCAD) may cause a severe metabolic illness in children or a lipid storage myopathy in adults [2].
  • These results suggest that in some patients with multiple acyl-CoA dehydrogenase deficiency riboflavin supplementation may be effective in restoring the activity of SCAD, and possibly of other mitochondrial flavin-dependent enzymes [3].
  • RESULTS: Significantly increased butyryl CoA dehydrogenase activity was found in mucosa from patients with ulcerative colitis (33.2 (28.3, 38.1) mumol/g wet weight/min:mean (95% CI)) compared with activity in mucosa from control patients (24.3 (20.9, 27.7) mumol/g wet weight/min:mean (95% CI)) p < 0.02 [4].
  • The effects of aromatic stacking interactions on the stabilization of reduced flavin adenine dinucleotide (FAD) and substrate/product have been investigated in short-chain acyl-coenzyme A dehydrogenase (SCAD) from Megasphaera elsdenii [5].

Psychiatry related information on ACADS

  • The Wechsler scales data show some evidence for 'ACID' and 'SCAD' profile effects on the subtests, with specifically weak Index scores on Freedom from Distractibility and Processing Speed [6].

High impact information on ACADS

  • The primary amino acid sequence of CsgA exhibits homology with members of the short-chain alcohol dehydrogenase (SCAD) family and several lines of evidence suggest that NAD(P)+ binding is essential for biological activity [7].
  • S135 and K155 are conserved amino acids in the catalytic domain of SCAD members [7].
  • Two distinct mutant alleles of the precursor (p) short chain acyl-CoA dehydrogenase (SCAD) gene were identified in a SCAD-deficient patient (YH2065) using the polymerase chain reaction to amplify cDNA synthesized from total RNA from her fibroblasts [8].
  • Cells from this patient had previously been shown to synthesize a labile variant SCAD in contrast to the normal stability of variant SCADs in two other SCAD-deficient cell lines (Naito, E., Y. Indo, and K. Tanaka. 1989. J. Clin. Invest. 84:1671-1674) [8].
  • These C----T transitions result in the substitution of Arg-22 and Arg-83 of the mature SCAD with Trp and Cys, respectively [8].

Chemical compound and disease context of ACADS


Biological context of ACADS

  • CONCLUSIONS: SCADD is far more common than assumed previously, and clinical symptoms in SCADD are nonspecific, generally uncomplicated, often transient, and not correlated with specific ACADS genotypes [13].
  • These results suggest that the defects in SCAD in these cell lines are caused by a point mutation [14].
  • We conclude that ethylmalonic aciduria, a commonly detected biochemical phenotype, is a complex multifactorial/polygenic condition where, in addition to the emerging role of SCAD susceptibility alleles, other genetic and environmental factors are involved [15].
  • The first SCAD-deficient patient was a compound heterozygote for two mutations, 274G-->T and 529T-->C [15].
  • The SCAD gene is approximately 13 kb in length and consists of 10 exons [1].

Anatomical context of ACADS

  • We also studied mutant human SCAD in cultured skin fibroblasts from three patients with hereditary SCAD deficiency [14].
  • We have now characterized three disease-causing mutations (confirmed by lack of enzyme activity after expression in COS-7 cells) and a new susceptibility variant in the SCAD gene of two patients with SCAD deficiency, and investigated their frequency in patients with elevated EMA excretion [15].
  • In muscle mitochondria, activities of both short-chain acyl-CoA dehydrogenase (SCAD) and medium-chain acyl-CoA dehydrogenase (MCAD) were 35% of normal [3].
  • Antibodies against purified SCAD, MCAD, and electron-transfer flavoprotein were used for detection of cross-reacting material (CRM) in the patient's mitochondria [3].
  • We show an absence of enzyme protein in skeletal muscle, which both confirms the original diagnosis and suggests that the two forms of SCAD deficiency have a different molecular basis [2].

Associations of ACADS with chemical compounds

  • The ACADS genotype showed a statistically significant association with EMA and C4-C levels, but not with clinical characteristics [13].
  • Complementary DNAs encoding the precursor of human placental short chain acyl-coenzyme A (CoA) dehydrogenase (SCAD) (EC were cloned and sequenced [14].
  • In some cases (e.g. SCAD and MCPA-CoA) inhibition was accompanied by flavin bleaching [16].
  • In contrast, mitochondrial butyryl-CoA dehydrogenase [butyryl-CoA: (acceptor) oxidoreductase, EC] activity in these cells was preserved at normal levels [17].
  • A rare disease-associated mutation in the medium-chain acyl-CoA dehydrogenase (MCAD) gene changes a conserved arginine, previously shown to be functionally essential in short-chain acyl-CoA dehydrogenase (SCAD) [18].

Other interactions of ACADS

  • The realization that the effect of the monogene, such as disease-causing mutations in the VLCAD, MCAD, and SCAD genes, may be modified by variations in other genes presages the need for profile analyses of additional genetic variations [19].

Analytical, diagnostic and therapeutic context of ACADS


  1. Structural organization of the human short-chain acyl-CoA dehydrogenase gene. Corydon, M.J., Andresen, B.S., Bross, P., Kjeldsen, M., Andreasen, P.H., Eiberg, H., Kølvraa, S., Gregersen, N. Mamm. Genome (1997) [Pubmed]
  2. Absence of immunoreactive enzyme protein in short-chain acylcoenzyme A dehydrogenase deficiency. Farnsworth, L., Shepherd, I.M., Johnson, M.A., Bindoff, L.A., Turnbull, D.M. Ann. Neurol. (1990) [Pubmed]
  3. Normalization of short-chain acylcoenzyme A dehydrogenase after riboflavin treatment in a girl with multiple acylcoenzyme A dehydrogenase-deficient myopathy. DiDonato, S., Gellera, C., Peluchetti, D., Uziel, G., Antonelli, A., Lus, G., Rimoldi, M. Ann. Neurol. (1989) [Pubmed]
  4. Mucosal enzyme activity for butyrate oxidation; no defect in patients with ulcerative colitis. Allan, E.S., Winter, S., Light, A.M., Allan, A. Gut (1996) [Pubmed]
  5. Role of aromatic stacking interactions in the modulation of the two-electron reduction potentials of flavin and substrate/product in Megasphaera elsdenii short-chain acyl-coenzyme A dehydrogenase. Pellett, J.D., Becker, D.F., Saenger, A.K., Fuchs, J.A., Stankovich, M.T. Biochemistry (2001) [Pubmed]
  6. Monitoring dyslexics' intelligence and attainments: a follow-up study. Thomson, M. Dyslexia (Chichester, England) (2003) [Pubmed]
  7. A tactile sensory system of Myxococcus xanthus involves an extracellular NAD(P)(+)-containing protein. Lee, B.U., Lee, K., Mendez, J., Shimkets, L.J. Genes Dev. (1995) [Pubmed]
  8. Identification of two variant short chain acyl-coenzyme A dehydrogenase alleles, each containing a different point mutation in a patient with short chain acyl-coenzyme A dehydrogenase deficiency. Naito, E., Indo, Y., Tanaka, K. J. Clin. Invest. (1990) [Pubmed]
  9. Butyryl-CoA dehydrogenase from Megasphaera elsdenii. Specificity of the catalytic reaction. Williamson, G., Engel, P.C. Biochem. J. (1984) [Pubmed]
  10. Large-scale preparation and reconstitution of apo-flavoproteins with special reference to butyryl-CoA dehydrogenase from Megasphaera elsdenii. Hydrophobic-interaction chromatography. Van Berkel, W.J., Van den Berg, W.A., Müller, F. Eur. J. Biochem. (1988) [Pubmed]
  11. Purification of electron-transferring flavoprotein from Megasphaera elsdenii and binding of additional FAD with an unusual absorption spectrum. Sato, K., Nishina, Y., Shiga, K. J. Biochem. (2003) [Pubmed]
  12. Intrinsic crotonase activity in a bacterial butyryl-CoA dehydrogenase. Ellison, P.A., Engel, P.C. Biochem. Mol. Biol. Int. (1993) [Pubmed]
  13. Clinical, biochemical, and genetic heterogeneity in short-chain acyl-coenzyme A dehydrogenase deficiency. van Maldegem, B.T., Duran, M., Wanders, R.J., Niezen-Koning, K.E., Hogeveen, M., Ijlst, L., Waterham, H.R., Wijburg, F.A. JAMA (2006) [Pubmed]
  14. Molecular cloning and nucleotide sequence of complementary DNAs encoding human short chain acyl-coenzyme A dehydrogenase and the study of the molecular basis of human short chain acyl-coenzyme A dehydrogenase deficiency. Naito, E., Ozasa, H., Ikeda, Y., Tanaka, K. J. Clin. Invest. (1989) [Pubmed]
  15. Identification of four new mutations in the short-chain acyl-CoA dehydrogenase (SCAD) gene in two patients: one of the variant alleles, 511C-->T, is present at an unexpectedly high frequency in the general population, as was the case for 625G-->A, together conferring susceptibility to ethylmalonic aciduria. Gregersen, N., Winter, V.S., Corydon, M.J., Corydon, T.J., Rinaldo, P., Ribes, A., Martinez, G., Bennett, M.J., Vianey-Saban, C., Bhala, A., Hale, D.E., Lehnert, W., Kmoch, S., Roig, M., Riudor, E., Eiberg, H., Andresen, B.S., Bross, P., Bolund, L.A., Kølvraa, S. Hum. Mol. Genet. (1998) [Pubmed]
  16. Novel methylenecyclopropyl-based acyl-CoA dehydrogenase inhibitor. Broadway, N.M., Engel, P.C. FEBS Lett. (1998) [Pubmed]
  17. Demonstration of a specific mitochondrial isovaleryl-CoA dehydrogenase deficiency in fibroblasts from patients with isovaleric acidemia. Rhead, W.J., Tanaka, K. Proc. Natl. Acad. Sci. U.S.A. (1980) [Pubmed]
  18. A rare disease-associated mutation in the medium-chain acyl-CoA dehydrogenase (MCAD) gene changes a conserved arginine, previously shown to be functionally essential in short-chain acyl-CoA dehydrogenase (SCAD). Andresen, B.S., Bross, P., Jensen, T.G., Winter, V., Knudsen, I., Kølvraa, S., Jensen, U.B., Bolund, L., Duran, M., Kim, J.J. Am. J. Hum. Genet. (1993) [Pubmed]
  19. Mutation analysis in mitochondrial fatty acid oxidation defects: Exemplified by acyl-CoA dehydrogenase deficiencies, with special focus on genotype-phenotype relationship. Gregersen, N., Andresen, B.S., Corydon, M.J., Corydon, T.J., Olsen, R.K., Bolund, L., Bross, P. Hum. Mutat. (2001) [Pubmed]
  20. Purification and characterization of two polymorphic variants of short chain acyl-CoA dehydrogenase reveal reduction of catalytic activity and stability of the Gly185Ser enzyme. Nguyen, T.V., Riggs, C., Babovic-Vuksanovic, D., Kim, Y.S., Carpenter, J.F., Burghardt, T.P., Gregersen, N., Vockley, J. Biochemistry (2002) [Pubmed]
  21. Role of common gene variations in the molecular pathogenesis of short-chain acyl-CoA dehydrogenase deficiency. Corydon, M.J., Vockley, J., Rinaldo, P., Rhead, W.J., Kjeldsen, M., Winter, V., Riggs, C., Babovic-Vuksanovic, D., Smeitink, J., De Jong, J., Levy, H., Sewell, A.C., Roe, C., Matern, D., Dasouki, M., Gregersen, N. Pediatr. Res. (2001) [Pubmed]
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