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

• The absorption coefficient of butyryl-CoA dehydrogenase from Megasphaera elsdenii at 450 nm is determined as 14.4 mM-1 X cm-1 in the CoA-free form and 14.2 mM-1 X cm-1 in the CoA-liganded form (both yellow) [9].
• Lipoamide dehydrogenase from Azotobacter vinelandii and butyryl-CoA dehydrogenase from Megasphaera elsdenii are selected to demonstrate the usefulness of the method [10].
• Electron-transferring flavoprotein (ETF), its redox partner flavoproteins, i.e., D-lactate dehydrogenase and butyryl-CoA dehydrogenase, and another well-known flavoprotein, flavodoxin, were purified from the same starting cell paste of an anaerobic bacterium, Megasphaera elsdenii [11].
• Butyryl-CoA, crotonyl-CoA or 3-hydroxybutyryl-CoA all ultimately form an enzyme-acetoacetyl-CoA complex upon aerobic addition to butyryl-CoA dehydrogenase purified from Megasphaera elsdenii, implying the presence of crotonase activity [12].

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 1.3.99.2) 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 1.3.99.2] 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

• Labeling fibroblast cultures with [35S]-methionine followed by immunoprecipitation with anti-SCAD antibody revealed that a normal size variant SCAD protein was synthesized [14].
• In all of the three SCAD-deficient cell lines, the size of variant SCAD mRNA as determined by Northern blotting using one of the normal SCAD cDNA as a probe was also normal, and no difference was observed on Southern blots in the restriction patterns of mutant genomic DNA using EcoRI, TaqI, HincII, and BamHI [14].
• To characterize the biochemical consequences of these variations, in vitro site-directed mutagenesis and prokaryotic expression were used to produce the corresponding SCAD variant proteins [20].
• To substantiate this notion we performed sequence analysis of the SCAD gene in 10 patients with ethylmalonic aciduria and diagnosed with SCAD deficiency in fibroblasts [21].
• Using fluorescence in-situ hybridization, we confirm the localization of the human SCAD gene to the distal part of Chromosome (Chr) 12 and suggest that the SCAD gene is a single-copy gene [1].

References