Disease relevance of ACADSB

• RESULTS: After adjustments for age, body mass index, present illness (hyperlipidaemia, diabetes mellitus), and lifestyle (smoking, alcohol consumption), multivariate logistic regression analysis revealed that -512A>G in ACADSB was associated with hypertension in women (AA vs AG + GG: odds ratio = 0.70, 95% confidence interval = 0.53-0.94) [1].
• In contrast, short/branched-chain acyl-CoA dehydrogenase (SBCAD) and 2-methyl-3-hydroxybutyryl-CoA dehydrogenase (MHBD) deficiencies are recently described and relatively rare defects which present with predominantly neurological manifestations, although acute metabolic decompensation may occur in the early newborn period [2].

High impact information on ACADSB

• In vitro transcription/translation experiments and overexpression in COS cells confirmed the disease-causing nature of the mutant SBCAD protein and showed that ACAD-8 is an isobutyryl-CoA dehydrogenase and that both wild-type proteins are imported into mitochondria and form tetramers [3].
• Our identification of the SBCAD gene structure (11 exons; >20 kb) enabled analysis of genomic DNA [3].
• In conclusion, we report the first mutation in the SBCAD gene, show that it results in an isolated defect in isoleucine catabolism, and indicate that ACAD-8 is a mitochondrial enzyme that functions in valine catabolism [3].
• Site-directed mutagenesis was used to match the human IVD active site with that of potato 2MBCD [4].
• However, recombinant St-IVD1 had maximal activity with 2-methylbutyryl-CoA, which in humans is dehydrogenated by short/branched-chain acyl-CoA dehydrogenase (SBCAD) [4].

Biological context of ACADSB

• Localization of short/branched chain acyl-CoA dehydrogenase (ACADSB) to human chromosome 10 [5].
• Association of genetic polymorphisms of ACADSB and COMT with human hypertension [1].
• After adjustments described above, -512 A>G and -254G>A in ACADSB were associated with variations in systolic blood pressure [1].
• ACADSB was in tight linkage disequilibrium with MGC35392 across a distance of 18.3 kb [1].
• The 2MBCD active site was compared with that of human SBCAD using molecular modeling [4].

Anatomical context of ACADSB

• Southern blot analysis of DNA from a panel of human/rodent somatic cell hybrids localized ACADSB to human chromosome 10, and fluorescence in situ hybridization experiments confirmed the chromosomal assignment and refined the subchromosomal localization to 10q25-q26 [5].
• In vitro oxidation studies in cultured fibroblasts using 13C- and 14C-labeled branched chain amino acids indicated an isolated block in 2-methylbutyryl-CoA dehydrogenase (2-MBCDase) [6].
• These observations suggested that the production of branched chain fatty acids in the Harderian gland of golden hamster is inhibited by testosterone at the step of isovaleryl-CoA dehydrogenase and 2-methyl branched-chain acyl-CoA dehydrogenase[7]

Associations of ACADSB with chemical compounds

• 2-Methylbutyryl-coenzyme A dehydrogenase deficiency: a new inborn error of L-isoleucine metabolism [6].
• Residues Met-361 and Ala-365 of 2MBCD appear to partially substitute for the function of Tyr-380 in human SBCAD, binding the methyl branch linked to C2 of 2-methylbutyryl-CoA, whereas residues Val-88, Val-92, and Val-96 appear to bind the distal C4 methyl group [4].
• Tandem MS analysis of acylcarnitines may reveal elevated C5 (SBCAD) or C5:1 and/or OH-C5 species (MHBD and beta-KT deficiencies) but the abnormalities are non-diagnostic and may be intermittent or absent [2].
• These results and those of other studies suggest that testosterone controls the enzymes isovaleryl acyl-CoA dehydrogenase and 2-methyl branched-chain acyl-CoA dehydrogenase; in the absence of these enzymes, the primers for the synthesis of methyl-branched chain fatty acids are produced [8].
• The enzymatic basis for the metabolism and inhibitory effects of valproic acid: dehydrogenation of valproyl-CoA by 2-methyl-branched-chain acyl-CoA dehydrogenase [9].

Other interactions of ACADSB

• Sequence analysis of candidate ACADs revealed heterozygosity for the common short-chain ACAD A625 variant allele and no mutations in ACAD-8 but a 100-bp deletion in short/branched-chain ACAD (SBCAD) cDNA from the patient [3].

References