Disease relevance of ACAD8

• We have used expression in Escherichia coli to produce a previously uncharacterized ACD-like sequence (ACAD8) and define its substrate specificity [1].

High impact information on ACAD8

• 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 [2].
• Isobutyryl-CoA dehydrogenase (IBD) is involved in the catabolism of valine and catalyzes the conversion of isobutyryl-CoA to methacrylyl-CoA [3].
• IBD has a shorter and wider substrate-binding cavity relative to short-chain acyl-CoA dehydrogenase, permitting the optimal binding of the isobutyryl-CoA substrate [3].
• The dramatic lateral expansion of the binding cavity seen in isovaleryl-CoA dehydrogenase is not observed in IBD [3].
• The overall structure of IBD is similar to those of previously determined acyl-CoA dehydrogenases and consists of an NH2-terminal alpha-helical domain, a medial beta-strand domain and a C-terminal alpha-helical domain [3].

Biological context of ACAD8

• Molecular genetic analysis revealed seven new rare variations in the IBD gene (c.348C>A, c.400G>T, c.409G>A, c.455T>C, c.958G>A, c.1000C>T and c.1154G>A) [4].
• Functional studies in isolated mitochondria demonstrated that the IBD variations present in the Danish newborn (c.409G>A and c.958G>A) together with a previously published IBD variation (c.905G>A) disturbed protein folding and reduced the levels of correctly folded IBD tetramers [4].

Anatomical context of ACAD8

• Amplified ACAD8 cDNA made from patient fibroblast mRNA was homozygous for a single nucleotide change (905G>A) in the ACAD8 coding region compared to the sequence from control cells [1].

Associations of ACAD8 with chemical compounds

• 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 [2].
• These data confirm further the presence of a separated ACD in humans specific to valine catabolism (isobutyryl-CoA dehydrogenase, IBDH), along with the first enzymatic and molecular confirmation of a deficiency of this enzyme in a patient [1].
• Isobutyryl-CoA dehydrogenase deficiency in a fourth infant was confirmed after isolated elevation of C4-carnitine in the acylcarnitine profile [5].
• We show that methylmalonyl-CoA mutase, an R-specific crotonase, isobutyryl-CoA dehydrogenase, and a GTPase are involved in glyoxylate regeneration [6].
• Since then, three infants with short-chain acyl-CoA dehydrogenase (SCAD) and one with isobutyryl-CoA dehydrogenase deficiency were detected on the basis of elevated butyrylcarnitine/isobutyrylcarnitine (C4-carnitine) concentrations in newborn blood spots analyzed by tandem mass spectrometry [5].

Other interactions of ACAD8

• 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 [2].

References