ACAD8 Human
Description
Gene Overview
The ACAD8 gene (OMIM #604773) is located on chromosome 11q25 and spans 11 exons. It encodes a 415-amino acid mitochondrial enzyme involved in the third step of valine breakdown, converting isobutyryl-CoA to methylacrylyl-CoA . The enzyme functions as a homotetramer and shares structural similarities with other acyl-CoA dehydrogenases, including an N-terminal α-helical domain and a central β-strand domain .
Enzyme Characteristics
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Catalytic Role: ACAD8 specifically targets isobutyryl-CoA in valine catabolism, requiring electron transfer flavoprotein (ETF) as a cofactor .
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Recombinant Form: Recombinant ACAD8 (45.1 kDa) produced in E. coli retains biochemical activity and is stabilized in Tris-HCl buffer with 30% glycerol .
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Structural Features: Key conserved residues include an active site glutamic acid and tetramer-stabilizing regions .
Isobutyryl-CoA Dehydrogenase Deficiency (IBDD)
IBDD is an autosomal recessive disorder caused by ACAD8 mutations. Key findings include:
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Mutation Spectrum: Over 46 unique ACAD8 variants reported globally, including missense, frameshift, and splicing mutations . Six novel variants (e.g., c.911A>T, c.1166G>A) were recently identified .
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Biochemical Markers: Elevated C4 (butyrylcarnitine) levels in blood and ethylmalonic acid in urine are diagnostic hallmarks .
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Clinical Variability: Most patients are asymptomatic, but 20–30% exhibit mild symptoms such as growth retardation, cardiomyopathy, or developmental delays .
Table 1: Common ACAD8 Mutations and Clinical Outcomes
Research Advancements
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Screening Programs: Tandem mass spectrometry (MS/MS) and urine GC-MS have improved IBDD detection in newborns, with a prevalence of ~1:30,000 in some cohorts .
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Functional Studies: Mutations like c.553C>T reduce enzyme activity by >90%, correlating with severe metabolic dysfunction .
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Case Studies: A 2022 study of 10 IBDD patients revealed novel variants and highlighted the role of heterozygous carriers in population-level risk .
Therapeutic and Diagnostic Implications
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Management: Asymptomatic cases require monitoring, while symptomatic patients benefit from protein-restricted diets and carnitine supplementation .
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Genetic Testing: Targeted sequencing panels and Sanger verification are critical for confirming ACAD8 mutations .
Unresolved Questions
Product Specs
Product Science Overview
ACAD8 is a mitochondrial enzyme that is involved in the catabolism of the branched-chain amino acid valine. It specifically catalyzes the conversion of 2-methylpropanoyl-CoA to (2E)-2-methylpropenoyl-CoA in the valine catabolic pathway . To a lesser extent, it can also catalyze the oxidation of (2S)-2-methylbutanoyl-CoA .
The human recombinant form of ACAD8 is produced in Escherichia coli and is a single, non-glycosylated polypeptide chain containing 416 amino acids (23-415) with a molecular mass of 45.1 kDa . It is fused to a 23 amino acid His-tag at the N-terminus and purified using proprietary chromatographic techniques .
The human recombinant form of ACAD8 is used in various research applications to study its role in fatty acid and amino acid metabolism. It is also used to investigate the molecular mechanisms underlying isobutyryl-CoA dehydrogenase deficiency and to develop potential therapeutic interventions.
