Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans


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NGUYEN, Tien V., Brage S. ANDRESEN, Thomas J. CORYDON, Sandro GHISLA, Nasser ABD-EL RAZIK, Al-Walid A. MOHSEN, Stephen D. CEDERBAUM, Diane S. ROE, Charles R. ROE, Nicolas J. LENCH, Jerry VOCKLEY, 2002. Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans. In: Molecular Genetics and Metabolism. 77(1-2), pp. 68-79. ISSN 1096-7192

@article{Nguyen2002Ident-7938, title={Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans}, year={2002}, doi={10.1016/S1096-7192(02)00152-X}, number={1-2}, volume={77}, issn={1096-7192}, journal={Molecular Genetics and Metabolism}, pages={68--79}, author={Nguyen, Tien V. and Andresen, Brage S. and Corydon, Thomas J. and Ghisla, Sandro and Abd-El Razik, Nasser and Mohsen, Al-Walid A. and Cederbaum, Stephen D. and Roe, Diane S. and Roe, Charles R. and Lench, Nicolas J. and Vockley, Jerry} }

Mohsen, Al-Walid A. Mohsen, Al-Walid A. Corydon, Thomas J. The acyl-CoA dehydrogenases (ACDs) are a family of related enzymes that catalyze the α,β-dehydrogenation of acyl-CoA esters. Two homologues active in branched chain amino acid metabolism have previously been identified. We have used expression in Escherichia coli to produce a previously uncharacterized ACD-like sequence (ACAD8) and define its substrate specificity. Purified recombinant enzyme had a kcat/Km of 0.8, 0.23, and 0.04 (μM−1 s−1) with isobutyryl-CoA, (S) 2-methylbutyryl-CoA, and n-propionyl-CoA, respectively, as substrates. Thus, this enzyme is an isobutyryl-CoA dehydrogenase. A single patient has previously been described whose fibroblasts exhibit a specific deficit in the oxidation of valine. 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. This encodes an Arg302Gln substitution in the full-length protein (position 280 in the mature protein), a position predicted by molecular modeling to be important in subunit interactions. The mutant enzyme was stable but inactive when expressed in E. coli. It was also stable and appropriately targeted to mitochondria, but inactive when expressed in mammalian cells. 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. Nguyen, Tien V. Abd-El Razik, Nasser Andresen, Brage S. application/pdf Vockley, Jerry Nguyen, Tien V. Roe, Charles R. Corydon, Thomas J. Identification of isobutyryl-CoA dehydrogenase and its deficiency in humans deposit-license Vockley, Jerry Roe, Diane S. Cederbaum, Stephen D. 2011-03-24T17:38:41Z Roe, Charles R. 2002 Ghisla, Sandro Lench, Nicolas J. Lench, Nicolas J. Cederbaum, Stephen D. First publ. in: Molecular Genetics and Metabolism 77 (2002), 1-2, pp. 68-79 Ghisla, Sandro eng Andresen, Brage S. Roe, Diane S. 2011-03-24T17:38:41Z Abd-El Razik, Nasser

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