Compared effects of missense mutations in Very-Long-Chain Acyl-CoA Dehydrogenase deficiency: Combined analysis by structural, functional and pharmacological approaches
Autor: | Fatima Djouadi, Stéphanie Gobin-Limballe, Jung-Ja P. Kim, Ryan P. McAndrew, Jean Bastin |
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Jazyk: | angličtina |
Předmět: |
Adult
Fatty acid ß-oxidation Protein Conformation Blotting Western Mutation Missense Biology medicine.disease_cause 3-D modeling VLCAD deficiency Lipid Metabolism Inborn Errors Article Very-Long-Chain-Acyl-CoA Dehydrogenase Very Long-Chain Acyl-CoA Dehydrogenase Deficiency Structure-Activity Relationship Protein structure medicine Missense mutation Humans Structure–function analysis Molecular Biology Skin chemistry.chemical_classification Genetics Mutation Bezafibrate Acyl-CoA Dehydrogenase Long-Chain Fatty Acids Acyl CoA dehydrogenase Pharmacological therapy Fibroblasts Enzyme structure Amino acid Biochemistry chemistry Amino Acid Substitution Case-Control Studies biology.protein Molecular Medicine medicine.drug |
Zdroj: | Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease. (5):478-484 |
ISSN: | 0925-4439 |
DOI: | 10.1016/j.bbadis.2010.01.001 |
Popis: | Very-Long-Chain Acyl-CoA Dehydrogenase deficiency (VLCADD) is an autosomal recessive disorder considered as one of the more common ß-oxidation defects, possibly associated with neonatal cardiomyopathy, infantile hepatic coma, or adult-onset myopathy. Numerous gene missense mutations have been described in these VLCADD phenotypes, but only few of them have been structurally and functionally analyzed, and the molecular basis of disease variability is still poorly understood. To address this question, we first analyzed fourteen disease-causing amino acid changes using the recently described crystal structure of VLCAD. The predicted effects varied from the replacement of amino acid residues lining the substrate binding cavity, involved in holoenzyme–FAD interactions or in enzyme dimerisation, predicted to have severe functional consequences, up to amino acid substitutions outside key enzyme domains or lying on near enzyme surface, with predicted milder consequences. These data were combined with functional analysis of residual fatty acid oxidation (FAO) and VLCAD protein levels in patient cells harboring these mutations, before and after pharmacological stimulation by bezafibrate. Mutations identified as detrimental to the protein structure in the 3-D model were generally associated to profound FAO and VLCAD protein deficiencies in the patient cells, however, some mutations affecting FAD binding or monomer–monomer interactions allowed a partial response to bezafibrate. On the other hand, bezafibrate restored near-normal FAO rates in some mutations predicted to have milder consequences on enzyme structure. Overall, combination of structural, biochemical, and pharmacological analysis allowed assessment of the relative severity of individual mutations, with possible applications for disease management and therapeutic approach. |
Databáze: | OpenAIRE |
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