European journal of clinical investigation · 2001
Fibroblast studies documenting a case of peroxisomal 2-methylacyl-CoA racemase deficiency: possible link between racemase deficiency and malabsorption and vitamin K deficiency.
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Van Veldhoven P P, Meyhi E, Squires R H, Fransen M, Fournier B, Brys V, Bennett M J, Mannaerts G P
Аннотация
BACKGROUND: 2-Methylacyl-CoA racemase interconverts the 2-methyl group of pristanoyl-CoA or the 25-methyl group of hydroxylated cholestanoyl-CoAs, allowing further peroxisomal desaturation of these compounds in man by the branched chain acyl-CoA oxidase, which recognise only the S-isomers. Hence, oxidation studies in fibroblasts, currently based on the use of racemic substrates such as [1-14C] pristanic acid, do not allow us to distinguish between a deficient racemase or an impaired oxidase.
DESIGN: To evaluate the racemase activity directly, the 2R-isomer of[1-14C] pristanic acid, as well as the 2R-isomer of 2-methyl-[1-14C] hexadecanoic, a synthetic pristanic acid substitute, were prepared and their degradation by cultured human skin fibroblasts was compared to that of the racemic substrates.
RESULTS: In fibroblasts in a young girl, presenting with elevated urinary levels of trihydroxycholestanoic acid metabolites but normal plasma levels of very long chain fatty acids, a partial deficient degradation of racemic [1-14C] pristanic acid was observed. Incorporation of 2R-[1-14C] pristanic acid in glycerolipids of the patient's fibroblasts proceeded normally, but breakdown was impaired. Similar findings were seen with the 2R-isomer of 2-methyl-[1-14C] hexadecanoic. These data, combined with the fact that the branched chain acyl-CoA oxidase, catalyzing the first oxidation step of pristanic acid and bile acid intermediates in man, appeared normal, suggested a peroxisomal beta-oxidation defect in the patient at the level of 2-methylacyl-CoA racemase.
CONCLUSION: Carboxy-labelled 2R-methyl branched chain fatty acids might be useful tools to document cases of racemase deficiencies. Because a brother of the patient died with a diagnosis of vitamin K deficiency, an impaired racemase might be responsible for other cases of unexplicable malabsorption.
DESIGN: To evaluate the racemase activity directly, the 2R-isomer of[1-14C] pristanic acid, as well as the 2R-isomer of 2-methyl-[1-14C] hexadecanoic, a synthetic pristanic acid substitute, were prepared and their degradation by cultured human skin fibroblasts was compared to that of the racemic substrates.
RESULTS: In fibroblasts in a young girl, presenting with elevated urinary levels of trihydroxycholestanoic acid metabolites but normal plasma levels of very long chain fatty acids, a partial deficient degradation of racemic [1-14C] pristanic acid was observed. Incorporation of 2R-[1-14C] pristanic acid in glycerolipids of the patient's fibroblasts proceeded normally, but breakdown was impaired. Similar findings were seen with the 2R-isomer of 2-methyl-[1-14C] hexadecanoic. These data, combined with the fact that the branched chain acyl-CoA oxidase, catalyzing the first oxidation step of pristanic acid and bile acid intermediates in man, appeared normal, suggested a peroxisomal beta-oxidation defect in the patient at the level of 2-methylacyl-CoA racemase.
CONCLUSION: Carboxy-labelled 2R-methyl branched chain fatty acids might be useful tools to document cases of racemase deficiencies. Because a brother of the patient died with a diagnosis of vitamin K deficiency, an impaired racemase might be responsible for other cases of unexplicable malabsorption.