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Biochemistry and molecular biology
Background: Acyl-CoA thioesterases are enzymes that hydrolyze acyl-CoAs to the free fatty acid and coenzyme A (CoASH). These enzymes have been identified in several cellular compartments and are thought to regulate intracellular levels of acyl-CoAs, free fatty acids and CoASH. However, to date no patients deficient in acyl-CoA thioesterases have been identified. Design: Acyl-CoA thioesterase activity was measured in human skin fibroblasts. Western blot analysis was used to determine Type-II acyl-CoA thioesterase protein levels in patients. Results: Activity was found in human fibroblasts with all saturated acyl-CoAs from C4:0- to C18:0-CoA, with highest activity detected with lauroyl-CoA and myristoyl-CoA (C12:0 and C14:0-CoA). An antibody that recognizes all isoforms of Type-II acyl-CoA thioesterases, precipitated the majority of acyl-CoA thioesterase activity in fibroblasts, showing that the major activity in fibroblasts is catalyzed by Type-II thioesterases. Measurement of acyl-CoA thioesterase activity from fibroblasts of 40 patients with putative fatty acid oxidation disorders resulted in the identification of 3 patients with lowered Type-II acyl- CoA thioesterase activity in fibroblasts. These patients also had lowered expression of Type-II acyl-CoA thioesterase protein in fibroblasts as judged by Western blot analysis. However, mutation analysis failed to identify any mutation in the coding sequences for the mitochondrial acyl-CoA thioesterase II (MTE-II) or the cytosolic acyl-CoA thioesterase II (CTE-II). Conclusions: We have described 3 patients with lowered Type-II acyl-CoA thioesterase protein and activity in human skin fibroblasts, which is the first description of patients with a putative defect in acyl-CoA thioesterases.
Hunt, M., Ruiter, P., Mooyer, C., Van Roermond, T., Ofman, R., Ljlst, L., Wanders, R.: Identification of fatty acid oxidation disorder patients with lowered acyl-CoA thioesterase activity in human skin fibroblasts. European Journal of Clinical Investigation, Vol. 35, (1) 2005, pp. 38–46. doi:10.1111/j.1365-2362.2005.01447.x