AIMS: Statins - inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase - are known to reduce blood cholesterol levels. In this paper, we present a Saccharomyces cerevisiae expression system, which enables quick evaluation of the sensitivity of the wild-type and/or mutant forms of human HMG-CoA reductase towards statins or other drugs. METHODS AND RESULTS: We analysed the sequence of the HMG-CoA reductase gene in DNA extracted from blood samples of 16 patients with cardiovascular disorders. We applied the yeast system to examine the sensitivity of the wild-type and mutated versions of the hHMG-CoA reductase to different types of statins. CONCLUSION: The yeast and mammalian HMG-CoA reductases demonstrate structural and functional conservation, and expression of human HMG-CoA reductase in yeast complements the lethal phenotype of strains lacking the HMG1 and HMG2 genes. SIGNIFICANCE AND IMPACT OF THE STUDY: These data indicate that a yeast expression system can serve to study the influence of selected mutations in human HMG-CoA reductase on the sensitivity of the enzyme to commonly prescribed statins. Our results suggest that this model system is suitable for the development and selection of lipid-lowering drugs as well as for the examination of DNA sequence variations in the context of statin therapy.
AIMS: Statins - inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase - are known to reduce blood cholesterol levels. In this paper, we present a Saccharomyces cerevisiae expression system, which enables quick evaluation of the sensitivity of the wild-type and/or mutant forms of humanHMG-CoA reductase towards statins or other drugs. METHODS AND RESULTS: We analysed the sequence of the HMG-CoA reductase gene in DNA extracted from blood samples of 16 patients with cardiovascular disorders. We applied the yeast system to examine the sensitivity of the wild-type and mutated versions of the hHMG-CoA reductase to different types of statins. CONCLUSION: The yeast and mammalian HMG-CoA reductases demonstrate structural and functional conservation, and expression of humanHMG-CoA reductase in yeast complements the lethal phenotype of strains lacking the HMG1 and HMG2 genes. SIGNIFICANCE AND IMPACT OF THE STUDY: These data indicate that a yeast expression system can serve to study the influence of selected mutations in humanHMG-CoA reductase on the sensitivity of the enzyme to commonly prescribed statins. Our results suggest that this model system is suitable for the development and selection of lipid-lowering drugs as well as for the examination of DNA sequence variations in the context of statin therapy.