Functional expression of human HMG-CoA reductase in Saccharomyces cerevisiae: a system to analyse normal and mutated versions of the enzyme in the context of statin treatment.
OBJECTIVE
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.


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.


CONCLUSIONS
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.


CONCLUSIONS
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.
Wysocka-Kapcinska
M
M
Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Warsaw, Poland.
Lutyk-Nadolska
J
J
Kiliszek
M
M
Plochocka
D
D
Maciag
M
M
Leszczynska
A
A
Rytka
J
J
Burzynska
B
B
D002318:Cardiovascular Diseases / Q000188:drug therapy*; D017931:DNA Primers / Q000235:genetics; D005091:Exons; D024243:HMGB1 Protein / Q000235:genetics; D024261:HMGB2 Protein / Q000235:genetics; D006801:Humans; D006903:Hydroxymethylglutaryl CoA Reductases / Q000235:genetics*; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D016297:Mutagenesis, Site-Directed; D016133:Polymerase Chain Reaction; D012441:Saccharomyces cerevisiae / Q000187:drug effects / Q000201:enzymology*
D017931:DNA Primers; D024243:HMGB1 Protein; D024261:HMGB2 Protein; D019161:Hydroxymethylglutaryl-CoA Reductase Inhibitors; D006903:Hydroxymethylglutaryl CoA Reductases