The effects of statins on the mevalonic acid pathway in recombinant yeast strains expressing human HMG-CoA reductase

BMC Biotechnology

Research Article

Grazyna Sygitowicz¹  Agata Maciejak²  Monika Wysocka-Kapcinska²  Joanna Kaminska²  Danuta Plochocka²  Dorota Tulacz²  Joanna Siedlecka²  Ilona Warchol²  Monika Gora²  Agata Leszczynska²  Anna Szkopinska²  Beata Burzynska²  Ewa Swiezewska²  Norbert Odolczyk²  Witold Danikiewicz³  Maciej Sojka³ 

[1] Department of Biochemistry and Clinical Chemistry, Medical University of Warsaw, Warsaw, Poland;Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A, 02-106, Warsaw, Poland;Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland;

关键词: HMG-CoA reductase;    Statins;    Yeast expression system;    Heterologous proteins;    Mevalonate pathway;   

DOI  :  10.1186/1472-6750-13-68

 received in 2013-04-03, accepted in 2013-08-29,  发布年份 2013

来源: Springer

【 摘 要 】

BackgroundThe yeast Saccharomyces cerevisiae can be a useful model for studying cellular mechanisms related to sterol synthesis in humans due to the high similarity of the mevalonate pathway between these organisms. This metabolic pathway plays a key role in multiple cellular processes by synthesizing sterol and nonsterol isoprenoids. Statins are well-known inhibitors of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGR), the key enzyme of the cholesterol synthesis pathway. However, the effects of statins extend beyond their cholesterol-lowering action, since inhibition of HMGR decreases the synthesis of all products downstream in the mevalonate pathway. Using transgenic yeast expressing human HMGR or either yeast HMGR isoenzyme we studied the effects of simvastatin, atorvastatin, fluvastatin and rosuvastatin on the cell metabolism.ResultsStatins decreased sterol pools, prominently reducing sterol precursors content while only moderately lowering ergosterol level. Expression of genes encoding enzymes involved in sterol biosynthesis was induced, while genes from nonsterol isoprenoid pathways, such as coenzyme Q and dolichol biosynthesis or protein prenylation, were diversely affected by statin treatment. Statins increased the level of human HMGR protein substantially and only slightly affected the levels of Rer2 and Coq3 proteins involved in non-sterol isoprenoid biosynthesis.ConclusionStatins influence the sterol pool, gene expression and protein levels of enzymes from the sterol and nonsterol isoprenoid biosynthesis branches and this effect depends on the type of statin administered. Our model system is a cheap and convenient tool for characterizing individual statins or screening for novel ones, and could also be helpful in individualized selection of the most efficient HMGR inhibitors leading to the best response and minimizing serious side effects.

【 授权许可】

Unknown   
© Maciejak et al.; licensee BioMed Central Ltd. 2013. This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.