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

BMC Biotechnology

Agata Maciejak¹  Agata Leszczynska¹  Ilona Warchol¹  Monika Gora¹  Joanna Kaminska¹  Danuta Plochocka¹  Monika Wysocka-Kapcinska¹  Dorota Tulacz¹  Joanna Siedlecka¹  Ewa Swiezewska¹  Maciej Sojka²  Witold Danikiewicz²  Norbert Odolczyk¹  Anna Szkopinska¹  Grazyna Sygitowicz³  Beata Burzynska¹ 

[1] Institute of Biochemistry and Biophysics, Polish Academy of Sciences, Pawinskiego 5A, 02-106 Warsaw, Poland

[2] Institute of Organic Chemistry, Polish Academy of Sciences, Warsaw, Poland

[3] Department of Biochemistry and Clinical Chemistry, Medical University of Warsaw, Warsaw, Poland

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

Others  :  1089658
DOI  :  10.1186/1472-6750-13-68

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

【 摘 要 】

Background

The 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.

Results

Statins 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.

Conclusion

Statins 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】

   
2013 Maciejak et al.; licensee BioMed Central Ltd.

【 图 表 】

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