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

Abstract

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.

Short-chain polyisoprenoids in the yeast Saccharomyces cerevisiae — New companions of the old guys

“…These results correlate with reduction of expression of RER2 and SEC59 genes in yeast cells treated with statins [39]. Moreover, oral administration of mevinolin (lovastatin) to rats…”

Morphological and Molecular Differentiation of Sporidiobolus johnsonii ATCC 20490 and Its Coenzyme Q10 Overproducing Mutant Strain UF16

“…In yeasts, the isoprene units of CoQ 10 are derived from mevalonate (isoprenoid) pathway [44]. Statins are competitive inhibitors of HMG-CoA reductase, which catalyses the conversion of HMG-CoA to mevalonate, a rate-limiting step in isoprenoid biosynthetic pathway involved in synthesis of CoQ 10 [18,45]. Enhanced production of CoQ 10 in Schizosaccharomyces pombe have been reported by overexpressing HMG-CoA reductase gene and induction with arachidonic acid [46].…”

“…Improving the yields of CoQ 10 in S. johnsonii would be beneficial so as to take the advantage of having more biomass production in yeast fermentation. Additionally, yeasts like S. johnsonii becomes a promising source of natural CoQ 10 derived from eukaryote kingdom having high degree of conservation with mammalian system and its biosynthetic pathways [18]. During strain improvement program on this strain, the improved mutant strain EA22 was previously generated by EMS mutagenesis followed by rational selection [19] on atorvastatin (20 lg ml -1 ) [17].…”

Saccharomyces cerevisiae as a tool for mining, studying and engineering fungal polyketide synthases

“…However, the advantages of S. cerevisiae have allowed increased understanding of fungal polyketide pathways and biosynthesis (Tsunematsu et al, 2013). For example, of the polyketides in Figure 1, the lovastatin and brefeldin A biosynthetic pathways were identified using heterologous yeast expression (Barriuso et al, 2011; Ma et al, 2009; Zabala et al, 2014), and the effects of statins, brefeldin A, mycophenolic acid, and griseofulvin have all been studied in yeast (Athlin et al, 1987; Desmoucelles et al, 2002; Kuranda et al, 2010; Leszczynska et al, 2009; Maciejak et al, 2013; Shah and Klausner, 1993). Aflatoxin pathway genes have been expressed heterologously in yeast in order to study aflatoxin biosynthesis, and its mode of action has also been studied using yeast (Fasullo et al, 2008; Kelly et al, 2002; Yabe et al, 2012).…”