Statins prenylation

Prenylation has been implicated in the prevention of HIV infection. Statins have been used to inhibit HIV infection by interacting with Rho GTPases and suppress the intercellular adhesion required for viral entry. In another study with statins and HIV the mechanism of action was elucidated. The lypophilic statins... 

Statins were also instrumental in the discovery of protein prenylation. In 1984, Glomset and coworkers used mevinolin (lovastatin) and radiolabeled mevalonate to demonstrate that a product of mevalonate could become posttranslationally incorporated into select proteins [115]. The use of the statin to deplete cells of endogenous mevalonate and downstream isoprenoids enabled sufficient incorporation of the exogenous radiolabeled mevalonate and subsequent detection of the radiolabeled protein fraction. 

Statins, by virtue of their ability to deplete cells of all isoprenoid species downstream of mevalonate, including FPP and GGPP, globally diminish protein prenylation. Submicromolar doses of lovastatin can decrease intracellular FPP and GGPP levels in cultured cells [123] however under those conditions, disruption of protein prenylation is not detected. Work done in cultured cells has demonstrated that relative levels of FPP and GGPP vary amongst cell and tissue type, that disparate concentrations of statin are needed to lower FPP and GGPP levels by equivalent amounts, and that there is a hierarchy with respect to the conservation of prenylation of different prenylated proteins under conditions of mevalonate depletion [123-125] (R.J. Hohl, personal communication). Further studies are needed to better understand the relationship between isoprenoid flux and protein prenylation. 

Prenylation also influences the balance between myocyte viability and apoptosis. Statin-induced apoptosis has been demonstrated in vitro, using myotubes [84], myoblasts [85], and differentiated primary human skeletal muscle cells [86], This effect can be reproduced by geranyl-geranyl-transferase inhibitors, and rescued by replacement of mevalonic acid [84], Compelling evidence suggests that statins cause apoptosis in skeletal muscle by disrupting the prenylation of small G proteins like Rho [85],... 

Rab [87], and Rap [84], For example, statins induce apoptosis at concentrations that suppress the prenylation of Rap la (a 21 kDa GTPase) [84], and Itagaki et al. have shown that this process is accompanied by the redistribution of small G proteins in myoblasts [88], It remains unclear, however, whether the altered prenylation of small G-proteins is necessary and sufficient to produce myopathy in vivo, or whether myocyte apoptosis is first activated by disrupted Ca2+ homeostasis following mitochondrial injury. 

Despite inhibition of HMG-CoA reductase by statins, cells compensate by increasing enzyme expression several fold. However, the total body cholesterol is reduced by 20-40% due to increased expression of LDL-receptors after statin administration this enhances LDL (the major cholesterol carrying lipoprotein) clearance from serum with a net reduction of serum cholesterol (Chapter 20). Individuals who lack functional LDL-receptors (homozygous familial hypercholesterolemia. Chapter 20) do not benefit from statin therapy. However, statin therapy is useful in the treatment of heterozygous familial hypercholesterolemia. Since HMG-CoA reductase plays a pivotal role in the synthesis of many products vital for cellular metabolism, inhibitors of the enzyme may have toxic effects. Monitoring of liver and muscle function may be necessary to detect any toxicity of statin drug therapy. A decreased risk of bone fractures with statin therapy has been observed in subjects age 50 years or older, who are being treated for hypercholesterolemia. The mechanism of action of statins in bone metabolism may involve inhibition of prenylation... 

Figure 10.4 Rab prenylation events are involved in statin-induced muscle toxicity, (a) Co-treatment with statin and GGPP restores ATP levels. However, addition of BMS3, an inhibitor of...

We thus reasoned that if we suppressed the effects of statins on muscle toxicity by co-treatment with GGPP, we could then determine whether Rac/Rho prenylation or Rab prenylation was the important factor by additional treatment with GGTase inhibitors. This experiment revealed that treatment with simvastatin, GGPP, and GGTI-2133 did not decrease ATP levels, but treatment with simvastatin, GGPP, and BMS3 did result in a decrease in cellular ATP levels (Figure 10.4). These results showed that a Rab prenylation event was responsible for statin-induced muscle toxicity. 

This study provides evidence that Rab prenylation is important to statin-induced muscle toxicity, and that it is possible to identify suppressive small molecules that should not inhibit the beneficial effects of statins on blood cholesterol levels. The use of small molecules to dissect biosynthetic pathways is certainly not new, but affords a precise and rapid understanding of the phenotypic consequences of cellular perturbations. For the future, modern chemical biology techniques, including affinity labeling of isoprenoids [11], provide an attractive opportunity to identify the specific Rabs responsible for statin-induced muscle toxicity. As a common laboratory tool compound, G66976 is unlikely to become a clinical candidate. 

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