Mevalonate
The mevalonate pathway, both the main trunk and its various branch points, has been the subject of intense biochemical and chemical research activity. There are several reasons for this interest. First, the wide variety of biologically important metabolites, which play a role in many cellular functions, naturally leads to research in this area. The development of hydroxymethylglutaryl-CoA reductase inhibitors as powerful pharmaceutical agents which lower blood cholesterol levels and decrease the rates of heart disease relies in part on our knowledge of the role of the pathway in cholesterol biosynthesis. The discovery of protein prenylation as a necessary step in the activation of Ras oncogene products spurred intense pharmaceutical interest in protein prenyltransferase inhibitors as potential novel anticancer agents. Inhibition of enzymes in the mevalonate pathway has also proved to be an effective route to the development of antifungal agents useful in human and animal therapeutics and in other agrochemical applications.
The novel and complex chemical structures produced by some of the later enzymes in the mevalonate pathway has provided impetus for research in this field. In particular, the study of the elegant cyclization/rearrangement cascade catalyzed by oxidosqualene cyclase was a key driver in the development of the field of bioorganic chemistry. A further driving force for the study of enzymes in the mevalonate pathway has been the novel chemical mechanism utilized by the majority of them. Almost all other enzymes that form carbon–carbon bonds do so through intermediates that are, at least formally, carbanions. However, most enzymes in the mevalonate pathway carry out their transformations through carbocationic intermediates. The unusual chemistry catalyzed by enzymes in the mevalonate pathway and the associated prenyltransferases and cyclases was developed in large part through the use of labeled isoprenoid variants, and isoprenoid analogs. Some key examples of this elegant work come from the work of Poulter (studies on FPP synthase and squalene synthase , Croteau (studies on monoterpene cyclases, Cane (studies on sesquiterpene cyclases, and Prestwich (studies on oxidosqualene cyclase and related enzymes. A particularly noteworthy example is the elegant physical-organic chemistry studies of Poulter, using fluorinated substrate analogs, that confirmed the carbocationic nature of the reaction catalyzed by FPP synthase. This work was a natural precursor to the use of isoprenoid derivatives as chemical probes for protein prenylation. Understanding of both the enzymatic mechanism of prenyl transfer, and these studies are described in the following sections of this review.
The mevalonate pathway leads to the synthesis of sterols and isoprenoids that are shown to be crucial for tumor-growth. Multiple enzymes of this pathway are recognized to be essential for proliferation and survival of various types of cancer cells. The first committed step of the mevalonate pathway is conversion of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) to mevalonic acid (mevalonate) by HMG-CoA reductase (HMGCR). In the next step of the pathway mevalonate is metabolized to isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP). Farnesyl pyrophosphate synthase catalyzes sequential condensation reactions of DMAPP with two units of IPP to form farnesyl pyrophosphate (FPP) and geranylgeranyl pyrophosphate