The conversion of HMG-CoA to mevalonate by HMG-CoA reductase is the rate-limiting step of cholesterol biosynthesis and is under strict regulatory control (see Figure 1 ). HMGR is the target of compounds that are effective in lowering serum cholesterol levels. Human HMG-CoA reductase consists of a single polypeptide chain of 888 amino acids. The amino-terminal residues are membrane bound and reside in the endoplasmic reticulum membrane, while the catalytic site of the protein resides in its cytoplasmic, soluble carboxy-terminal portion. A linker region connects the two portions of the protein.
The MEP pathway starts with the condensation of pyruvate and D-glyceraldehyde-3-phosphate to 1-deoxy-D-xylulose-5-phosphate (DXP or DOXP). The key isomers DMAPP and IPP are subsequently formed via a series of enzymatic steps starting with the conversion of DXP to 2C-methyl-D-erythritol-4-phosphate (MEP). Enzymes of this MEP pathway are attractive targets for the development of drugs targeting infectious diseases such as malaria and tuberculosis, because this pathway occurs in pathogenic prokaryotes but is absent in human metabolic pathways.