Structure of 4-diphosphocytidyl-2-C-methylerythritol synthetase involved in mevalonate-independent isoprenoid biosynthesis

The YgbP protein of Escherichia coli encodes the enzyme 4-diphosphocytidyl- 2-C-methylerythritol (CDP-ME) synthetase, a member of the cytidyltransferas e family of enzymes. CDP-ME is an intermediate in the mevalonatein-dependen t pathway for isoprenoid biosynthesis in a number of prokaryotic organisms, algae, the plant plastids and the malaria parasite. Because vertebrates sy nthesize isoprenoid precursors using a mevalonate pathway. CDP-ME synthetas e and other enzymes of the mevalonate-independent pathway for isoprenoid pr oduction represent attractive targets for the structure-based design of sel ective antibacterial. herbicidal and antimalarial drugs. The high-resolutio n structures of E. coli CDP-ME synthetase in the apo form and complexed wit h both CTP-Mg2+ and CDP-ME-Mg2+ reveal the stereochemical principles underl ying both substrate and product recognition as well as catalysis in CDP-ME synthetase. Moreover, these complexes represent the first experimental stru ctures for any cytidyltransferase with both substrates and products bound.