Isoprenoid biosynthetic pathways as anti-infective drug targets

Abstract

IPP (isopentenyl diphosphate) and DMAPP (dimethylallyl diphosphate) serve as the universal precursors for the biosynthesis of isoprenoids. Besides the well-known mevalonate pathway, the existence of a second biosynthetic pathway conducive to IPP and DMAPP formation through 1-deoxy-D-xylulose 5-phosphate and 2C-methyl-D-erythritol 4-phosphate was discovered approx. 10 years ago in plants and certain eubacteria. It is now known that this pathway is widely distributed in the bacterial kingdom including major human pathogens, such as Mycobacterium tuberculosis and Helicobacter pylori. The pathway is also essential in the malaria vector Plasmodium falciparum. During the last few years, the genes, enzymes, intermediates and mechanisms of the biosynthetic route have been elucidated by a combination of comparative genomics, enzymology, advanced NMR technology and crystallography. The results provide the basis for the development of novel anti-infective drugs.