nonmevalonate

Nonmevalonate pathway, also called the methylerythritol phosphate (MEP) pathway, is an alternative route to isoprenoid biosynthesis found in many bacteria, algae, apicomplexan parasites, and plant plastids. It provides the universal isoprenoid precursors isopentenyl pyrophosphate (IPP) and dimethylallyl pyrophosphate (DMAPP) without using the mevalonate pathway.

The pathway begins with pyruvate and glyceraldehyde-3-phosphate and proceeds through a series of enzymatic steps catalyzed by DXS, DXR, IspD, IspE, IspF, IspG, and IspH. The first step forms 1-deoxy-D-xylulose-5-phosphate (DXP); DXR converts DXP to 2-C-methyl-D-erythritol-4-phosphate (MEP). IspD converts MEP to CDP-ME; IspE phosphorylates to CDP-MEP; IspF cyclizes to MEcPP; IspG reduces MEcPP to HMBPP; IspH then reduces HMBPP to IPP and DMAPP. IPP and DMAPP feed into the synthesis of a wide range of isoprenoids, including quinones, carotenoids, sterols, and prenylated compounds.

Biological significance and applications: The MEP pathway is widespread in many bacteria and in the plastids of plants, as well as in certain algae and parasites. Humans and other animals lack this pathway, relying instead on the mevalonate pathway, which makes the nonmevalonate route an attractive target for antimicrobial and antiparasitic drug development. Inhibitors such as fosmidomycin target DXR and have shown activity against malaria and other infections, illustrating the pathway’s potential for selective therapeutics.