Biochemistry of the non-mevalonate isoprenoid pathway

Abstract

The non-mevalonate pathway of isoprenoid (terpenoid) biosynthesis is essential in many eubacteria including the major human pathogen, Mycobacterium tuberculosis, in apicomplexan protozoa including the Plasmodium spp. causing malaria, and in the plastids of plants. The metabolic route is absent in humans and is therefore qualified as a promising target for new anti-infective drugs and herbicides. Biochemical and structural knowledge about all enzymes involved in the pathway established the basis for discovery and development of inhibitors by high-throughput screening of compound libraries and/or structure-based rational design.

Transcriptomic Analysis Reveals Evidence for a Cryptic Plastid in the Colpodellid Voromonas pontica, a Close Relative of Chromerids and Apicomplexan Parasites

“…Isoprenoids are assembled from two basic building blocks, isopentyl diphosphate (IPP) and its isomer dimethylallyl diphosphate (DMAPP), both of which are synthesized via one of two distinct pathways, the mevalonate (MVA) pathway, and the non-mevalonate or methylerythretol pathway (MEP) [78]. The distribution of these two pathways appears to be quite complex in bacteria, where one, both, or neither pathway may be present with little regard to phylogenetic affinity.…”

Advances in Antimalarial Drug Evaluation and New Targets for Antimalarials

“…In P. falciparum, it maintains a 35-kb circular genome and several particular biochemical pathways that are present in bacteria and plants but are absent in humans, thus providing many attractive targets that are extensively investigated for drug development. These pathways include the type II fatty acid biosynthesis pathway, which involves 6 distinct enzymes in Plasmodium while in human the type I fatty acid biosynthesis pathway involves a multifunctional enzyme, the 1-deoxy D xylulose 5 phosphate (DOXP) isoprenoid biosynthesis pathway that is mevalonateindependent in the malaria parasite contrary to humans, and apicoplast replication, transcription and translation which involve enzymes of bacterial origins (Dahl & Rosenthal, 2008, Goodman & McFadden, 2007, Grawert et al, 2011, Jayabalasingham et al, 2010. Pioneering works led to the emergence of promising antimalarials such as triclosan (believed to target the NADH-dependent enoyl ACP reductase or FabI enzyme), thiolactomycin (targeting FabH and FabB enzymes) and fosmidomycin (targeting the DOXP reductoisomerase) to name the main ones.…”

Downstream reactions and engineering in the microbially reconstituted pathway for Taxol

“…Isoprenoid biosynthesis substrates can be derived from one of two pathways, and both have been used in previous heterologous settings. The mevalonate (MVA) pathway, native to S. cerevisiae, begins with acetyl-CoA (Bloch 1992;Miziorko 2011); whereas, the alternative methylerythritol phosphate (MEP) pathway, native to E. coli, begins with a molecule each of pyruvate and glyceraldehyde 3-phosphate (Grawert et al 2011;Rohmer 1999). These substrates can be linked to primary metabolic pathways that must be re-routed when triggered (either natively or heterologously) for isoprenoid biosynthesis.…”