Inhibition Studies on Enzymes Involved in Isoprenoid Biosynthesis: Focus on Two Potential Drug Targets: DXR and IDI-2 Enzymes

Current Enzyme Inhibition
Jérôme de RuyckC D Poulter

Abstract

Isoprenoid compounds constitute an immensely diverse group of acyclic, monocyclic and polycyclic compounds that play important roles in all living organisms. Despite the diversity of their structures, this plethora of natural products arises from only two 5-carbon precursors, isopentenyl diphosphate (IPP) and dimethylallyl diphosphate (DMAPP). This review will discuss the enzymes in the mevalonate (MVA) and methylerythritol phosphate (MEP) biosynthetic pathways leading to IPP and DMAPP with a particular focus on MEP synthase (DXR) and IPP isomerase (IDI), which are potential targets for the development of antibiotic compounds. DXR is the second enzyme in the MEP pathway and the only one for which inhibitors with antimicrobial activity at pharmaceutically relevant concentrations are known. All of the published DXR inhibitors are fosmidomycin analogues, except for a few bisphosphonates with moderate inhibitory activity. These far, there are no other candidates that target DXR. IDI was first identified and characterised over 40 years ago (IDI-1) and a second convergently evolved isoform (IDI-2) was discovered in 2001. IDI-1 is a metalloprotein found in Eukarya and many species of Bacteria. Its mechanism has been extensively studie...Continue Reading

Citations

Apr 17, 2012·Biochimie·Karine BerthelotFrédéric Peruch
Jan 22, 2019·Chemical Biology & Drug Design·Subhashree Rout, Rajani Kanta Mahapatra
Mar 7, 2014·Acta Crystallographica. Section F, Structural Biology Communications·Jerome de RuyckC Dale Poulter
Jan 8, 2020·Metabolic Engineering Communications·Cheng LiAnthony J Sinskey

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