title: Mechanism and inhibition of 1-deoxy-D-xylulose-5-phosphate reductoisomerase.
abstract: The non-mevalonate or 2-C-methyl-d-erythritol-4-phosphate (MEP) pathway is responsible for generating isoprenoid precursors in plants, protozoa, and bacteria. Because this pathway is absent in humans, its enzymes represent potential targets for the development of herbicides and antibiotics. 1-Deoxy-d-xylulose (DXP) reductoisomerase (DXR) is a particularly attractive target that catalyzes the pathway's first committed step: the sequential isomerization and NADPH-dependent reduction of DXP to MEP. This article provides a comprehensive review of the mechanistic and structural investigations on DXR, including its discovery and validation as a drug target, elucidation of its chemical and kinetic mechanisms, characterization of inhibition by the natural antibiotic fosmidomycin, and identification of structural features that provide the molecular basis for inhibition of and catalysis.
authors.affiliation: Department of Chemistry, University at Buffalo, Buffalo, NY 14260-3000, United States. Electronic address: amurkin@buffalo.edu.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Murkin
authors.affiliation: Department of Chemistry, University at Buffalo, Buffalo, NY 14260-3000, United States.
authors.forename: Kathryn A
authors.initials: KA
authors.lastname: Manning
authors.affiliation: Department of Chemistry, University at Buffalo, Buffalo, NY 14260-3000, United States.
authors.forename: Svetlana A
authors.initials: SA
authors.lastname: Kholodar
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism*; D000818:Animals; D000900:Anti-Bacterial Agents / Q000494:pharmacology*; D001419:Bacteria / Q000187:drug effects / Q000201:enzymology*; D001424:Bacterial Infections / Q000188:drug therapy / Q000201:enzymology / Q000382:microbiology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005578:Fosfomycin / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D008958:Models, Molecular; D058990:Molecular Targeted Therapy
chemical_list: D000900:Anti-Bacterial Agents; D004791:Enzyme Inhibitors; D005578:Fosfomycin; C024640:fosmidomycin; C114231:1-deoxy-D-xylulose 5-phosphate reductoisomerase; D019747:Aldose-Ketose Isomerases
keywords: 1-Deoxy-d-xylulose 5-phosphate (DXP); DXR; Enzyme mechanism; Fosmidomycin; Kinetic mechanism; Malaria; Reductoisomerase; Tuberculosis