title: Validation of a homology model of Mycobacterium tuberculosis DXS: rationalization of observed activities of thiamine derivatives as potent inhibitors of two orthologues of DXS.
abstract: The enzyme DXS catalyzes the first, rate-limiting step of the 2-C-methyl-d-erythritol-4-phosphate (MEP, 1) pathway using thiamine diphosphate (ThDP) as cofactor; the DXS-catalyzed reaction constitutes also the first step in vitamin B1 and B6 metabolism in bacteria. DXS is the least studied among the enzymes of this pathway in terms of crystallographic information, with only one complete crystal structure deposited in the Protein Data Bank (Deinococcus radiodurans DXS, PDB: ). We synthesized a series of thiamine and ThDP derivatives and tested them for their biochemical activity against two DXS orthologues, namely D. radiodurans DXS and Mycobacterium tuberculosis DXS. These experimental results, combined with advanced docking studies, led to the development and validation of a homology model of M. tuberculosis DXS, which, in turn, will guide medicinal chemists in rationally designing potential inhibitors for M. tuberculosis DXS.
authors.affiliation: Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG Groningen, The Netherlands. a.k.h.hirsch@rug.nl.
authors.forename: T
authors.initials: T
authors.lastname: Masini
authors.forename: B
authors.initials: B
authors.lastname: Lacy
authors.forename: L
authors.initials: L
authors.lastname: Monjas
authors.forename: D
authors.initials: D
authors.lastname: Hawksley
authors.forename: A R
authors.initials: AR
authors.lastname: de Voogd
authors.forename: B
authors.initials: B
authors.lastname: Illarionov
authors.forename: A
authors.initials: A
authors.lastname: Iqbal
authors.forename: F J
authors.initials: FJ
authors.lastname: Leeper
authors.forename: M
authors.initials: M
authors.lastname: Fischer
authors.forename: M
authors.initials: M
authors.lastname: Kontoyianni
authors.forename: A K H
authors.initials: AK
authors.lastname: Hirsch
mesh_terms: D034301:Deinococcus / Q000737:chemistry / Q000201:enzymology; D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D062105:Molecular Docking Simulation; D009169:Mycobacterium tuberculosis / Q000737:chemistry / Q000187:drug effects / Q000201:enzymology*; D011487:Protein Conformation; D040681:Structural Homology, Protein; D013831:Thiamine / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014166:Transferases / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D014376:Tuberculosis / Q000188:drug therapy / Q000382:microbiology
chemical_list: D004791:Enzyme Inhibitors; D014166:Transferases; C109461:deoxyxylulose-5-phosphate synthase; D013831:Thiamine