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.

The expression of TwDXS in the MEP pathway specifically affects the accumulation of triptolide

“…The DXS gene encodes the first rate‐limiting enzyme in the plant MEP pathway (Carretero‐Paulet et al ), and it has become a new target for antimalarial and antibacterial drugs (Singh et al , Masini et al ). A snapshot of the conformational dynamics of DXS exhibited three regions near the active center (spanning residues 42–58, 183–199, and 278–298) displaying both EX1 (monomolecular) and EX2 (bimolecular) H/D exchange (HDX) kinetic behavior in both ligand‐free and ligand‐bound states (Zhou et al ).…”

Challenges and Hallmarks of Establishing Alkylacetylphosphonates as Probes of Bacterial 1-Deoxy-d-xylulose 5-Phosphate Synthase

“…1−3,12−16 In part, this is due to the challenge of selectively targeting a bacterial ThDP-dependent enzyme. However, there is mounting evidence to suggest DXP synthase is unique among ThDP-dependent enzymes.…”

Hit-optimization using target-directed dynamic combinatorial chemistry: development of inhibitors of the anti-infective target 1-deoxy-d-xylulose-5-phosphate synthase

“…Despite substantial efforts dedicated to the discovery of inhibitors for DXPS, to date, very few active compounds are known, which fulll the requirements as an ideal candidate for further development. [13][14][15][16][17] The scarcity of inhibitors and X-ray crystal structures of the antiinfective target DXPS makes tdDCC a particularly attractive approach for the discovery of new inhibitors.…”