Leeper Group



Interactions of 2-HEdeazaTPP with DXPS T. Masini, B. Lacy, L. Monjas, D. Hawksley, A. R. de Voogd, B. Illarionov, A. Iqbal, F. J. Leeper, M. Fischer, M. Kontoyianni, A. K. H. Hirsch,
"Validation of a homology model of Mycobacterium tuberculosis DXS: rationalization of activity differences of thiamine derivatives as potent inhibitors of two orthologues of DXS"
Org. Biol. Chem., 2015, 13, 11263–11277. Abstract, Full text.

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: 2O1X). 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.

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Department of Chemistry
University of Cambridge