Competence of Thiamin Diphosphate-Dependent Enzymes with 2'-Methoxythiamin Diphosphate Derived from Bacimethrin, a Naturally Occurring Thiamin Anti-vitamin

Biochemistry
Natalia S NemeriaFrank Jordan

Abstract

Bacimethrin (4-amino-5-hydroxymethyl-2-methoxypyrimidine), a natural product isolated from some bacteria, has been implicated as an inhibitor of bacterial and yeast growth, as well as in inhibition of thiamin biosynthesis. Given that thiamin biosynthetic enzymes could convert bacimethrin to 2'-methoxythiamin diphosphate (MeOThDP), it is important to evaluate the effect of this coenzyme analogue on thiamin diphosphate (ThDP)-dependent enzymes. The potential functions of MeOThDP were explored on five ThDP-dependent enzymes: the human and Escherichia coli pyruvate dehydrogenase complexes (PDHc-h and PDHc-ec, respectively), the E. coli 1-deoxy-D-xylulose 5-phosphate synthase (DXPS), and the human and E. coli 2-oxoglutarate dehydrogenase complexes (OGDHc-h and OGDHc-ec, respectively). Using several mechanistic tools (fluorescence, circular dichroism, kinetics, and mass spectrometry), it was demonstrated that MeOThDP binds in the active centers of ThDP-dependent enzymes, however, with a binding mode different from that of ThDP. While modest activities resulted from addition of MeOThDP to E. coli PDHc (6-11%) and DXPS (9-14%), suggesting that MeOThDP-derived covalent intermediates are converted to the corresponding products (albeit wi...Continue Reading

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Citations

Jun 22, 2017·Future Medicinal Chemistry·Robin Matthias GierseAnna Kh Hirsch
May 23, 2018·The Journal of Biological Chemistry·Alicia A DeColliCaren L Freel Meyers
Aug 16, 2017·Proceedings of the National Academy of Sciences of the United States of America·Jieyu ZhouFrank Jordan
Aug 26, 2020·Nature Chemical Biology·Fabian Rabe von PappenheimKai Tittmann
Sep 17, 2019·Biochemistry. Biokhimii︠a︡·V A AleshinV I Bunik

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