Mycobacterium tuberculosis IMPDH in complexes with substrates, products and antitubercular compounds

Magdalena Makowska-Grzyska, Youngchang Kim, Suresh Kumar Gorla, Yang Wei, Kavitha Mandapati, Minjia Zhang, Natalia Maltseva, Gyan Modi, Helena I. Boshoff, Minyi Gu, Courtney Aldrich, Gregory D. Cuny, Lizbeth Hedstrom, Andrzej Joachimiak

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

Tuberculosis (TB) remains a worldwide problem and the need for new drugs is increasingly more urgent with the emergence of multidrug- and extensively-drug resistant TB. Inosine 5′-monophosphate dehydrogenase 2 (IMPDH2) from Mycobacterium tuberculosis (Mtb) isan attractive drug target. The enzyme catalyzes the conversion of inosine 5′-monophosphate into xanthosine 5′-monophosphate with the concomitant reduction of NAD+ to NADH. This reaction controls flux into the guanine nucleotide pool. We report seventeen selective IMPDH inhibitors with antitubercular activity. The crystal structures of a deletion mutant of MtbIMPDH2 in the apo form and in complex with the product XMP and substrate NAD+ are determined. We also report the structures of complexes with IMP and three structurally distinct inhibitors, including two with antitubercular activity. These structures will greatly facilitate the development of MtbIMPDH2-targeted antibiotics.

Original languageEnglish (US)
Article numbere0138976
JournalPloS one
Volume10
Issue number10
DOIs
StatePublished - Oct 6 2015

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© 2015, Public Library of Science. All rights reserved. This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.

Copyright:
Copyright 2015 Elsevier B.V., All rights reserved.

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