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

doi:10.1371/journal.pone.0138976

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Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds

Journal article

Open access

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, …

PloS One, Vol.10(10), pp.e0138976-e0138976

2015

DOI: https://doi.org/10.1371/journal.pone.0138976

PMCID: PMC4594927

PMID: 26440283

Abstract

IMP Dehydrogenase - metabolism

IMP Dehydrogenase - antagonists & inhibitors

IMP Dehydrogenase - chemistry

Mycobacterium tuberculosis - enzymology

Antitubercular Agents - pharmacology

Enzyme Inhibitors - pharmacology

Protein Binding

Antitubercular Agents - metabolism

Binding Sites

IMP Dehydrogenase - genetics

Mycobacterium tuberculosis - drug effects

NAD - metabolism

Biological Sciences

Enzymes

Tuberculosis

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) is an 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.

UN Sustainable Development Goals (SDGs)

This output has contributed to the advancement of the following goals:

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Title: Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds
Creators: Magdalena Makowska-Grzyska - Center for Structural Genomics of Infectious Diseases, University of Chicago, Chicago, IL, United States of America
Youngchang Kim - Center for Structural Genomics of Infectious Diseases, University of Chicago, Chicago, IL, United States of America; Structural Biology Center, Biosciences, Argonne National Laboratory, 9700 S Cass Ave. Argonne, IL, United States of America
Suresh Kumar Gorla - Department of Biology, Brandeis University, 415 South St. Waltham, MA, United States of America
Yang Wei - Department of Biology, Brandeis University, 415 South St. Waltham, MA, United States of America
Kavitha Mandapati - Department of Biology, Brandeis University, 415 South St. Waltham, MA, United States of America
Minjia Zhang - Department of Biology, Brandeis University, 415 South St. Waltham, MA, United States of America
Natalia Maltseva - Center for Structural Genomics of Infectious Diseases, University of Chicago, Chicago, IL, United States of America
Gyan Modi - Department of Biology, Brandeis University, 415 South St. Waltham, MA, United States of America
Helena I Boshoff - Tuberculosis Research Section, National Institute of Allergy and Infectious Diseases, Bethesda, MD, United States of America
Minyi Gu - Center for Structural Genomics of Infectious Diseases, University of Chicago, Chicago, IL, United States of America
Courtney Aldrich - Center for Drug Design, Academic Health Center, University of Minnesota, 516 Delaware St. SE, Minneapolis, MN, United States of America
Gregory D Cuny - Department of Pharmacological and Pharmaceutical Sciences, College of Pharmacy, University of Houston, 549A Science and Research Building 2, Houston, TX, United States of America; Department of Chemistry, Brandeis University, 415 South St. Waltham, MA, United States of America
Lizbeth Hedstrom - Department of Biology, Brandeis University, 415 South St. Waltham, MA, United States of America; Department of Chemistry, Brandeis University, 415 South St. Waltham, MA, United States of America
Andrzej Joachimiak - Center for Structural Genomics of Infectious Diseases, University of Chicago, Chicago, IL, United States of America; Structural Biology Center, Biosciences, Argonne National Laboratory, 9700 S Cass Ave. Argonne, IL, United States of America
Publication Details: PloS One, Vol.10(10), pp.e0138976-e0138976
Publisher: United States
Grant note: HHSN272200700058C / NIAID NIH HHS AI093459 / NIAID NIH HHS R01 AI093459 / NIAID NIH HHS HHSN272201200026C / NIAID NIH HHS
Identifiers: 9923957933101921
Academic Unit: Department of Chemistry; Department of Biology
Language: English
Resource Type: Journal article

Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds

Abstract

UN Sustainable Development Goals (SDGs)

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