Journal Article

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

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

2015

Overview

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.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Antibiotics / Antitubercular agents / Antitubercular Agents - metabolism / Antitubercular Agents - pharmacology / BASIC BIOLOGICAL SCIENCES / Binding Sites / Biology / Biosynthesis / Complications and side effects / Crystal structure / Dehydrogenases / Deletion mutant / Dosage and administration / Drug resistance / Drug therapy / Enzyme Inhibitors - pharmacology / Enzymes / Genetic aspects / Genomics / Guanine / IMP Dehydrogenase - antagonists & inhibitors / IMP Dehydrogenase - chemistry / IMP Dehydrogenase - genetics / IMP Dehydrogenase - metabolism / Infectious diseases / Inhibitors / Inosine monophosphate / Laboratories / Mycobacterium tuberculosis / Mycobacterium tuberculosis - drug effects / Mycobacterium tuberculosis - enzymology / NAD / NAD - metabolism / NADH / Nicotinamide adenine dinucleotide / Oxidoreductases / Pathogens / Physiological aspects / Protein Binding / Proteins / Science & Technology - Other Topics / Substrates / Tritrichomonas foetus / Tuberculosis