Mycobacterium tuberculosis IMPDH in Complexes with Substrates, Products and Antitubercular Compounds.
oleh: 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
| Format: | Article |
|---|---|
| Diterbitkan: | Public Library of Science (PLoS) 2015-01-01 |
Deskripsi
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.