Structure of Ddn, the Deazaflavin-Dependent Nitroreductase from Mycobacterium tuberculosis Involved in Bioreductive Activation of PA-824

Cellitti, Susan E.; Shaffer, Jennifer; Jones, David H.; Mukherjee, Tathagata; Gurumurthy, Meera; Bursulaya, Badry; Boshoff, Helena I.; Choi, Inhee; Nayyar, Amit; Lee, Yong Sok; Cherian, Joseph; Niyomrattanakit, Pornwaratt; Dick, Thomas; Manjunatha, Ujjini H.; Barry, Clifton E.; Spraggon, Glen; Geierstanger, Bernhard H.

doi:10.1016/j.str.2011.11.001

Structure of Ddn, the Deazaflavin-Dependent Nitroreductase from Mycobacterium tuberculosis Involved in Bioreductive Activation of PA-824

Journal Article · Sat Dec 31 23:00:00 EST 2011 · Structure

DOI:https://doi.org/10.1016/j.str.2011.11.001· OSTI ID:1623721

Cellitti, Susan E. ^[1]; Shaffer, Jennifer ^[2]; Jones, David H. ^[2]; Mukherjee, Tathagata ^[3]; Gurumurthy, Meera ^[4]; Bursulaya, Badry ^[2]; Boshoff, Helena I. ^[3]; Choi, Inhee ^[3]; Nayyar, Amit ^[3]; Lee, Yong Sok ^[5]; Cherian, Joseph ^[4]; Niyomrattanakit, Pornwaratt ^[4]; Dick, Thomas ^[4]; Manjunatha, Ujjini H. ^[4]; Barry, Clifton E. ^[3]; Spraggon, Glen ^[2]; Geierstanger, Bernhard H. ^[2]

Genomics Inst. of the Novartis Research Foundation, San Diego, CA (United States); DOE/OSTI
Genomics Inst. of the Novartis Research Foundation, San Diego, CA (United States)
National Institutes of Health (NIH), Bethesda, MD (United States). Tuberculosis Research Section
Novartis Institute for Tropical Diseases (Singapore)
National Institutes of Health (NIH), Bethesda, MD (United States). Center for Information Technology. Center for Molecular Modeling

Tuberculosis continues to be a global health threat, making bicyclic nitroimidazoles an important new class of therapeutics. A deazaflavin-dependent nitroreductase (Ddn) from Mycobacterium tuberculosis catalyzes the reduction of nitroimidazoles such as PA-824, resulting in intracellular release of lethal reactive nitrogen species. The N-terminal 30 residues of Ddn are functionally important but are flexible or access multiple conformations, preventing structural characterization of the full-length, enzymatically active enzyme. Several structures were determined of a truncated, inactive Ddn protein core with and without bound F deazaflavin coenzyme as well as of a catalytically competent homolog from Nocardia farcinica .Mutagenesis studies based on these structures identified residues important for binding of F and PA-824. The proposed orientation of the tail of PA-824 toward the N terminus of Ddn is consistent with current structure-activity relationship data.

View Accepted Manuscript (DOE)

Research Organization:: Lawrence Berkeley National Laboratory (LBNL), Berkeley, CA (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: AC02-05CH11231

OSTI ID:: 1623721

Journal Information:: Structure, Journal Name: Structure Journal Issue: 1 Vol. 20; ISSN 0969-2126

Publisher:: ElsevierCopyright Statement

Country of Publication:: United States

Language:: English

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A novel F ₄₂₀ ‐dependent anti‐oxidant mechanism protects M ycobacterium tuberculosis against oxidative stress and bactericidal agents Gurumurthy, Meera; Rao, Martin; Mukherjee, Tathagata Molecular Microbiology, Vol. 87, Issue 4 https://doi.org/10.1111/mmi.12127	journal	December 2012
Mutations in Genes for the F ₄₂₀ Biosynthetic Pathway and a Nitroreductase Enzyme Are the Primary Resistance Determinants in Spontaneous In Vitro -Selected PA-824-Resistant Mutants of Mycobacterium tuberculosis Haver, Hana L.; Chua, Adeline; Ghode, Pramila Antimicrobial Agents and Chemotherapy, Vol. 59, Issue 9 https://doi.org/10.1128/aac.00308-15	journal	June 2015
Cofactor F420-Dependent Enzymes: An Under-Explored Resource for Asymmetric Redox Biocatalysis Shah, Mihir V.; Antoney, James; Kang, Suk Woo Catalysts, Vol. 9, Issue 10 https://doi.org/10.3390/catal9100868	journal	October 2019

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