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

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• 作者：Susan  ; E. Cellitti¹ ; Jennifer Shaffer¹ ; David  ; H. Jones¹ ; Tathagata Mukherjee² ; Meera Gurumurthy³ ; Badry Bursulaya¹ ; Helena  ; I. Boshoff² ; Inhee Choi² ; Amit Nayyar² ; Yong  ; Sok Lee⁴ ; Joseph Cherian³ ; Pornwaratt Niyomrattanakit³ ; Thomas Dick³ ; Ujjini  ; H. Manjunatha³ ; ⁵ ; Clifton  ; E. Barry III² ; ⁵ ; Glen Spraggon¹ ; ⁵ ; ^{gspraggon@gnf.org} ; Bernhard  ; H. Geierstanger¹ ; ⁵ ; ^{bgeierst@gnf.org}
• 刊名：Structure
• 出版年：2012
• 出版时间：11 January 2012
• 年：2012
• 卷：20
• 期：1
• 页码：101-112
• 全文大小：1535 K

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Summary

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 F₄₂₀ 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 F₄₂₀ 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.