Nitroreductase

Function

Nitroreductase or oxygen-insensitive NAD(P)H nitroreductase (NR) is involved in the reduction of nitrogen-containing compounds including those containing NO₂ group. The NO₂ group is reduced to hydroxylamine^[1]. NR uses FMN as cofactor. Among NRs are the oxygen-insensitive NAD(P)H NR and NADH dehydrogenase.

Copper-induced nitroreductase protects Lactococcus lactis against oxidative stress exerted by nitroaromatic compounds and copper^[2].
Nitrobenzoate nitroreductase metabolises 2-nitrobenzoate to form the antioxidant 3-hydroxyanthranilate in Pseudomonas fluorescens^[3].
Deazaflavin-dependent nitroreductase catalyses the reduction of nitroimidazoles into reactive nitrogen species in Mycobacterium tuberculosis ^[4].

Relevance

NR is of special interest due to its potential use as activator of prodrugs in cancer therapy^[5].

Structural highlights

NR while the . Water molecules are shown as red spheres.

3D structures of nitroreductase

Nitroreductase 3D structures

E. coli nitroreductase dimer containing FMN and nicotinic acid (PDB entry 1icr)

Drag the structure with the mouse to rotate

ReferencesReferences

↑ Lovering AL, Hyde EI, Searle PF, White SA. The structure of Escherichia coli nitroreductase complexed with nicotinic acid: three crystal forms at 1.7 A, 1.8 A and 2.4 A resolution. J Mol Biol. 2001 May 25;309(1):203-13. PMID:11491290 doi:10.1006/jmbi.2001.4653
↑ Mermod M, Mourlane F, Waltersperger S, Oberholzer AE, Baumann U, Solioz M. Structure and function of CinD (YtjD) of Lactococcus lactis, a copper-induced nitroreductase involved in defense against oxidative stress. J Bacteriol. 2010 Aug;192(16):4172-80. Epub 2010 Jun 18. PMID:20562311 doi:10.1128/JB.00372-10
↑ Iwaki H, Muraki T, Ishihara S, Hasegawa Y, Rankin KN, Sulea T, Boyd J, Lau PC. Characterization of a pseudomonad 2-nitrobenzoate nitroreductase and its catabolic pathway-associated 2-hydroxylaminobenzoate mutase and a chemoreceptor involved in 2-nitrobenzoate chemotaxis. J Bacteriol. 2007 May;189(9):3502-14. PMID:17277060 doi:10.1128/JB.01098-06
↑ Cellitti SE, Shaffer J, Jones DH, Mukherjee T, Gurumurthy M, Bursulaya B, Boshoff HI, Choi I, Nayyar A, Lee YS, Cherian J, Niyomrattanakit P, Dick T, Manjunatha UH, Barry CE 3rd, Spraggon G, Geierstanger BH. Structure of Ddn, the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis involved in bioreductive activation of PA-824. Structure. 2012 Jan 11;20(1):101-12. PMID:22244759 doi:10.1016/j.str.2011.11.001
↑ Williams EM, Little RF, Mowday AM, Rich MH, Chan-Hyams JV, Copp JN, Smaill JB, Patterson AV, Ackerley DF. Nitroreductase gene-directed enzyme prodrug therapy: insights and advances toward clinical utility. Biochem J. 2015 Oct 15;471(2):131-53. doi: 10.1042/BJ20150650. PMID:26431849 doi:http://dx.doi.org/10.1042/BJ20150650

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Michal Harel, Alexander Berchansky, Joel L. Sussman

[1] Lovering AL, Hyde EI, Searle PF, White SA. The structure of Escherichia coli nitroreductase complexed with nicotinic acid: three crystal forms at 1.7 A, 1.8 A and 2.4 A resolution. J Mol Biol. 2001 May 25;309(1):203-13. PMID:11491290 doi:10.1006/jmbi.2001.4653

[2] Mermod M, Mourlane F, Waltersperger S, Oberholzer AE, Baumann U, Solioz M. Structure and function of CinD (YtjD) of Lactococcus lactis, a copper-induced nitroreductase involved in defense against oxidative stress. J Bacteriol. 2010 Aug;192(16):4172-80. Epub 2010 Jun 18. PMID:20562311 doi:10.1128/JB.00372-10

[3] Iwaki H, Muraki T, Ishihara S, Hasegawa Y, Rankin KN, Sulea T, Boyd J, Lau PC. Characterization of a pseudomonad 2-nitrobenzoate nitroreductase and its catabolic pathway-associated 2-hydroxylaminobenzoate mutase and a chemoreceptor involved in 2-nitrobenzoate chemotaxis. J Bacteriol. 2007 May;189(9):3502-14. PMID:17277060 doi:10.1128/JB.01098-06

[4] Cellitti SE, Shaffer J, Jones DH, Mukherjee T, Gurumurthy M, Bursulaya B, Boshoff HI, Choi I, Nayyar A, Lee YS, Cherian J, Niyomrattanakit P, Dick T, Manjunatha UH, Barry CE 3rd, Spraggon G, Geierstanger BH. Structure of Ddn, the deazaflavin-dependent nitroreductase from Mycobacterium tuberculosis involved in bioreductive activation of PA-824. Structure. 2012 Jan 11;20(1):101-12. PMID:22244759 doi:10.1016/j.str.2011.11.001

[5] Williams EM, Little RF, Mowday AM, Rich MH, Chan-Hyams JV, Copp JN, Smaill JB, Patterson AV, Ackerley DF. Nitroreductase gene-directed enzyme prodrug therapy: insights and advances toward clinical utility. Biochem J. 2015 Oct 15;471(2):131-53. doi: 10.1042/BJ20150650. PMID:26431849 doi:http://dx.doi.org/10.1042/BJ20150650

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