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Nitroreductases and Nitro-Reduction
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Nitroreductases and Nitro-Reduction

A special issue of International Journal of Molecular Sciences (ISSN 1422-0067). This special issue belongs to the section "Biochemistry".

Deadline for manuscript submissions: closed (30 June 2023) | Viewed by 5728

Special Issue Editor

Prof. Dr. Narimantas K. Cenas

E-Mail Website
Guest Editor
Institute of Biochemistry of Vilnius University, Saulėtekio 7, LT-10257 Vilnius, Lithuania
Interests: flavoenzyme catalysis; oxidative stress; bioreductive activation; redox active drugs; quinones; aromatic nitrocompounds and N-oxides; polyphenols
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues, 

Nitroaromatic compounds with worldwide production of up to 108 tons per year maintain their importance in relation to industrial processes, military activities, environmental pollution, and pharmaceutical application. Because of the contamination of groundwater and soil at military and industrial sites by nitroaromatics, that exhibit toxic, mutagenic, and cancerogenic activities, there has been a significant increase in research to understand and apply biological processes for their degradation. On the other hand, the electron-attracting ability and redox activity make the nitro group a versatile group in medicinal chemistry. Nitroaromatic compounds have a long history of use as antibacterial and antiparasitic drugs, radiosensitizers, and hypoxia-selective anticancer agents. Importantly, both the biodegradation of nitroaromatic environmental pollutants and the manifestation of toxicity/therapeutic action of nitroaromatic drugs may involve similar initial reduction steps, performed by various flavoenzymes and/or their physiological redox partners, metalloproteins. However, in spite of the rapidly increasing amount of information in this area, the still incompletely resolved questions are the identification, characterization and optimization of the specific enzymes that are involved in the bioreduction of nitroaromatics and their reaction mechanisms.

This Special Issue invites research findings and reviews of recent works which share updates on and enrich our knowledge nitroreductases and related enzymes. The Special Issue targets research on a molecular to cellular level: reaction intermediates, electron/hydride transfer reactions, substrate recognition, structure–function relation, environmental and therapeutic application utilizing spectroscopic, kinetic, and structural analyses, computational science, genomics, proteomics, and metabolomics approaches. We believe that this Special Issue, “Nitroreductases and Nitroreduction”, will help to highlight the most recent advances in this field.

We look forward to your contribution.

Prof. Dr. Narimantas K. Cenas
Guest Editor

Manuscript Submission Information

Manuscripts should be submitted online at www.mdpi.com by registering and logging in to this website. Once you are registered, click here to go to the submission form. Manuscripts can be submitted until the deadline. All submissions that pass pre-check are peer-reviewed. Accepted papers will be published continuously in the journal (as soon as accepted) and will be listed together on the special issue website. Research articles, review articles as well as short communications are invited. For planned papers, a title and short abstract (about 100 words) can be sent to the Editorial Office for announcement on this website.

Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. International Journal of Molecular Sciences is an international peer-reviewed open access semimonthly journal published by MDPI.

Please visit the Instructions for Authors page before submitting a manuscript. There is an Article Processing Charge (APC) for publication in this open access journal. For details about the APC please see here. Submitted papers should be well formatted and use good English. Authors may use MDPI's English editing service prior to publication or during author revisions.

Keywords

  • nitroreductase
  • nitroaromatics
  • flavoenzymes
  • substrate recognition
  • physiological redox partners

Published Papers (4 papers)

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Research

16 pages, 1206 KiB  
Article
Enzymatic Redox Properties and Cytotoxicity of Irreversible Nitroaromatic Thioredoxin Reductase Inhibitors in Mammalian Cells
by Aušra Nemeikaitė-Čėnienė, Lina Misevičienė, Audronė Marozienė, Violeta Jonušienė and Narimantas Čėnas
Int. J. Mol. Sci. 2023, 24(15), 12460; https://doi.org/10.3390/ijms241512460 - 05 Aug 2023
Cited by 1 | Viewed by 1148
Abstract
NADPH:thioredoxin reductase (TrxR) is considered a potential target for anticancer agents. Several nitroheterocyclic sulfones, such as Stattic and Tri-1, irreversibly inhibit TrxR, which presumably accounts for their antitumor activity. However, it is necessary to distinguish the roles of enzymatic redox cycling, an inherent [...] Read more.
NADPH:thioredoxin reductase (TrxR) is considered a potential target for anticancer agents. Several nitroheterocyclic sulfones, such as Stattic and Tri-1, irreversibly inhibit TrxR, which presumably accounts for their antitumor activity. However, it is necessary to distinguish the roles of enzymatic redox cycling, an inherent property of nitroaromatics (ArNO2), and the inhibition of TrxR in their cytotoxicity. In this study, we calculated the previously unavailable values of single-electron reduction potentials of known inhibitors of TrxR (Stattic, Tri-1, and 1-chloro-2,4-dinitrobenzene (CDNB)) and inhibitors identified (nitrofuran NSC697923 and nitrobenzene BTB06584). These calculations were according to the rates of their enzymatic single-electron reduction (PMID: 34098820). This enabled us to compare their cytotoxicity with that of model redox cycling ArNO2. In MH22a and HCT-116 cells, Tri-1, Stattic, CDNB, and NSC697023 possessed at least 10-fold greater cytotoxicity than can be expected from their redox cycling activity. This may be related to TrxR inhibition. The absence of enhanced cytotoxicity in BTB06548 may be attributed to its instability. Another known inhibitor of TrxR, tetryl, also did not possess enhanced cytotoxicity, probably because of its detoxification by DT-diaphorase (NQO1). Apart from the reactions with NQO1, the additional mechanisms influencing the cytotoxicity of the examined inhibitors of TrxR are their reactions with cytochromes P-450. Furthermore, some inhibitors, such as Stattic and NSC697923, may also inhibit glutathione reductase. We suggest that these data may be instrumental in the search for TrxR inhibitors with enhanced cytotoxic/anticancer activity. Full article
(This article belongs to the Special Issue Nitroreductases and Nitro-Reduction)
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16 pages, 5099 KiB  
Article
The Crystal Structure of Engineered Nitroreductase NTR 2.0 and Impact of F70A and F108Y Substitutions on Substrate Specificity
by Abigail V. Sharrock, Jeff S. Mumm, Gintautas Bagdžiūnas, Narimantas Čėnas, Vickery L. Arcus and David F. Ackerley
Int. J. Mol. Sci. 2023, 24(7), 6633; https://doi.org/10.3390/ijms24076633 - 01 Apr 2023
Viewed by 1595
Abstract
Bacterial nitroreductase enzymes that convert prodrugs to cytotoxins are valuable tools for creating transgenic targeted ablation models to study cellular function and cell-specific regeneration paradigms. We recently engineered a nitroreductase (“NTR 2.0”) for substantially enhanced reduction of the prodrug metronidazole, which permits faster [...] Read more.
Bacterial nitroreductase enzymes that convert prodrugs to cytotoxins are valuable tools for creating transgenic targeted ablation models to study cellular function and cell-specific regeneration paradigms. We recently engineered a nitroreductase (“NTR 2.0”) for substantially enhanced reduction of the prodrug metronidazole, which permits faster cell ablation kinetics, cleaner interrogations of cell function, ablation of previously recalcitrant cell types, and extended ablation paradigms useful for modelling chronic diseases. To provide insight into the enhanced enzymatic mechanism of NTR 2.0, we have solved the X-ray crystal structure at 1.85 Angstroms resolution and compared it to the parental enzyme, NfsB from Vibrio vulnificus. We additionally present a survey of reductive activity with eight alternative nitroaromatic substrates, to provide access to alternative ablation prodrugs, and explore applications such as remediation of dinitrotoluene pollutants. The predicted binding modes of four key substrates were investigated using molecular modelling. Full article
(This article belongs to the Special Issue Nitroreductases and Nitro-Reduction)
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17 pages, 2273 KiB  
Article
Nitrite Reductase Activity of Ferrous Nitrobindins: A Comparative Study
by Giovanna De Simone, Alessandra di Masi, Grazia R. Tundo, Massimo Coletta and Paolo Ascenzi
Int. J. Mol. Sci. 2023, 24(7), 6553; https://doi.org/10.3390/ijms24076553 - 31 Mar 2023
Viewed by 1048
Abstract
Nitrobindins (Nbs) are all-β-barrel heme proteins spanning from bacteria to Homo sapiens. They inactivate reactive nitrogen species by sequestering NO, converting NO to HNO2, and promoting peroxynitrite isomerization to NO3−. Here, the nitrite reductase activity of Nb(II) [...] Read more.
Nitrobindins (Nbs) are all-β-barrel heme proteins spanning from bacteria to Homo sapiens. They inactivate reactive nitrogen species by sequestering NO, converting NO to HNO2, and promoting peroxynitrite isomerization to NO3−. Here, the nitrite reductase activity of Nb(II) from Mycobacterium tuberculosis (Mt-Nb(II)), Arabidopsis thaliana (At-Nb(II)), Danio rerio (Dr-Nb(II)), and Homo sapiens (Hs-Nb(II)) is reported. This activity is crucial for the in vivo production of NO, and thus for the regulation of blood pressure, being of the utmost importance for the blood supply to poorly oxygenated tissues, such as the eye retina. At pH 7.3 and 20.0 °C, the values of the second-order rate constants (i.e., kon) for the reduction of NO2− to NO and the concomitant formation of nitrosylated Mt-Nb(II), At-Nb(II), Dr-Nb(II), and Hs-Nb(II) (Nb(II)-NO) were 7.6 M−1 s−1, 9.3 M−1 s−1, 1.4 × 101 M−1 s−1, and 5.8 M−1 s−1, respectively. The values of kon increased linearly with decreasing pH, thus indicating that the NO2−-based conversion of Nb(II) to Nb(II)-NO requires the involvement of one proton. These results represent the first evidence for the NO2 reductase activity of Nbs(II), strongly supporting the view that Nbs are involved in NO metabolism. Interestingly, the nitrite reductase reactivity of all-β-barrel Nbs and of all-α-helical globins (e.g., myoglobin) was very similar despite the very different three-dimensional fold; however, differences between all-α-helical globins and all-β-barrel Nbs suggest that nitrite reductase activity appears to be controlled by distal steric barriers, even though a more complex regulatory mechanism can be also envisaged. Full article
(This article belongs to the Special Issue Nitroreductases and Nitro-Reduction)
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21 pages, 3638 KiB  
Article
Structure and Dynamics of Three Escherichia coli NfsB Nitro-Reductase Mutants Selected for Enhanced Activity with the Cancer Prodrug CB1954
by Martin A. Day, Andrew J. Christofferson, J. L. Ross Anderson, Simon O. Vass, Adam Evans, Peter F. Searle, Scott A. White and Eva I. Hyde
Int. J. Mol. Sci. 2023, 24(6), 5987; https://doi.org/10.3390/ijms24065987 - 22 Mar 2023
Viewed by 1442
Abstract
Escherichia coli NfsB has been studied extensively for its potential for cancer gene therapy by reducing the prodrug CB1954 to a cytotoxic derivative. We have previously made several mutants with enhanced activity for the prodrug and characterised their activity in vitro and in [...] Read more.
Escherichia coli NfsB has been studied extensively for its potential for cancer gene therapy by reducing the prodrug CB1954 to a cytotoxic derivative. We have previously made several mutants with enhanced activity for the prodrug and characterised their activity in vitro and in vivo. Here, we determine the X-ray structure of our most active triple and double mutants to date, T41Q/N71S/F124T and T41L/N71S. The two mutant proteins have lower redox potentials than wild-type NfsB, and the mutations have lowered activity with NADH so that, in contrast to the wild-type enzyme, the reduction of the enzyme by NADH, rather than the reaction with CB1954, has a slower maximum rate. The structure of the triple mutant shows the interaction between Q41 and T124, explaining the synergy between these two mutations. Based on these structures, we selected mutants with even higher activity. The most active one contains T41Q/N71S/F124T/M127V, in which the additional M127V mutation enlarges a small channel to the active site. Molecular dynamics simulations show that the mutations or reduction of the FMN cofactors of the protein has little effect on its dynamics and that the largest backbone fluctuations occur at residues that flank the active site, contributing towards its broad substrate range. Full article
(This article belongs to the Special Issue Nitroreductases and Nitro-Reduction)
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