Home Blog of Signal Transduction DNA Damage/DNA Repair DNA alkylator The Crystal Structure of Engineered Nitroreductase NTR 2.0 and Impact of F70A and F108Y Substitutions on Substrate Specificity

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The Crystal Structure of Engineered Nitroreductase NTR 2.0 and Impact of F70A and F108Y Substitutions on Substrate Specificity

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.

 

Comments:

It sounds like you're describing a research study or a scientific paper related to the engineering and characterization of a modified nitroreductase enzyme (NTR 2.0) for enhanced reduction of the prodrug metronidazole. This modified enzyme has significant implications for creating targeted ablation models to study cellular function, cell-specific regeneration, and modeling chronic diseases. The study involved solving the X-ray crystal structure of NTR 2.0, comparing it to the parental enzyme NfsB from Vibrio vulnificus, and exploring its reductive activity with various nitroaromatic substrates for potential applications in alternative ablation prodrugs and environmental remediation.

If you have any specific questions about this research or if there's something specific you would like to know or discuss regarding this topic, please feel free to ask!

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S7829 Tretazicar (CB1954) Tretazicar (CB1954) is a anticancer prodrug that is converted in the presence of the enzyme NQO2 and co-substrate caricotamide ( EP-0152R) (EP) into a potent cytotoxic bifunctional alkylating agent. It can be activated by NAD(P)H quinone oxidoreductase 2.

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DNA alkylator