Microbial nitroreductases: A versatile tool for biomedical and environmental applications

Abstract

Nitroreductases, enzymes found mostly in bacteria and also in few eukaryotes, use nicotinamide adenine dinucleotide (NADH) or nicotinamide adenine dinucleotide phosphate (NADPH) as a cofactor for their activity and metabolize an enormous list of a diverse nitro group-containing compounds. Nitroreductases that are capable of metabolizing nitroaromatic and nitro heterocyclic compounds have drawn great attention in recent years owing to their biotechnological, biomedical, environmental, and human impact. These enzymes attracted medicinal chemists and pharmacologists because of their prodrug selectivity for activation/reduction of nitro compounds that wipe out pathogens/cancer cells, leaving the host/normal cells unharmed. It is applied in diverse fields of study like prodrug activation in treating cancer and leishmaniasis, designing fluorescent probes for hypoxia detection, cell imaging, ablation of specific cell types, biodegradation of nitro-pollutants, and interpretation of mutagenicity of nitro compounds. Keeping in view the immense prospects of these enzymes and a large number of research contributions in this area, the present review encompasses the enzymatic reaction mechanism, their role in antibiotic resistance, hypoxia sensing, cell imaging, cancer therapy, reduction of recalcitrant nitro chemicals, enzyme variants, and their specificity to substrates, reaction products, and their applications.

Streptococcus suis Encodes Multiple Allelic Variants of a Phase-Variable Type III DNA Methyltransferase, ModS, That Control Distinct Phasevarions

“…Multiple transcriptional regulators were upregulated by expression of ModS1, including the replication initiator protein DnaA ( 24) and a YlbF/ YmcA-type protein (25), as well as transcription factors and repressors. Many ribosomal subunits were upregulated, as well as those involved in general metabolism, such as a nitroreductase (26), glucokinase (27), and a protein involved in alkylphosphonate utilization (28) (Table 2). Conversely, in strains where ModS1 was not expressed, proteins such as ribosomal proteins, several components of ABC transporters, and the fatty acid binding protein DegV (29) were all increased in expression (Table 2).…”

Streptococcus suisencodes multiple allelic variants of a phase-variable Type III DNA methyltransferase, ModS, that control distinct phasevarions

“…Multiple transcriptional regulators were upregulated by expression of ModS1 such as the replication initiator protein DnaA (24), and a YlbF/ YmcA type protein (25), as well as transcription factors and repressors. Many ribosomal subunits were upregulated as well as those involved in general metabolism such as a nitroreductase (26), glucokinase (27) and a protein involve in alkylphosphonate utilisation (28) (Table 2). Conversely, in strains where ModS1 was not expressed, proteins such as ribosomal proteins, several components of ABC transporters, and the fatty acid binding protein DegV ( 29) were all increased in expression (Table 2).…”

Structure and substrate specificity determinants of NfnB, a dinitroaniline herbicide–catabolizing nitroreductase from Sphingopyxis sp. strain HMH

“…The physiological roles of nitroreductases remain unknown, but these versatile enzymes with broad substrate specificity exhibit catalytic activity toward both natural and synthetic compounds. Therefore, nitroreductases are highly attractive for their biotechnological applications in bioremediation ( 8 ), biocatalysis ( 1 , 9 ), and prodrug activation gene therapy for cancer treatment ( 10 ). In bioremediation, bacteria containing nitroreductases with the desired activity are employed to degrade or biotransform toxic and persistent nitroaromatic compounds that are produced by anthropogenic activities or industrial processes ( 11 ).…”

“…Transgenic plants harboring bacterial genes, including pentaerythritol tetranitrate reductase, nitroreductase, or cytochrome P450, have become tolerant to TNT, and phytoremediation has been proposed for detoxifying nitroaromatic explosives. More examples of remediation using bacterial nitroreductase have been reviewed extensively elsewhere ( 8 , 14 , 15 ).…”