Nitroreductases : Enzymes with Environmental , Biotechnological and Clinical Importance

Abstract

The nitroreductase family comprises a group of flavin mononucleotide (FMN)- or flavin adenine dinucleotide (FAD) - dependent enzymes that are able to metabolize nitroaromatic and nitroheterocyclic derivatives (nitrosubstituted compounds) using the reducing power of nicotinamide adenine dinucleotide (NAD(P)H). These enzymes can be found in bacterial species and, to a lesser extent, in eukaryotes. The nitroreductase proteins play a central role in the activation of nitrocompounds and have received a lot of attention in recent decades based on their (a) environmental and human health importance due to their central role in mediating nitrosubstituted compound toxicity; (b) biotechnological application for bioremediation biocatalysis; and (c) clinical importance in chemotherapeutic tumor treatment, ablation of specific cells and antibiotic resistance. Nitrosubstituted compounds are mainly produced by industrial processes or other human activities and have become an important group of environmental pollutants. Human health concerns have arisen with regard to these compounds because their metabolization leads to the formation of potent genotoxic and mutagenic metabolites and to the generation of reactive nitrogen oxide species, which readily react with biological macromolecules. In addition, many genotoxic tests have been performed using mutant strains of bacteria such as Salmonella typhimurium that do not express or overexpress these enzymes, to identify and elucidate the molecular mechanism of mutagenesis caused by several nitrocompounds. Bioremediation treatments for nitroaromatic and nitroheterocyclic compounds, in particular phytoremediation using transgenic plants expressing bacterial nitroreductases or soil bacteria such as Bacillus sp., may be effective in decontaminating soil in situ. The nitroreductases have clinical application due to their ability to convert non- toxic prodrugs such as CB1954 (5-[aziridin-1-yl]-2,4-dinitrobenzamide) into a potent DNA-crosslinking cytotoxic agent that kills tumor cells. These enzymes have great clinical interest because they are used in techniques such as gene (or virus) directed enzyme prodrug therapy (GDEPT or VDEPT) and antibody-directed enzyme prodrug therapy (ADEPT) for potential use in the treatment of certain tumors. Nitroreductases are also involved in resistance to metronidazole, a drug used mainly in infections caused by Helicobacter pylori, which causes gastric ulcers and constitutes a risk factor for adenocarcinoma and gastric lymphoma. In this chapter, the most relevant aspects of nitroreductases enzymes are presented and discussed: the occurrence of these enzymes in organisms, their catalytic reduction mechanism, physiological role and importance in mediating the toxicity of nitrocompounds, and their influence on the environment and human health, as well as their potential biotechnological and medical applications.