Nitrofuran reductase

The mechanism of antibacterial action of the furan derivatives is unknown. However, the reduced forms of nitrofurans are highly reactive and are thought to inhibit many bacterial enzyme systems, including the oxidative decarboxylation of pyruvate to acetylcoenzyme A. Nitrofurans (see list in Table 1.7) are bacteriostatic but, at high concentrations, can be bactericidal to sensitive organisms. Both chromosomal and plasmid-mediated mechanisms of resistance to nitrofurantoin occur, and these most commonly involve the inhibition of nitrofuran reductase. 

Although never commercially marketed, nifurquinazole has been shown to be a powerfixl nitrofuran-based bactericidal. Nitrofuran-based antibiotics function by a complex set of mechanisms that result in the degradation of bacterial macromolecules. Rapid reduction of nitrofurans via flavoproteins, specifically nitrofuran reductase, occurs inside the bacterial cell. The highly reactive species that are generated in this process are ultimately responsible for damage to ribosomal proteins and DNA, and they... 

Doi, T., H. Yoshimura, and K. Tatsumi. 1983. Properties of nitrofuran reductases from Escherichia coli B/r. Chem. Pharm. Bull. 31 1105-1107. 

Tatsumi, K., T. Doi, H. Yoshimura, H. Koga, and T. Horiuchi. 1982. Oxygen-insensitive nitrofuran reductases in Salmonella typhimuhum TAIOO. J. Pharm. Dyn. 5 423-429. 

Type 1 are 02-insensitive six-electron reductases that catalyze the sequential reduction of nitroarenes to nitroso, hydroxylamino, and amino arenes. They are encoded in E. coli by NfsA for the major enzyme and NfsB for the minor (Rau and Stolz 2003), and are also important in establishing resistance to nitrofuran drugs (Koziarz et al. 1998). 

Nitrotoluenes including 2,4,6-trinitrotoluene (TNT) are important components of explosives and several nitroarenes including the antibacterial nitrofurans have established mntagenicity (Purohit and Basu 2000). Substantial effort has been directed to the degradation of nitroarenes, and to their reduction to amines. Although nitroarene reductases, noted in Chapter 3, Part 3, are distribnted in a range of biota, the products may not necessarily represent intermediates in the degradation... 

Bryant and DeLuca (5) purified and characterized a Type I nitroreductase from Enterobacter cloacae. The protein is a monomer of approximately 27 kDa, it has a loosely bound FMN cofactor and uses NAD(P)H as an electron donor. The substrate range of the enzyme includes nitrofurans, nitrobenzenes, nitrotoluenes and quinones. The enzyme appears to produce the hydroxylamino derivative of nitroflirazone under aerobic conditions, but the product was not thoroughly characterized. Under anaerobic conditions the product is the amine. The authors did not test the effect of metals on enzyme activity, and no inhibition studies were reported. Therefore, it is not known if this enzyme is a metalloprotein. The gene encoding the Enterobacter reductase was cloned and sequenced (7). The authors found a 651 base pair open reading frame corresponding to a protein of 23.9 kDa. Comparison of the Enterobacter and Salmonella amino acid sequences revealed 88% sequence identity between the two proteins (7). 

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