Oxygen-insensitive NADPH nitroreductase (NfsA) (NfsA)

Oxygen-insensitive NADPH nitroreductase (NfsA) is a flavin mononucleotide (FMN)-dependent enzyme primarily found in bacteria such as Escherichia coli (UniProt P17117) [1.3.1]. It catalyzes the two-electron reduction of nitroaromatic and nitroheterocyclic compounds using NADPH as an electron donor [1.3.5, 1.4.1]. This activity is essential for the activation of nitrofuran antibiotics, including nitrofurantoin and nitrofurazone, which are converted into toxic intermediates that cause bacterial DNA damage [1.2.1, 1.2.2]. In cancer therapy, NfsA is a key candidate for Gene-Directed Enzyme Prodrug Therapy (GDEPT), where the nfsA gene is delivered to tumor cells to enable the localized activation of prodrugs like CB1954 (tretazicar) into potent cytotoxins [1.4.2, 1.4.4]. Its oxygen-insensitive nature allows it to function effectively in the hypoxic environments of solid tumors, providing a therapeutic advantage over oxygen-sensitive nitroreductases [1.1.1, 1.4.1]. Additionally, the enzyme can reduce quinones to quinols, contributing to cellular redox homeostasis or the activation of quinone-based prodrugs [1.4.1, 1.4.3].

Other names

Nitroreductase IAMdaAModulator of drug activity ANADPH-dependent nitroreductase

NfsA catalyzes the two-electron reduction of nitro groups to hydroxylamines or amines via a ping-pong bi-bi mechanism, using NADPH as the reducing agent and FMN as a cofactor [1.3.1, 1.4.1]. This reduction converts relatively non-toxic nitroaromatic prodrugs into highly reactive, cytotoxic DNA-alkylating agents [1.4.2].