Oxygen-insensitive NAD(P)H nitroreductase (NfsB) (NfsB)

Oxygen-insensitive NAD(P)H nitroreductase, commonly known as NfsB, is a bacterial flavoenzyme that facilitates the two-electron reduction of nitroaromatic compounds and quinones (UniProt P38489). It is a homodimeric protein that utilizes flavin mononucleotide (FMN) as a cofactor and can use both NADH and NADPH as reducing equivalents (PubMed 8947835). NfsB is a prominent tool in Gene-Directed Enzyme Prodrug Therapy (GDEPT), where it is targeted to tumor cells to activate prodrugs like CB1954 (tretazicar) into potent DNA-crosslinking agents (PubMed 26431849). This enzymatic activation results in a robust bystander effect, allowing the killing of nearby non-transduced cancer cells (PubMed 15684426). In addition to its role in cancer therapy, NfsB is responsible for the activation of nitrofuran antibiotics, such as nitrofurantoin, in pathogenic bacteria (PubMed 11489869). Mutations or deletions of the nfsB gene are frequently associated with the development of bacterial resistance to these antimicrobial agents (Wikipedia). The enzyme's oxygen-insensitive nature allows it to maintain activity in aerobic environments, distinguishing it from Type II nitroreductases (InterPro IPR033878).

Other names

Nitrofuran sensitivity protein BNfnBMinor oxygen-insensitive nitroreductaseNTRType I nitroreductaseNAD(P)H:nitroreductaseDihydropteridine reductase

NfsB catalyzes the obligatory two-electron reduction of nitro groups in prodrugs and antibiotics to form cytotoxic hydroxylamine or amine derivatives. This process utilizes NAD(P)H as an electron donor and a flavin mononucleotide (FMN) cofactor, operating via a ping-pong Bi-Bi kinetic mechanism. In the context of cancer therapy, this activation leads to DNA interstrand cross-linking and subsequent cell death.