title: Activation of nitrofurazone by azoreductases: multiple activities in one enzyme.
abstract: Azoreductases are well known for azo pro-drug activation by gut flora. We show that azoreductases have a wider role in drug metabolism than previously thought as they can also reduce and hence activate nitrofurazone. Nitrofurazone, a nitroaromatic drug, is a broad spectrum antibiotic which has until now been considered as activated in bacteria by nitroreductases. The structure of the azoreductase with nitrofurazone bound was solved at 2.08 Å and shows nitrofurazone in an active conformation. Based on the structural information, the kinetics and stoichiometry of nitrofurazone reduction by azoreductase from P. aeruginosa, we propose a mechanism of activation which accounts for the ability of azoreductases to reduce both azo and nitroaromatic drugs. This mode of activation can explain the cytotoxic side-effects of nitrofurazone through human azoreductase homologues.
authors.affiliation: Pharmacology Department, University of Oxford, OX1 3QT.
authors.forename: Ali
authors.initials: A
authors.lastname: Ryan
authors.forename: Elise
authors.initials: E
authors.lastname: Kaplan
authors.forename: Nicola
authors.initials: N
authors.lastname: Laurieri
authors.forename: Edward
authors.initials: E
authors.lastname: Lowe
authors.forename: Edith
authors.initials: E
authors.lastname: Sim
mesh_terms: D001711:Biotransformation; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000737:chemistry / Q000378:metabolism*; D009583:Nitrofurazone / Q000737:chemistry / Q000493:pharmacokinetics*; D009601:Nitroreductases
chemical_list: D009247:NADH, NADPH Oxidoreductases; D009601:Nitroreductases; C021106:azoreductase; D009583:Nitrofurazone