Activation of nitrofurazone by azoreductases: multiple activities in one enzyme

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...

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Bibliographic Details
Published inScientific reports Vol. 1; no. 1; p. 63
Main Authors Ryan, Ali, Kaplan, Elise, Laurieri, Nicola, Lowe, Edward, Sim, Edith
Format Journal Article
LanguageEnglish
Published England Nature Publishing Group 12.08.2011
Subjects
Antibiotics
Azoreductase
Bacteria
Biotransformation
Conformation
Cytotoxicity
Drug metabolism
Drugs
E coli
Enzymes
Intestinal microflora
Metabolism
Models, Molecular
NADH, NADPH Oxidoreductases - chemistry
NADH, NADPH Oxidoreductases - metabolism
Nitrofurazone - chemistry
Nitrofurazone - pharmacokinetics
Nitroreductases
Spectrum analysis
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Summary: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.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep00063