A novel mechanism for azoreduction.

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Ryan A, Laurieri N, Westwood I, Wang CJ, Lowe E, Sim E

A novel mechanism for azoreduction.

J Mol Biol. 2010 Jul 2;400(1):24-37. doi: 10.1016/j.jmb.2010.04.023. Epub 2010 Apr 24.

PubMed ID

20417637 [ View in PubMed

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Abstract

Azoreductases are important due to their ability to activate anti-inflammatory azo pro-drugs and to detoxify azo dyes. Three genes encoding azoreductases have been identified in Pseudomonas aeruginosa. We describe here a comparison of the three enzymes. The pure recombinant proteins each have a distinct substrate specificity profile against a range of azo substrates. Using the structure of P. aeruginosa azoreductase (paAzoR) 1 and the homology models of paAzoR2 and paAzoR3, we have identified residues important for substrate specificity. We have defined a novel flavin mononucleotide binding cradle, which is a recurrent motif in many flavodoxin-like proteins. A novel structure of paAzoR1 with the azo pro-drug balsalazide bound within the active site was determined by X-ray crystallography and demonstrates that the substrate is present in a hydrazone tautomer conformation. We propose that the structure with balsalazide bound represents an enzyme intermediate and, together with the flavin mononucleotide binding cradle, we propose a novel catalytic mechanism.

DrugBank Data that Cites this Article

Drug Enzymes

Drug	Enzyme	Kind	Organism	Pharmacological Action	Actions
Balsalazide	NADPH azoreductase	Protein	Bacillus sp. (strain OY1-2)	Unknown	Substrate	Details