Structural highlights
Function[XDH_BOVIN] Key enzyme in purine degradation. Catalyzes the oxidation of hypoxanthine to xanthine. Catalyzes the oxidation of xanthine to uric acid. Contributes to the generation of reactive oxygen species. Publication Abstract from PubMedFYX-051, 4-[5-(pyridin-4-yl)-1H-1,2,4-triazol-3-yl]pyridine-2-carbonitrile, is a potent inhibitor of bovine milk xanthine oxidoreductase (XOR). Steady-state kinetics study showed that it initially behaved as a competitive-type inhibitor with a Ki value of 5.7x10(-9) M, then after a few minutes it formed a tight complex with XOR via a Mo-oxygen-carbon atom covalent linkage, as previously reported (Okamoto et al., 2004). Thus, FYX-051 is a hybrid-type inhibitor exhibiting both structure-based and mechanism-based inhibition. The FYX-051 XOR complex decomposed with a half-life of 20.4 hours, but the enzyme activity did not fully recover. This was found to be due to XOR-mediated conversion of FYX-051 to 2-hydroxy-FYX-051, as well as formation of di- and trihydroxy-FYX-051 during prolonged incubation for up to 72 hours. A distinct charge-transfer band was observed concomitantly with the formation of trihydroxy-FYX-051 XOR complex. Crystallographic analysis of the charge-transfer complex indicated that a Mo-nitrogen-carbon bond was formed between molybdenum of XOR and the nitrile group of trihydroxy-FYX-051. FYX-051 showed a potent and long-lasting hypouricemic effect in a rat model of potassium oxonate-induced hyperuricemia, and it seems to be a promising candidate for clinical treatment of hyperuricemia. FYX-051 : A novel and potent hybrid type inhibitor of xanthine oxidoreductase.,Matsumoto K, Okamoto K, Ashizawa N, Nishino T J Pharmacol Exp Ther. 2010 Oct 15. PMID:20952484[1] From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine. See AlsoReferences
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