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The Journal of Biochemistry
Year: 2010  |  Volume: 148  |  Issue: 1  |  Page No.: 25 - 28

Ligand orientation governs conjugation capacity of UDP-glucuronosyltransferase 1A1

Y Takaoka, M Ohta, A Takeuchi, K Miura, M Matsuo, T Sakaeda, A Sugano and H. Nishio    

Abstract:

UDP-glucuronosyltransferase 1A1 (UGT1A1) is an endoplasmic reticulum membrane protein that catalyses glucuronidation. Mutant UGT1A1 possesses a different conjugation capacity, and the molecular mechanisms regulating these conjugation reactions are as yet unclear. To elucidate these molecular mechanisms, we simulated and analysed the glucuronidation of wild-type UGT1A1 and six UGT1A1 mutants, with bilirubin as the substrate. We found that only the orientation of the substrates correlated with the conjugation capacity in in vitro experiments. Inasmuch as glucuronidation is an intermolecular rearrangement reaction, we find that the conjugation reaction proceeds only when the hydroxyl group of the substrate is oriented towards the coenzyme, which allows the proton transfer to occur.

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