Reassessment of the reaction mechanism in the heme dioxygenases

Nishma Chauhan, Sarah J Thackray, Sara A Rafice, Graham Eaton, Michael Lee, Igor Efimov, Jaswir Basran, Paul R Jenkins, Christopher G Mowat, Stephen K Chapman, Emma Lloyd Raven

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    Abstract

    Indoleamine 2,3-dioxygenase (IDO) and tryptophan 2,3-dioxygenase (TDO) are heme enzymes that catalyze the O(2)-dependent oxidation of L-tryptophan to N-formyl-kynurenine. Previous proposals for the mechanism of this reaction have suggested that deprotonation of the indole NH group, either by an active-site base or by oxygen bound to the heme iron, as the initial step. In this work, we have examined the activity of 1-Me-L-Trp with three different heme dioxygenases and their site-directed variants. We find, in contrast to previous work, that 1-Me-L-Trp is a substrate for the heme dioxygenase enzymes. These observations suggest that deprotonation of the indole N(1) is not essential for catalysis, and an alternative reaction mechanism, based on the known chemistry of indoles, is presented.

    Original languageEnglish
    Pages (from-to)4186-4187
    Number of pages2
    JournalJournal of the American Chemical Society
    Volume131
    Issue number12
    DOIs
    Publication statusPublished - 1 Apr 2009

    Keywords

    • CATALYSIS
    • TRYPTOPHAN 2,3-DIOXYGENASE
    • HUMAN INDOLEAMINE 2,3-DIOXYGENASE

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    Chauhan, N., Thackray, S. J., Rafice, S. A., Eaton, G., Lee, M., Efimov, I., Basran, J., Jenkins, P. R., Mowat, C. G., Chapman, S. K., & Raven, E. L. (2009). Reassessment of the reaction mechanism in the heme dioxygenases. Journal of the American Chemical Society, 131(12), 4186-4187. https://doi.org/10.1021/ja808326g