The mechanism of formation of N -formylkynurenine by heme dioxygenases

Jaswir Basran, Igor Efimov, Nishma Chauhan, Sarah J. Thackray, James L. Krupa, Graham Eaton, Gerry A. Griffith, Christopher G. Mowat, Sandeep Handa, Emma Lloyd Raven*

*Corresponding author for this work

Research output: Contribution to journalArticle (Academic Journal)

49 Citations (Scopus)

Abstract

Heme dioxygenases catalyze the oxidation of l-tryptophan to N-formylkynurenine (NFK), the first and rate-limiting step in tryptophan catabolism. Although recent progress has been made on early stages in the mechanism, there is currently no experimental data on the mechanism of product (NFK) formation. In this work, we have used mass spectrometry to examine product formation in a number of dioxygenases. In addition to NFK formation (m/z = 237), the data identify a species (m/z = 221) that is consistent with insertion of a single atom of oxygen into the substrate during O 2-driven turnover. The fragmentation pattern for this m/z = 221 species is consistent with a cyclic amino acetal structure; independent chemical synthesis of the 3a-hydroxypyrroloindole-2-carboxylic acid compound is in agreement with this assignment. Labeling experiments with 18O 2 confirm the origin of the oxygen atom as arising from O 2-dependent turnover. These data suggest that the dioxygenases use a ring-opening mechanism during NFK formation, rather than Criegee or dioxetane mechanisms as previously proposed.

Original languageEnglish
Pages (from-to)16251-16257
Number of pages7
JournalJournal of the American Chemical Society
Volume133
Issue number40
DOIs
Publication statusPublished - 12 Oct 2011

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