Evidence for a ferryl intermediate in a heme-based dioxygenase

Ariel Lewis-Ballester, Dipanwita Batabyal, Tsuyoshi Egawa, Changyuan Lu, Yu Lin, Marcelo A. Marti, Luciana Capece, Dario A. Estrin, Syun-Ru Yeh

Research output: Contribution to journalArticle

81 Citations (Scopus)

Abstract

In contrast to the wide spectrum of cytochrome P450 monooxygenases, there are only 2 heme-based dioxygenases in humans: tryptophan dioxygenase (hTDO) and indoleamine 2,3-dioxygenase (hIDO). hTDO and hIDO catalyze the same oxidative ring cleavage reaction of L-tryptophan to N-formyl kynurenine, the initial and rate-limiting step of the kynurenine pathway. Despite immense interest, the mechanism by which the 2 enzymes execute the dioxygenase reaction remains elusive. Here, we report experimental evidence for a key ferryl intermediate of hIDO that supports a mechanism in which the 2 atoms of dioxygen are inserted into the substrate via a consecutive 2-step reaction. This finding introduces a paradigm shift in our understanding of the heme-based dioxygenase chemistry, which was previously believed to proceed via simultaneous incorporation of both atoms of dioxygen into the substrate. The ferryl intermediate is not observable during the hTDO reaction, highlighting the structural differences between the 2 dioxygenases, as well as the importance of stereoelectronic factors in modulating the reactions.

Original languageEnglish (US)
Pages (from-to)17371-17376
Number of pages6
JournalProceedings of the National Academy of Sciences of the United States of America
Volume106
Issue number41
DOIs
StatePublished - Oct 13 2009

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Dioxygenases
Heme
Indoleamine-Pyrrole 2,3,-Dioxygenase
Tryptophan
Kynurenine
Oxygen
Mixed Function Oxygenases
Cytochrome P-450 Enzyme System
Enzymes

Keywords

  • Indoleamine 2,3-dioxygenase
  • Reasonance raman spectroscopy
  • Tryptophan dioxygenase

ASJC Scopus subject areas

  • General

Cite this

Evidence for a ferryl intermediate in a heme-based dioxygenase. / Lewis-Ballester, Ariel; Batabyal, Dipanwita; Egawa, Tsuyoshi; Lu, Changyuan; Lin, Yu; Marti, Marcelo A.; Capece, Luciana; Estrin, Dario A.; Yeh, Syun-Ru.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 106, No. 41, 13.10.2009, p. 17371-17376.

Research output: Contribution to journalArticle

Lewis-Ballester, A, Batabyal, D, Egawa, T, Lu, C, Lin, Y, Marti, MA, Capece, L, Estrin, DA & Yeh, S-R 2009, 'Evidence for a ferryl intermediate in a heme-based dioxygenase', Proceedings of the National Academy of Sciences of the United States of America, vol. 106, no. 41, pp. 17371-17376. https://doi.org/10.1073/pnas.0906655106
Lewis-Ballester, Ariel ; Batabyal, Dipanwita ; Egawa, Tsuyoshi ; Lu, Changyuan ; Lin, Yu ; Marti, Marcelo A. ; Capece, Luciana ; Estrin, Dario A. ; Yeh, Syun-Ru. / Evidence for a ferryl intermediate in a heme-based dioxygenase. In: Proceedings of the National Academy of Sciences of the United States of America. 2009 ; Vol. 106, No. 41. pp. 17371-17376.
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