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 journalArticlepeer-review

111 Scopus citations


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
Issue number41
StatePublished - Oct 13 2009


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

ASJC Scopus subject areas

  • General


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