Evidence for a ferryl intermediate in a heme-based dioxygenase

Lewis-Ballester, Ariel; Batabyal, Dipanwita; Egawa, Tsuyoshi; Lu, Chong‐Dao; Lin, Yu; Marti, Marcelo Adrian; Capece, Luciana; Estrin, Darı́o A.; Yeh, Syun Ru

doi:10.1073/pnas.0906655106

Cited by 115 publications

(253 citation statements)

References 56 publications

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“…The first resonance Raman spectroscopy (17) and x-ray crystallography (8) studies of recombinant human IDO (rIDO) supported this mechanism. However, recent resonance Raman data support a role for a ferryl-oxo (Fe IV ϭO), compound IItype species (18,19). These findings along with other recent experimental and theoretical data support a new mechanism where the initial ternary complex (Fe III -superoxo-Trp) reacts via a radical 2-alkyl-peroxo-transition state to form compound II and indole 2,3-epoxide (Trp-epoxide).…”

mentioning

confidence: 62%

“…Measuring the RR spectra in the low wavenumber region for H 2 16 O 2 -and H 2 18 O 2 -treated rIDO in the presence of L-Trp, we noted that the difference between the two spectra revealed an oxygen isotope-sensitive band peak at ϳ799 cm Ϫ1 (Fig. 7C), a band recently assigned as the Fe IV ϭO 2Ϫ stretching mode of a compound II-type species in rIDO (18,26).…”

Section: H 2 O 2 Promotes the Oxidation Of L-trp By Rido To Formmentioning

confidence: 99%

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Human Indoleamine 2,3-Dioxygenase Is a Catalyst of Physiological Heme Peroxidase Reactions

Freewan

Rees

Plaza

et al. 2013

Journal of Biological Chemistry

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Background: Certain heme proteins exhibit a pseudo-peroxidase activity that alters their function. Results: H 2 O 2 engages the peroxidase activity of indoleamine 2,3-dioxygenase (IDO) to oxidatively inactivate its dioxygenase activity, consume nitric oxide, and promote IDO protein nitration. Conclusion: IDO is a catalyst of physiological peroxidase reactions. Significance: IDO peroxidase activity has novel implications for the control and biological actions of this important immune regulatory enzyme.

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mentioning

confidence: 62%

Section: H 2 O 2 Promotes the Oxidation Of L-trp By Rido To Formmentioning

confidence: 99%

Human Indoleamine 2,3-Dioxygenase Is a Catalyst of Physiological Heme Peroxidase Reactions

Freewan

Rees

Plaza

et al. 2013

Journal of Biological Chemistry

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“…Resonance Raman experiments indicating formation of IDO compound II after reaction of IDOFe 3+ with H 2 O 2 provide the only evidence for formation of a higher oxidation state by this enzyme (9,11,12). Oxygenation of the neutral indole by IDO compound II is unlikely, however, given that transfer of the ferryl oxygen would generate IDOFe 2+ and lead to IDOFe 3+ -O 2…”

mentioning

confidence: 99%

“…Recently, reactivity of the enzyme with H 2 O 2 has received considerable attention in light of spectroscopic detection of a compound II-like ferryl species (11,12) and quantum mechanics/ molecular mechanics simulations implicating a role for this intermediate in the catalytic cycle (13). Subsequently, the peroxidase activity of IDO has received renewed attention (9).…”

mentioning

confidence: 99%

Indole peroxygenase activity of indoleamine 2,3-dioxygenase

Kuo

Mauk

2012

Proc. Natl. Acad. Sci. U.S.A.

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The heme enzyme indoleamine 2,3-dioxygenase (IDO) was found to catalyze the oxidation of indole by H 2 O 2 , with generation of 2-and 3-oxoindole as the major products. This reaction occurred in the absence of O 2 and reducing agents and was not inhibited by superoxide dismutase or hydroxyl radical scavengers, although it was strongly inhibited by L-Trp. The stoichiometry of the reaction indicated a one-to-one correspondence for the consumption of indole and H 2 O 2 . The 18 O-labeling experiments indicated that the oxygen incorporated into the monooxygenated products was derived almost exclusively from H 2 18 O 2 , suggesting that electron transfer was coupled to the transfer of oxygen from a ferryl intermediate of IDO. These results demonstrate that IDO oxidizes indole by means of a previously unrecognized peroxygenase activity. We conclude that IDO inserts oxygen into indole in a reaction that is mechanistically analogous to the "peroxide shunt" pathway of cytochrome P450.monooxygenase | oxygen isotopic labeling T he heme enzyme indoleamine 2,3-dioxygenase (IDO) catalyzes the first and rate-determining step of L-tryptophan metabolism in nonhepatic mammalian tissues by inserting both atoms of O 2 into the indole ring to form N-formylkynurenine (N-FK) (1). This dioxygenase activity of IDO requires O 2 and the reduced (Fe 2+ ) enzyme or O 2•− and the oxidized (Fe 3+ ) enzyme. In recent years, an increasing number of physiological consequences of IDO activity have been identified, including links to neural, ocular, and immunological disorders (2). Of these roles, the ability of IDO expressed by tumors to suppress the normal response of T lymphocytes and enable tumor survival and growth has attracted the most intense interest, owing to its implications for the development of new therapeutic approaches in cancer treatment (3).Aside from tryptophan (Trp), the dioxygenase activity of IDO extends to oxidation of other indoleamines, such as 5-hydroxy-LTrp, serotonin, and tryptamine, whereas indole, 3-methylindole, and indoleacetic acid are not substrates (4-6). Although indole can apparently bind to the oxygenated enzyme (IDOFe 3+ -O 2•− ) or to the IDOFe 2+ -CO complex (7), autoxidation to IDOFe 3+ is unaffected by the presence of indole, and oxidation of indole does not occur (5). Notably, IDO does not catalyze oxidation of L-Trp by H 2 O 2 (4, 8, 9). Consequently, the reactivity of IDO with H 2 O 2 received little attention for more than 30 years. During that time, IDO was noted to have peroxidase activity (6) and to catalyze the H 2 O 2 -supported N-demethylation of benzphetamine and hydroxylation of aniline (10), but these activities were not studied further.Recently, reactivity of the enzyme with H 2 O 2 has received considerable attention in light of spectroscopic detection of a compound II-like ferryl species (11, 12) and quantum mechanics/ molecular mechanics simulations implicating a role for this intermediate in the catalytic cycle (13). Subsequently, the peroxidase activity of IDO has received renewed atten...

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“…Recently, the oxygen-isotope-sensitive Raman bands have been reported for IDO in the presence and absence of Trp. 4,5 The RR bands at ca. 570 and ca.…”

mentioning

confidence: 99%

Identification of the Fe–O2 and the Fe=O Heme Species for Indoleamine 2,3-Dioxygenase during Catalytic Turnover

Yanagisawa¹,

Yotsuya²,

Hashiwaki³

et al. 2009

Chemistry Letters

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Resonance Raman spectroscopy has been applied to two distinct temporal species of indoleamine 2,3-dioxygenase during catalytic turnover. We have identified two oxygen-isotopesensitive Raman modes at 569 and 798 cm ¹1 for the two respective species. The O analysis of the 798 cm ¹1 band indicates the existence of a ferryl-oxo heme, which is inconsistent with the previously proposed reaction mechanism. The present study thus provides a physical basis for the structures of the possible reaction intermediates.Indoleamine 2,3-dioxygenase (IDO) is a heme-containing dioxygenase 1 localized in several different mammalian tissues, with the exception of liver.2 This enzyme catalyzes a dioxygenation reaction for incorporation of two oxygen atoms from O 2 into L-tryptophan (Trp) in the production of N-formylkynurenine, which is the main catabolic pathway of Trp. The absorption spectra of the two distinct species of IDO are shown in Figure S1.6 Figure S1A 6 was obtained for the reduced IDO samples after addition of dioxygen. The spectrum exhibits absorption maxima at 413, 542, and 577 nm and is consistent with the reported spectra for oxygenated IDO. 7 The spectrum of Figure S1B 6 was obtained for oxygenated IDO samples after addition of Trp and exhibits absorption maxima at 410, 544, and 577 nm with decreased intensities relative to the absorption maxima of the oxygenated state. This spectrum also has a shoulder at 593 nm, and the intermediate represented in this spectrum, which has not hitherto been reported, is hereafter referred to as the "593 nm species." The absorption band at 593 nm is not seen in the absorption spectra of ferric and ferrous IDO (not shown), and the molar extinction coefficient at 593 nm is not known at present. If we assume that it is comparable to those of the ¡ and ¢ absorption bands of ferric and ferrous IDO, it is estimated that the fractional population of the 593 nm species seen in Figure S1B 6 is not smaller than 30%. We measured the time-dependent change of the concentrations of the 593 nm species and N-formylkynurenine during turnover. The results are shown in Figure S2. 6 When the time course of the absorption change at 321 nm ( Figure S2B 6 ) is compared with the time course of the absorption change at 593 nm ( Figure S2C 6

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Evidence for a ferryl intermediate in a heme-based dioxygenase

Cited by 115 publications

References 56 publications

Human Indoleamine 2,3-Dioxygenase Is a Catalyst of Physiological Heme Peroxidase Reactions

Human Indoleamine 2,3-Dioxygenase Is a Catalyst of Physiological Heme Peroxidase Reactions

Indole peroxygenase activity of indoleamine 2,3-dioxygenase

Identification of the Fe–O2 and the Fe=O Heme Species for Indoleamine 2,3-Dioxygenase during Catalytic Turnover

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