Properties and Function of Indoleamine 2, 3-Dioxygenase1

Hayaishi, Osamu

doi:10.1093/oxfordjournals.jbchem.a131115

Cited by 128 publications

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“…IDO and TDO catalyze the same oxidative cleavage of tryptophan (Trp) to N-formyl kynurenine (NFK), the initial and ratelimiting step of the kynurenine pathway, by adding both atoms of dioxygen to the C 2 ϭC 3 bond of the indole moiety of Trp (Scheme 1) (3,(10)(11)(12)(13)(14). Although they catalyze the same reaction, the 2 dioxygenases engage in distinct functions.…”

mentioning

confidence: 99%

“…Human TDO (hTDO) is a hepatic enzyme: it is inducible by glucocorticoid hormones and is critical for the control of the relative Trp flux in the serotonergic and kynurenic pathways (15,16). In contrast, human IDO (hIDO) is ubiquitously distributed in all tissues other than liver; it is inducible by IFN-␥ (10,17,18) and plays important immunoregulatory roles in a variety of pathophysiological conditions (3,(18)(19)(20).…”

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confidence: 99%

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Evidence for a ferryl intermediate in a heme-based dioxygenase

Lewis-Ballester

Batabyal

Egawa

et al. 2009

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

118

217

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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. indoleamine 2,3-dioxygenase ͉ reasonance Raman spectroscopy ͉ tryptophan dioxygenase

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confidence: 99%

mentioning

confidence: 99%

Evidence for a ferryl intermediate in a heme-based dioxygenase

Lewis-Ballester

Batabyal

Egawa

et al. 2009

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

118

217

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“…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)(5)(6). Although indole can apparently bind to the oxygenated enzyme (IDOFe 3+ -O 2…”

mentioning

confidence: 99%

“…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.…”

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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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“…1.13.11.42) catalyzes the oxidative cleavage of the essential amino acid tryptophan; the reaction product is N-formylkynurenine, which enzymatically or spontaneously converts to kynurenine [1,2]. IDO is a cytosolic, heme-containing, interferon-γ-inducible enzyme that is present in various mammalian tissues [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15]; however, the physiological function of IDO is not entirely known, except for the function of IDO in the context of host response to pathogens. During infection, cytokineinduced IDO activity [5,16] depletes tryptophan and forms toxic products, which are proposed to limit the proliferation of invading bacterial [16][17][18][19][20] and viral [21,22] pathogens.…”

Section: Introductionmentioning

confidence: 99%

Decreased protein nitration in macrophages that overexpress indoleamine 2, 3-dioxygenase

Keskin

Marshall

Munn

et al. 2007

Cellular and Molecular Biology Letters

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Abstract:The activity of indoleamine 2, 3-dioxygenase (IDO; E.C. 1.13.11.42) catalyzes the oxidative cleavage of tryptophan to form kynurenine. IDO activity consumes superoxide anions; therefore, we postulated that over-expression of IDO might mitigate superoxide-anion dependent, oxidative modification of cellular proteins in vitro. We prepared and characterized RAW 264.7 macrophages that were stably transfected with either an IDO expression vector or the control (empty) vector. We detected IDO mRNA, protein, and enzyme activity in the IDO-transfected macrophages, but not in the macrophages transfected with the empty vector. To generate superoxide anions in situ, we treated the IDO-and control-transfected cultures with xanthine or hypoxanthine, and then used ELISA methods to quantitate the relative levels of oxidatively modified proteins in total cell lysates. The levels of protein carbonyls were similar in IDO-transfected and vector-transfected macrophages; however, protein nitration was significantly less in IDO-transfected cells compared to control transfectants. In addition, steady-state levels of superoxide anions were significantly lower in the IDO-transfected cultures compared with control transfectants. Our results are consistent with the concept that, besides degrading tryptophan, IDO activity may protect cells from oxidative damage.

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Properties and Function of Indoleamine 2, 3-Dioxygenase1

Cited by 128 publications

References 0 publications

Evidence for a ferryl intermediate in a heme-based dioxygenase

Evidence for a ferryl intermediate in a heme-based dioxygenase

Indole peroxygenase activity of indoleamine 2,3-dioxygenase

Decreased protein nitration in macrophages that overexpress indoleamine 2, 3-dioxygenase

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