Molecular evidence that melatonin is enzymatically oxidized in a different manner than tryptophan: investigations with both indoleamine 2,3-dioxygenase and myeloperoxidase

Ferry, Gilles; Ubeaud, Caroline; Lambert, Pierre‐Herve; Bertin, Sophie; Cogé, Francis; Chomarat, Pascale; Delagrange, Philippe; Serkiz, Bernard; Bouchet, Jean‐Paul; Truscott, Roger J.W.; Boutin, Jean A.

doi:10.1042/bj20042075

Cited by 76 publications

(65 citation statements)

References 46 publications

(48 reference statements)

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…The reaction mechanism utilized by myeloperoxidase is intriguing because the enzyme used superoxide to oxidize melatonin. Although others have shown that myeloperoxidase uses hydrogen peroxide to oxidize melatonin to AFMK (34,39), we found that production of AFMK was much greater in the presence of superoxide. Furthermore, hydrogen peroxide was not essential for conversion of melatonin to AFMK.…”

Section: Discussionmentioning

confidence: 51%

Superoxide-dependent Oxidation of Melatonin by Myeloperoxidase

Ximenes

Silva

Rodrigues

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

Myeloperoxidase uses hydrogen peroxide to oxidize numerous substrates to hypohalous acids or reactive free radicals. Here we show that neutrophils oxidize melatonin to N 1 -acetyl-N 2 -formyl-5-methoxykynuramine (AFMK) in a reaction that is catalyzed by myeloperoxidase. Production of AFMK was highly dependent on superoxide but not hydrogen peroxide. It did not require hypochlorous acid, singlet oxygen, or hydroxyl radical. Purified myeloperoxidase and a superoxide-generating system oxidized melatonin to AFMK and a dimer. The dimer would result from coupling of melatonin radicals. Oxidation of melatonin was partially inhibited by catalase or superoxide dismutase. Formation of AFMK was almost completely eliminated by superoxide dismutase but weakly inhibited by catalase. In contrast, production of melatonin dimer was enhanced by superoxide dismutase and blocked by catalase. We propose that myeloperoxidase uses superoxide to oxidize melatonin by two distinct pathways. One pathway involves the classical peroxidation mechanism in which hydrogen peroxide is used to oxidize melatonin to radicals. Superoxide adds to these radicals to form an unstable peroxide that decays to AFMK. In the other pathway, myeloperoxidase uses superoxide to insert dioxygen into melatonin to form AFMK. This novel activity expands the types of oxidative reactions myeloperoxidase can catalyze. It should be relevant to the way neutrophils use superoxide to kill bacteria and how they metabolize xenobiotics.Catalysis of hypochlorous acid production is the accepted physiological function of myeloperoxidase (MPO) 2 (1, 2). This heme enzyme is the major protein in neutrophils and is also present in monocytes, macrophages, microglia (3), and neurons (4, 5). It reacts with hydrogen peroxide to form the redox intermediate compound I, which oxidizes chloride to hypochlorous acid with coincident regeneration of the native enzyme (Reactions 1 and 2). HOCl indicates hypochlorous acid.Myeloperoxidase also promotes the oxidation of numerous substrates (RH) to free radical intermediates via the classical peroxidase cycle involving compound I and compound II (Reactions 3 and 4).Klebanoff (6) was the first to show that myeloperoxidase has potent antimicrobial activity because of its ability to generate hypochlorous acid. He proposed that myeloperoxidase produces hypochlorous acid inside phagosomes where it reacts with and kills ingested bacteria. However, during microbial killing myeloperoxidase functions in the presence of a high flux of superoxide (7). Superoxide reacts rapidly with native enzyme to produce oxymyeloperoxidase or compound III (Reaction 5; k 5 ϭ 2 ϫ 10 6 M Ϫ1 s Ϫ1 (8)), which is the dominant form of myeloperoxidase in stimulated neutrophils (9). Reactions of superoxide with myeloperoxidase are likely to be important in host defense because it has been demonstrated that superoxide enhances myeloperoxidasedependent killing of Staphylococcus aureus by isolated human neutrophils (10). The nature of this interaction has yet to be revealed.Compound II...

show abstract

Section: Discussionmentioning

confidence: 51%

Superoxide-dependent Oxidation of Melatonin by Myeloperoxidase

Ximenes

Silva

Rodrigues

et al. 2005

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Although previous studies suggest that IDO can exhibit a peroxidase activity (24,25) and a recent study employed H 2 O 2 as a surrogate to form a compound II species (26), the possibility that IDO forms compound I and its implications for dioxygenase activity have not previously been addressed. This is likely due to the high reactivity of compound I making direct detection difficult, particularly in pseudo-peroxidases where the porphyrin radical rapidly transfers to adjacent amino acids to form protein-centered radicals, e.g.…”

Section: Discussionmentioning

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

View full text Add to dashboard Cite

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.

show abstract

“…of indole, as has been proposed for IDO oxidation of melatonin (8), but this possibility is ruled out for indole oxidation by incorporation of 18 O from H 2 18 O 2 . On the other hand, peroxidation could account for IDO-catalyzed ring opening of 3-methylindole and 2,3-dimethyl indole, neither of which incorporated 18 O from H 2 18 O 2 .…”

Section: •−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.…”

mentioning

confidence: 99%

Indole peroxygenase activity of indoleamine 2,3-dioxygenase

Kuo

Mauk

2012

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

View full text Add to dashboard Cite

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...

show abstract

Molecular evidence that melatonin is enzymatically oxidized in a different manner than tryptophan: investigations with both indoleamine 2,3-dioxygenase and myeloperoxidase

Cited by 76 publications

References 46 publications

Superoxide-dependent Oxidation of Melatonin by Myeloperoxidase

Superoxide-dependent Oxidation of Melatonin by Myeloperoxidase

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

Indole peroxygenase activity of indoleamine 2,3-dioxygenase

Contact Info

Product

Resources

About