J. Am. Chem. Soc.

1969

DOI: 10.1021/ja01042a028

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Reactions of resonance stabilized carbanions. XXXI. Oxidation of carbanions. 4. Oxidation of indoxyl to indigo in basic solution

Glen A. Russell¹,

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Cited by 120 publications

(68 citation statements)

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“…The formation of indigo and indirubin from the enzymatic hydroxylation products of indole is spontaneous and biocatalyst-independent. In short, condensation of two molecules of indoxyl followed by air oxidation leads to the production of indigo, whereas condensation of indoxyl and 2-indolinone yields indirubin (28,34). In addition, indirubin can also be formed by the reaction of indoxyl with isatin (4,35).…”

Section: Discussionmentioning

confidence: 99%

Hydroxylation of Indole by Laboratory-evolved 2-Hydroxybiphenyl 3-Monooxygenase

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et al. 2002

Journal of Biological Chemistry

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“…The formation of indigo and indirubin from the enzymatic hydroxylation products of indole is spontaneous and biocatalyst-independent. In short, condensation of two molecules of indoxyl followed by air oxidation leads to the production of indigo, whereas condensation of indoxyl and 2-indolinone yields indirubin (28,34). In addition, indirubin can also be formed by the reaction of indoxyl with isatin (4,35).…”

Section: Discussionmentioning

confidence: 99%

Hydroxylation of Indole by Laboratory-evolved 2-Hydroxybiphenyl 3-Monooxygenase

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,

²

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³

et al. 2002

Journal of Biological Chemistry

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“…A continuous spectral assay (20) has a complication in that only the initial event, 3-hydroxylation, is catalytic. 3-Hydroxyindole (indoxyl) undergoes rapid, base-catalyzed oxidation in the presence of O 2 to yield the blue dimer indigo (48). An assay has been developed in which the oxidation of indole (or a phenyl ring-substituted indole) is carried out and stopped by the addition of base after a fixed time, with some additional time allowed for development of the indigo, which is stable.…”

Section: Methodsmentioning

confidence: 99%

Analysis of Coumarin 7-Hydroxylation Activity of Cytochrome P450 2A6 using Random Mutagenesis

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2005

Journal of Biological Chemistry

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Cytochrome P450 (P450) 2A6 is an important human enzyme involved in the metabolism of many xenobiotic chemicals including coumarin, indole, nicotine, and carcinogenic nitrosamines. A combination of random mutagenesis and high-throughput screening was used in the analysis of P450 2A6, utilizing a fluorescent coumarin 7-hydroxylation assay. The steady-state kinetic parameters (k cat and K m ) for coumarin 7-hydroxylation by wild-type P450 2A6 and 35 selected mutants were measured and indicated that mutants throughout the coding region can have effects on activity. Five mutants showing decreased catalytic efficiency (k cat /K m ) were further analyzed for substrate selectivity and binding affinities and showed reduced catalytic activities for 7-methoxycoumarin O-demethylation, tert-butyl methyl ether O-demethylation, and indole 3-hydroxylation. All mutants except one (K476E) showed decreased coumarin binding affinities (and also higher K m values), indicating that this is a major basis for the decreased enzymatic activities. A recent x-ray crystal structure of P450 2A6 bound to coumarin (Yano, J. K., Hsu, M. H., Griffin, K. J., Stout, C. D., and Johnson, E. F. (2005) Nat. Struct. Mol. Biol. 12, 822-823) indicates that the recovered A481T and N297S mutations appear to be close to coumarin, suggesting direct perturbation of substrate interaction. The decreased enzymatic activity of the K476E mutant was associated with decreases both in NADPH oxidation and the reduction rate of the ferric P450 2A6-coumarin complex. The attenuation is caused in part to lower binding affinity for NADPH-P450 reductase, but the K476E mutant did not achieve the wild-type coumarin 7-hydroxylation activity even at high reductase concentrations. Cytochrome P4502 enzymes are the major catalysts involved in the oxidative metabolism of xenobiotic chemicals, a significant focus in the areas of toxicology, drug metabolism, and pharmacology (3-5). Human P450 2A6 was identified as the major coumarin 7-hydroxlylase in humans (6 -8), and this enzyme also plays an important role in the metabolism of many xenobiotics including coumarin, nicotine, and tobacco-specific nitrosamines (8 -12). Genetic polymorphisms have been identified, and their relevance to cancer risk has been proposed because of the variations in nicotine and N-nitrosamine metabolism (13-17). The oxidation of indoles by P450 2A6 has been characterized, and the new kinase inhibitors have been biosynthesized using P450 2A6 mutants (18 -22).Recently x-ray crystal structures have been reported for P450 2A6 bound with coumarin and methoxsalen (23). The active site of P450 2A6 is six times smaller than that of human P450 2C8 (23, 24), even smaller than that of bacterial P450 101A1 (25). The decrease in size of the active site in P450 2A6 relative to P450 2C8 is caused by repositioning of helix BЈ and helices F to H toward the active site. Large aromatic residues in the active site of P450 2A6 also reduce the volume of the substrate binding site.In recent years, random mutagenesis and high-thro...

“…Preparation of V was performed in situ by deesterification of 3-acetoxyindole with porcine liver esterase, and all work with this preparation before HPLC was performed anaerobically to prevent spontaneous oxidation of V to indigo blue (15,16). Under anaerobic conditions, V was stable for hours if either H 2 O 2 or IDOFe 3+ were excluded from solution, but with both enzyme and peroxide present, it was oxidized rapidly (Fig.…”

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confidence: 99%

Indole peroxygenase activity of indoleamine 2,3-dioxygenase

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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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