Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.17.3.2 (xanthine oxidase)
 8,383 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Benzene, a known human myelotoxin and leukemogen is metabolized by liver cytochrome P-450 monooxygenase to phenol. Further hydroxylation of phenol by cytochrome P-450 monooxygenase results in the formation of mainly hydroquinone, which accumulates in the bone marrow. Bone marrow contains high levels of myeloperoxidase. Here we report that phenol hydroxylation to hydroquinone is also catalyzed by human myeloperoxidase in the presence of a superoxide anion radical generating system, hypoxanthine and xanthine oxidase. No hydroquinone formation was detected in the absence of myeloperoxidase. At low concentrations superoxide dismutase stimulated, but at high concentrations inhibited, the conversion of phenol to hydroquinone. The inhibitory effect at high superoxide dismutase concentrations indicates that the active hydroxylating species of myeloperoxidase is not derived from its interaction with hydrogen peroxide. Furthermore, catalase a hydrogen peroxide scavenger, was found to have no significant effect on hydroxylation of phenol to hydroquinone, supporting the lack of hydrogen peroxide involvement. Mannitol (a hydroxyl radical scavenger) was found to have no inhibitory effect, but histidine (a singlet oxygen scavenger) inhibited hydroquinone formation. Based on these results we postulate that a myeloperoxidase-superoxide complex spontaneously rearranges to generate singlet oxygen and that this singlet oxygen is responsible for phenol hydroxylation to hydroquinone. These results also suggest that myeloperoxidase dependent hydroquinone formation could play a role in the production and accumulation of hydroquinone in bone marrow, the target organ of benzene-induced myelotoxicity.
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PMID:Hydroxylation of phenol to hydroquinone catalyzed by a human myeloperoxidase-superoxide complex: possible implications in benzene-induced myelotoxicity. 166 26

In low concentrations, benzene and its metabolite hydroquinone are known to have diverse biological effects on cells, including the synergistic stimulation with GM-CSF of hematopoietic colony formation in vitro, stimulation of granulocytic differentiation in vitro and in vivo, and general suppression of hematopoiesis in vivo. These chemicals are also known to be active in the induction of active oxygen species. We used several assays to determine the effects of benzene metabolites (hydroquinone, benzenetriol, benzoquinone) and active oxygen species (xanthine/xanthine oxidase) on cell growth and cell cycle kinetics of the human myeloid cell line HL-60. HL-60 cells treated with these chemicals for 2 h in PBS showed increased growth over untreated controls in a subsequent 18h growth period in complete media. Incorporation of 3H-thymidine was also increased proportionately by these treatments. Catalase treatment abrogated the increased cell growth of all chemicals, suggesting an oxidative mechanism for the effect of all treatments alike. Cell cycle kinetics assays showed that the growth increase was caused by an increased recruitment of cells from G0/G1 to S-phase for both hydroquinone and active oxygen, rather than a decrease in the length of the cell cycle. Benzene metabolite's enhancement of growth of myeloid cells through an active oxygen mechanism may be involved in a number of aspects of benzene toxicity, including enhanced granulocytic growth and differentiation, stimulation of GM-CSF-induced colony formation, apoptosis inhibition, and stimulation of progenitor cell mitogenesis in the bone marrow. These effects in sum may be involved in the benzene-induced "promotion" of a clonal cell population to the fully leukemic state.
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PMID:Enhancement of myeloid cell growth by benzene metabolites via the production of active oxygen species. 1019 77

The synthesis and structures of two types of molecules are presented: [MVIO3 - nSn(OSiR2R')]1- (M = Mo, n = 0-3; M = W, n = 3) and [MVIO2(OSiR2R')(bdt)]1- (M = Mo, W; bdt = benzene-1,2-dithiolate). For both types, R2R' are Me3, Pri3, Ph3, Me2But and Ph2But. The complete series of oxo/sulfido/silyloxo molybdenum complexes has been prepared. Complexes with n = 0 are readily prepared by the silylation of Ag2MoO4 and sustain mono- or disulfidation with Ph3SiSH to form a species with n = 1 and n = 2, respectively. Complexes with n = 3 are accessible by the silylation of [MOS3]2-. Structures of the representative series members [MoO3(OSiPh2But)]1-, [MoO2S(OSiPh3)]1-, [MoOS2(OSiPri3)]1-, [MoS3(OSiPh2But)]1-, and also [WS3(OSiMe2But)]1-, all with tetrahedral stereochemistry, are presented. Benzene-1,2-dithiolate complexes are prepared by the reaction of [MoO3(OSiR2R')]1-with the dithiol or by the silylation of previously reported [MO3(bdt)]2-. The structures of [MoO2(OSiPh2But)(bdt)]1- and [WO2(OSiPri3)(bdt)]1- conform to square-pyramidal stereochemistry with an oxo ligand in the apical position. The role of these complexes in the preparation of site analogues of the xanthine oxidoreductase enzyme family is noted. The sulfidation reactions reported here point to the utility of Ph3SiSH and Pri3SiSH as reagents for MoVI-based oxo-for-sulfido conversions.
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PMID:Silylation, sulfidation, and benzene-1,2-dithiolate complexation reactions of oxo- and oxosulfidomolybdates(VI) and -tungstates(VI). 1804 55

Two series of square pyramidal (SP) monodithiolene complexes, [M (VI)O 3- n S n (bdt)] (2-) and their silylated derivatives [M (VI)O 2- n S n (OSiR 3)(bdt)] (-) ( n = 0, M = Mo or W; n = 1, 2, M = W), synthesized in this and previous work, constitute the basic molecules in a biomimetic approach to structural analogues of the oxidized sites in the xanthine oxidoreductase enzyme family. Benzene-1,2-dithiolate (bdt) simulates native pyranopterindithiolene chelation in the basal plane, tungsten instead of the native metal molybdenum was employed in sulfido complexes to avoid autoreduction, and silylation models protonation. The complexes [MO 3(bdt)] (2-) and [MO 2(OSiR 3)(bdt)] (-) represent inactive sites, while [MO 2S(bdt)] (2-) and [MOS(OSiR 3)(bdt)] (-), with basal sulfido and silyloxo ligands, are the first analogues of the catalytic sites. Also prepared were [MOS 2(bdt)] (2-) and [MS 2(OSiR 3)(bdt)] (-), with basal sulfido and silyloxo ligands. Complexes are described by angular parameters which reveal occasional distortions from idealized SP toward a trigonal bipyramidal (TBP) structure arising from crystal packing forces in crystalline Et 4N (+) salts. Miminized energy structures from DFT calculations are uniformly SP and reproduce experimental structures. For example, the correct structure is predicted for [WO 2S(bdt)] (2-), whose basal and apical sulfido diastereomers are potentially interconvertible through a low-lying TBP transition state for pseudorotation. The lowest energy tautomer of the protonated form is calculated to be [WOS(OH)(bdt)] (-), with basal sulfido and hydroxo ligands. Computational and experimental structures indicate that protein sites adopt intrinsic coordination geometries rather than those dictated by protein structure and environment.
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PMID:A biomimetic approach to oxidized sites in the xanthine oxidoreductase family: synthesis and stereochemistry of tungsten(VI) analogue complexes. 1876 63