Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:1.10.3.3 (ascorbate oxidase)
778 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Binuclear cupric ion clusters have been established in: human ceruloplasmin, hemocyanin, and mushroom tyrosinase. Substantial evidence makes it very probable that fungal laccase and zucchini ascorbate oxidase contain this cluster. Some evidence makes it possible that copper clusters function in the catalytic cycles of cytochrome oxidase (mammalian) and dopamine-beta-hydroxylase. These studies throw light on the criteria which must be employed to establish the existence of functional binuclear copper clusters in enzymes: (1) Stoichiometric Criteria: binding of O2 and CO with Cu/ligand = 2; redox titrations with n = 2; (2) Physical and Chemical Criteria: magnetic evidence of diminished paramagnetism of cupric centers, EPR evidence of broadened or absent absorptions, EPR evidence of magnetic dipolar interactions among cupric ions; absorption bands characteristic of Cu(II)-Cu(II) complexes; laser resonance raman scattering characteristic of peroxidic dioxygen in the oxyforms.
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PMID:Binuclear copper clusters as active sites for oxidases. 18 78

The antithyroid drug, methimazole (1-methyl-2-thiolimidazole), is a powerful chelator of cupric ion. This is reflected in its ability to selectively inhibit certain copper oxidases. Uricase, ascorbic oxidase and monoamine oxidase are not affected. Ceruloplasmin oxidase is slightly inhibited and tyrosinase is markedly inhibited by methimazole.
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PMID:Copper ion binding and enzyme inhibitory properties of the antithyroid drug methimazole. 80 93

Tyrosinase usually catalyzes the conversion of monophenols to o-diphenols and oxidation of diphenols to the corresponding quinones. However, when 3,4-dihydroxymandelic acid was provided as the substrate, it catalyzed an unusual oxidative decarboxylation reaction generating 3,4-dihydroxybenzaldehyde as the sole product. The identity of the product was confirmed by high-performance liquid chromatography (HPLC) as well as ultraviolet and infrared spectral studies. None of the following enzymes tested catalyzed the new reaction: galactose oxidase, ceruloplasmin, superoxide dismutase, ascorbate oxidase, dopamine beta-hydroxylase, and peroxidase. Phenol oxidase inhibitors such as phenylthiourea, potassium cyanide, and sodium azide inhibited the reaction drastically, suggesting the participation of the active site copper of the enzyme in the catalysis. Mimosine, a well-known competitive inhibitor of tyrosinase, competitively inhibited the new reaction also. 4-Hydroxymandelic acid and 3-methoxy-4-hydroxymandelic acid neither served as substrates nor inhibited the reaction. Putative intermediates such as 3,4-dihydroxybenzyl alcohol and (3,4-dihydroxybenzoyl)formic acid did not accumulate during the reaction. Oxidation to a quinone methide derivative rather than conventional quinone accounts for this unusual oxidative decarboxylation reaction. Earlier from this laboratory, we reported the conversion of 4-alkylcatechols to quinone methides catalyzed by a cuticular phenol oxidase [Sugumaran, M., & Lipke, H. (1983) FEBS Lett. 155, 65-68]. Present studies demonstrate that mushroom tyrosinase will also catalyze quinone methide production with the same active site copper if a suitable substrate such as 3,4-dihydroxymandelic acid is provided.
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PMID:Tyrosinase catalyzes an unusual oxidative decarboxylation of 3,4-dihydroxymandelate. 309 74

The amino acid sequences of different copper proteins containing coupled binuclear copper centers are compared. Hemocyanins from arthropods and molluscs and tyrosinases from three different species were found to share a highly homologous region in the C-terminal parts. This region contains three invariant histidines previously identified as ligands to Cu(B) in Panulirus interruptus hemocyanin by X-ray crystallography (Gaykema et al., Nature 309, 23-29 (1984]. In contrast, the ligand environment for the second copper, Cu(A), proved to be quite variable. It is proposed that hemocyanin and tyrosinase have arisen from a common mononuclear copper protein with the typical Cu(B) site. From this ancestral protein two types of binuclear proteins evolved independently into a tyrosinase and an arthropodan hemocyanin type. The amino acid sequence comparison between human ceruloplasmin and Neurospora crassa laccase together with the results from a preliminary X-ray structure analysis of zucchini ascorbate oxidase showed a close relationship in primary and most likely also in tertiary structure in the C-terminal parts of these enzymes. It is suggested that the multicopper oxidases have evolved from an ancestral copper protein which presumably contained all the ligands required for the binding of one binuclear and two additional mononuclear metal centers.
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PMID:Evolutionary relationships among copper proteins containing coupled binuclear copper sites. 313 63

A comprehensive survey of the interaction of the copper proteins and oxygen is presented including a correlation of structure, function, and other properties of the known copper oxidases and of hemocyanin. The origin of their blue color and the structure of copper complexes and copper proteins are related to the oxidation state of copper ion and relevant electronic transitions probably arising from the formation of charge transfer complexes. The oxygen reactions of hemocyanin, ceruloplasmin, and cytochrome oxidase show half-saturation values far below the other Cu enzymes. The formation of hydrogen peroxide as a reaction product is associated with the presence of one Cu atom per oxidase molecule or catalytic system. Water is the corresponding product of the other Cu oxidases with four or more Cu atoms per molecule, except for monoamine oxidase. Mechanisms for the oxidase action of the two and four electron transfer Cu oxidases and tyrosinase are proposed. These reactions account for the number, the oxidation-reduction potential, and the oxidation state of Cu in the resting enzyme, the cyclical change from Cu(II) to Cu(I), the diatomic nature of O(2), the sequence of the oxidation and reduction reactions, and other salient features. The catalytic reactions involved in the oxidation of ascorbic acid by plant ascorbate oxidase, ceruloplasmin, and Cu(II) are compared. Finally the substrate specificity, inhibitory control, and the detailed mechanism of the oxidase activity of ceruloplasmin are summarized.
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PMID:Copper proteins and oxygen. Correlations between structure and function of the copper oxidases. 428 28

The dietary antagonism between copper and molybdate salts prompted a study of the inhibition of copper enzymes by thiomolybdate (TM). TM strongly inhibited the oxidase activity of five copper oxidase with I50% values in the 1-5 microM range. The mechanism of the TM effect on the copper oxidase, ceruloplasmin (Cp) (E.C. 1.16.3.1), was studied in detail. In Vmax vs. E plots, TM gave parallel data suggesting irreversibility but a large number of TM molecules per Cp were required. The inhibition of Cp by TM could not be reversed by dialysis. Isolation of TM-inhibited Cp on Sephadex G-10 did not yield any active Cp molecules. Cu(II) did not restore any inhibited oxidase activity. Gel electrophoresis supported the covalent binding of Cp by TM without any extensive change in protein structure. EPR results confirmed that Cu(II) is reduced to Cu(I) after reaction with TM. However, the Mo(VI) in MoS4(2-) did not change in oxidation number. Analysis of the TM-Cp compound accounted for all six Cu atoms as found in native Cp. The data suggest the covalent binding of sulfide to Cp copper. TM also inhibited the activity of ascorbate oxidase, cytochrome oxidase, superoxide dismutase, and tyrosinase. However, no inhibition of carbonic anhydrase, a zinc enzyme, was observed at 1 mM TM.
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PMID:Inhibition of ceruloplasmin and other copper oxidases by thiomolybdate. 609 47

The reaction between mushroom tyrosinase and L-ascorbic acid was studied by oxymetric assays and evidence pointing to ascorbate oxidase activity of this enzyme has been obtained. The activity is clearly linear to enzyme concentration and the Michaelis constant for L-ascorbic acid has a value of 2.69 +/- 0.11 mM. Maximum activity is obtained at pH 7.5. A possible reaction mechanism, which is based on the different enzymatic forms of tyrosinase, is also presented.
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PMID:Mushroom tyrosinase has an ascorbate oxidase activity. 766 34

Phenoxyl radicals are intermediates in the oxidation of phenolic compounds to quinoid derivatives (quinones, quinone methides), which are known to act as ultimate mutagenic, carcinogenic, and cytotoxic agents by directly interacting with macromolecular targets or by generating toxic reactive oxygen species. One-electron reduction of phenoxyl radicals may reverse oxidative activation of phenolic compounds to quinoids, thus preventing their cytotoxic effects. In the present work, we studied interactions of ascorbate, thiols (glutathione, dihydrolipoic acid, and metallothioneins), and combinations thereof with the phenoxyl radical generated by tyrosinase-catalyzed oxidation of VP-16 [etoposide, 4'-demethylepipodophyllotoxin-9-(4,6-O-ethylidene-beta-D-glucop yra noside)], a hindered phenol widely used as an antitumor drug. We found by liquid chromatography-ionspray mass spectrometry and electron spin resonance (ESR) that tyrosinase caused oxidation of VP-16 to its o-quinone and aromatized derivative via intermediate formation of the phenoxyl radical. Both ascorbate and thiols (GSH, dihydrolipoic acid, and metallothioneins) were able to directly reduce the VP-16 phenoxyl radical and prevent its oxidation. The characteristic ESR signal of the VP-16 phenoxyl radical was quenched by the reductants. The semidehydroascorbyl radical ESR signal was detected in the presence of ascorbate; thiols did not produce signals in the ESR spectra. In combinations, ascorbate plus GSH and ascorbate plus metallothionein acted independently and additively in reducing the VP-16 phenoxyl radical. Ascorbate was more reactive: the VP-16-dependent oxidation of GSH or metallothionein commenced only after complete oxidation of ascorbate. The semidehydroascorbyl radical ESR signal preceded the quenching of the VP-16 phenoxyl radical by GSH and metallothionein. In the presence of ascorbate plus dihydrolipoic acid, ascorbate was also more reactive toward the VP-16 phenoxyl radical than dihydrolipoic acid, but the ascorbate concentration was maintained at the expense of its regeneration from dehydroascorbate by dihydrolipoic acid. In ESR spectra, the semidehydroascorbyl radical ESR signal was continuously detected and then was abruptly substituted by the VP-16 phenoxyl radical signal. When VP-16 and tyrosinase were incubated in the presence of retina or hepatocyte homogenates, a two-phase lag period was observed by ESR for the appearance of the VP-16 radical signal: an ascorbate-dependent part (semidehydroascorbyl radical observable, sensitive to ascorbate oxidase) and thiol-dependent part (no radical signals in the spectra, sensitive to mersalyl acid). About 50% of the thiol-dependent part of the lag period could be accounted for by endogenous GSH (as revealed by treatment with GSH peroxidase+cumene hydroperoxide).(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Ascorbate is the primary reductant of the phenoxyl radical of etoposide in the presence of thiols both in cell homogenates and in model systems. 806 42

Many studies concerning the effect of ascorbic acid on the action of tyrosinase on several substrates have been carried out with contradictory results. The results shown in this work comprise a hypothetical reaction mechanism, which explains the ascorbate oxidase activity of frog epidermis tyrosinase. The reaction between frog epidermis tyrosinase and L-ascorbic acid was studied by oxymetric and spectrophotometric assays. The activity was linearly related to enzyme concentration, with a Michaelis constant for L-ascorbic acid of 0.160 +/- 0.009 mM and Vmax of 90 +/- 4 nM/s. Maximum activity was obtained at pH 7.5. The stoichiometry of the reaction was calculated by measuring the substrate (O2 and L-ascorbic acid) consumption as well as the initial rates of the consumption of oxygen and the disappearance of L-ascorbic acid. The stoichiometry was found to be 1:2 (O2:L-ascorbic acid). The action of the tyrosinase inhibitor tropolone was also studied. All the results present evidence concerning the ascorbate oxidase activity of frog epidermis tyrosinase and a possible reaction mechanism based on the different enzymatic forms of tyrosinase to explain such activity.
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PMID:Oxymetric and spectrophotometric study of the ascorbate oxidase activity shown by frog epidermis tyrosinase. 881 40

1. This study made use of a nitric oxide-sensitive electrode to examine possible means of generating nitric oxide from nitroxyl anion (NO(-)) released upon the decomposition of Angeli's salt. 2. Our results show that copper ions (from CuSO(4)) catalyze the rapid and efficient oxidation of nitroxyl to nitric oxide. Indeed, the concentrations of copper required to do so (0.1 - 100 microM) are roughly 100-times lower than those required to generate equivalent amounts of nitric oxide from S-nitroso-N-acetyl-D,L-penicillamine (SNAP). 3. Experiments with ascorbate (1 mM), which reduces Cu(2+) ions to Cu(+), and with the Cu(2+) chelators, EDTA and cuprizone, and the Cu(+) chelator, neocuproine, each at 1 mM, suggest that the oxidation is catalyzed by copper ions in both valency states. 4. Some compounds containing other transition metals, i.e. methaemoglobin, ferricytochrome c and Mn(III)TMPyP, were much less efficient than CuSO(4) in catalyzing the formation of nitric oxide from nitroxyl, while FeSO(4), FeCl(3), MnCl(2), and ZnSO(4) were inactive. 5. Of the copper containing enzymes examined, Cu-Zn superoxide dismutase and ceruloplasmin were weak generators of nitric oxide from nitroxyl, even at concentrations (2500 and 30 u ml(-1), respectively) vastly greater than are present endogenously. Two others, ascorbate oxidase (10 u ml(-1)) and tyrosinase (250 u ml(-1)) were inactive. 6. Our findings suggest that a copper-containing enzyme may be responsible for the rapid oxidation of nitroxyl to nitric oxide by cells, but the identity of such an enzyme remains elusive.
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PMID:Oxidation of nitroxyl anion to nitric oxide by copper ions. 1099 31


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