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:1.10.3.1 (tyrosinase)
9,065 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Some histochemical changes in adult C. sinensis collected from rats infected artificially and treated with pyquiton were observed. 1 h after administration the glycogen content showed a slight decrease which became prominent 24h later and almost disappeared at 48h post-medication. There was an increase in protein content in the parenchymal tissues of worms 1h after treatment, especially in the reproductive organ 24h after treatment. RNA content was decreased 1h post administration and continued decreasing gradually so that very little could be seen 48h later. An increase in the activities of SDH, MDH and Ca-ATPase was seen at the beginning and became marked 24h after medication, while that for G-6-PDH was detected 48h after drug administration. No obvious changes in DNA, lipid, AKP, ACP and phenolase were detected within 1-48h after treatment.
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PMID:[Histochemical changes in Clonorchis sinensis after pyquiton treatment]. 169 37

In the present work, we studied the effects of phenoxyl radicals, generated by tyrosinase-catalyzed oxidation of a phenolic antitumor drug, Etoposide (VP-16), on a purified dog kidney Na+/K(+)-ATPase by characterizing interactions of VP-16 phenoxyl radicals with the enzyme's SH-groups by ESR and correlating the loss of the enzymatic activity with the oxidation of its SH-groups, and oxidation of VP-16. VP-16/tyrosinase caused inhibition of Na+/K(+)-ATPase which was dependent on the incubation time and concentration of tyrosinase. The inhibition of Na+/K(+)-ATPase was accompanied by a decrease of DTNB (5,5'-dithiobis-(2-nitrobenzoic acid)-titratable SH-groups. In the presence of Na+/K(+)-ATPase, a typical ESR signal of the VP-16 phenoxyl radical could be observed only following a lag period the duration of which was proportional to the concentration of the Na+/K(+)-ATPase added. Our HPLC measurements demonstrated that Na+/K(+)-ATPase protected VP-16 against tyrosinase-catalyzed oxidation. Combined these results suggest that redox-cycling of VP-16/VP-16 phenoxyl radical by SH-groups of Na+/K(+)-ATPase occurred. Ascorbate which is known to reduce the VP-16 phenoxyl radicals, protected the enzyme against inactivation, prevented oxidation of the enzyme's SH-groups. Reduction of VP-16 phenoxyl radicals by ascorbate was directly observed by the semidehydroascorbyl radical signal in the ESR spectra. VP-16 phenoxyl radical-induced oxidation of sulfhydryls and inhibition of the Na+/K(+)-ATPase may be responsible for at least some of its clinical side effects (e.g., cardiotoxicity) which can be prevented by ascorbate.
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PMID:Inhibition of Na+/K(+)-ATPase by phenoxyl radicals of etoposide (VP-16): role of sulfhydryls oxidation. 749 37

The effectiveness of a phenolic antioxidant as a radical scavenger is determined by its reactivity toward peroxyl radicals and also by the reactivity of the anti-oxidant phenoxyl radical toward oxidation substrate. If the phenoxyl radical efficiently interacts with vitally important biomolecules, this interaction may result in oxidative damage rather than antioxidant protection. In the present work, we studied effects of phenoxyl radicals generated from a phenolic antitumor drug, Etoposide (VP-16), on oxidation of thiols and activity of Ca(2+)-ATPase in sarcoplasmic reticulum (SR) membranes from skeletal muscles. We found that VP-16 is an effective scavenger of peroxyl radicals as judged by its ability to inhibit a water-soluble azo-initiator, 2,2'-azobis(2-amidinopropane)dihydrochloride (AAPH)-induced (i) chemiluminescence (oxidation) of luminol, (ii) fluorescence decay (oxidation) of cis-parinaric acid incorporated in SR membranes, and (iii) peroxidation of SR membrane lipids. VP-16 did not prevent AAPH-induced oxidation of sulfhydryl groups and inhibition of Ca(2+)-ATPase in SR membranes. Electron spin resonance measurements showed that AAPH-induced VP-16 phenoxyl radicals were reduced by interaction with SR thiols. By using tyrosinase to generate VP-16 phenoxyl radicals as the only source of free radicals in the model system, we found that inhibition of Ca(2+)-ATPase was accompanied by oxidation of about 5 mol of Ca(2+)-ATPase SH groups per 1 mol of oxidized VP-16. Secondary products of VP-16 oxidation (including VP-16 o-quinone) were not efficient in inhibiting SR Ca(2+)-ATPase. Reduction of VP-16 phenoxyl radicals by ascorbate protected against AAPH- and tyrosinase-induced thiol oxidation and Ca(2+)-ATPase inhibition. The results suggest that efficient phenolic scavengers of peroxyl radicals such as VP-16--which are commonly considered as potent antioxidants--may themselves produce oxidative stress due to secondary reactions of their phenoxyl radicals with thiols.
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PMID:Antioxidant paradoxes of phenolic compounds: peroxyl radical scavenger and lipid antioxidant, etoposide (VP-16), inhibits sarcoplasmic reticulum Ca(2+)-ATPase via thiol oxidation by its phenoxyl radical. 763 14

The sequence of a cloned Anopheles stephensi gene showed 72% inferred amino acid identity with Drosophila melanogaster Dox-A2 and 93% with its putative ortholog in Anopheles gambiae. Dox-A2 is the reported but herein disputed structural locus for diphenol oxidase A2. Database searches identified Dox-A2 related gene sequences from 15 non-insect species from diverse groups. Phylogenetic trees based on alignments of inferred protein sequences, DNA, and protein motif searches and protein secondary structure predictions produced results consistent with expectations for genes that are orthologous. The only inconsistency was that the C-terminus appears to be more primitive in the yeasts than in plants. In mammals, plants, and yeast these genes have been shown to code for a non-ATPase subunit of the PA700 (19S) regulatory complex of 26S proteasome. The analyses indicated that the insect genes contain no divergent structural features, which taken within an appraisal of all available data, makes the reported alternative function highly improbable. A plausible additional role, in which the 26S proteasome is implicated in regulation of phenol oxidase, would also apply to at least the mammalian genes. No function has yet been reported for the other included sequences. These were from genome projects and included Caenorhabiditus elegans, Arabidopsis thaliana, Fugu rubripes, and Toxoplasma gondii. A consensus of the results predicts a protein containing exceptionally long stretches of helix with a hydrophilic C-terminus. Phosphorylation site motifs were identified at two conserved positions. Possible SRY and GATA-1 binding motifs were found at conserved positions upstream of the mosquito genes. The location of A. stephensi Dox-A2 was determined by in situ hybridization at 34D on chromosome arm 3R. It is in a conserved gene cluster with respect to the other insects. However, the A. stephensi cluster contains a gene showing significant sequence identity to human and pigeon carnitine acetyltransferase genes, therefore showing divergence with the distal end of the D. melanogaster cluster.
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PMID:Anopheles stephensi Dox-A2 shares common ancestry with genes from distant groups of eukaryotes encoding a 26S proteasome subunit and is in a conserved gene cluster. 1083 80

In this study, we describe the activation of melanogenesis by selective vacuolar type H(+)-ATPase inhibitors (bafilomycin A1 and concanamycin A) in amelanotic human and mouse melanoma cells which express tyrosinase but show no melanogenesis. Addition of the inhibitors activated tyrosinase within 4 h, and by 24 h the cells contained measurable amounts of melanin. These effects were not inhibited by cycloheximide (2 microgram/ml) which is consistent with a post-translational mechanism of activation. Our findings suggest that melanosomal pH could be an important and dynamic factor in the control of melanogenesis in mammalian cells.
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PMID:Activation of melanogenesis by vacuolar type H(+)-ATPase inhibitors in amelanotic, tyrosinase positive human and mouse melanoma cells. 1092 69

Menkes disease is an X-linked recessive copper deficiency disorder caused by mutations in the ATP7A (MNK) gene. The MNK gene encodes a copper-transporting P-type ATPase, MNK, which is localized predominantly in the trans-Golgi network (TGN). The MNK protein relocates to the plasma membrane in cells exposed to elevated copper where it functions in copper efflux. A role for MNK at the TGN in mammalian cells has not been demonstrated. In this study, we investigated whether the MNK protein is required for the activity of tyrosinase, a copper-dependent enzyme involved in melanogenesis that is synthesized within the secretory pathway. We demonstrate that recombinant tyrosinase expressed in immortalized Menkes fibroblast cell lines was inactive, whereas in normal fibroblasts known to express MNK protein there was substantial tyrosinase activity. Co-expression of the Menkes protein and tyrosinase from plasmid constructs in Menkes fibroblasts led to the activation of tyrosinase and melanogenesis. This MNK-dependent activation of tyrosinase was impaired by the chelation of copper in the medium of cells and after mutation of the invariant phosphorylation site at aspartic acid residue 1044 of MNK. Collectively, these findings suggest that the MNK protein transports copper into the secretory pathway of mammalian cells to activate copper-dependent enzymes and reveal a second copper transport role for MNK in mammalian cells. These findings describe a single cell-based system that allows both the copper transport and trafficking functions of MNK to be studied. This study also contributes to our understanding of the molecular basis of pigmentation in mammalian cells.
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PMID:The Menkes copper transporter is required for the activation of tyrosinase. 1109 60

The activity of tyrosinase, the rate-limiting enzyme for melanin synthesis, is higher in Black skin melanocytes than in melanocytes derived from Caucasian skin. This variation in enzyme activity is not due to differences in tyrosinase abundance or tyrosinase gene activity, but, rather, is due to differences in the catalytic activity of preexisting tyrosinase. In melanocytes, tyrosinase is localized to the membrane of melanosomes and in Caucasian melanocytes the melanosome-bound enzyme is largely inactive. Conversely, in melanosomes of Black melanocytes, tyrosinase has high catalytic activity. Treatment of Caucasian melanocytes with the lysosomotropic compound ammonium chloride or with the ionophores nigericin and monensin results in a rapid and pronounced increase in tyrosinase activity. This increase occurs without any change in tyrosinase abundance, indicating that these compounds are increasing the catalytic activity of preexisting enzyme. Inhibition of the vacuolar proton pump V-ATPase by treatment of Caucasian melanocytes with bafilomycin also increases tyrosinase activity. In contrast to the 10-fold increase in tyrosinase observed in Caucasian melanocytes, neither ammonium chloride, monensin, nigericin, nor bafilomycin is able to increase the already high level of tyrosinase activity present in melanosomes of melanocytes derived from Black skin. Finally, staining of Caucasian melanocytes with the fluorescent weak base acridine orange shows that melanosomes of Caucasian, but not Black, melanocytes are acidic organelles. These data support a model for racial pigmentation that is based on differences in melanosome pH in Black and Caucasian skin types. The models suggests that melanosomes of Caucasian melanocytes are acidic, while those of Black individuals are more neutral. Since tyrosinase is inactive in an acid environment, the enzyme is largely inactive in Caucasian melanosomes but fully active in Black melanosomes.
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PMID:Regulation of the catalytic activity of preexisting tyrosinase in black and Caucasian human melanocyte cell cultures. 1113 43

Enzymes were investigated for their occurrence in the cell wall fraction (4,000 g sediment of the homogenate) of Agaricus bisporus sporocarps. Besides the markers malate dehydrogenase (MalDH), hexokinase (HK) and ATPase, the range of entities studied included gamma-glutamyl transferase (gamma-GT), mannitol dehydrogenase (MDH), phenoloxidase, chitin and beta-1,3-glucan synthases (ChS, beta-GS), chitinase, beta-N-acetylhexosaminidase (HexNAc'ase) and beta-glucanase. Using the extractability in dilute buffer, digitonin and NaCl at high ionic strength as the operational criteria, four categories (I-IV) of enzyme-wall associations could be discerned: category I encompasses enzymes which are artefactually present (i.e. contaminants); category II, enzymes that are hydrophobically bound (which may or may not be genuinely wall-associated), III includes enzymes that are ionically bound and IV, enzymes whose bonding to the wall is in all probability covalent. The same enzyme entity may have representatives in more than one category, e.g. ChS and beta-GS (I, II, IV), phenolase (I, II, III, IV), beta-glucanase, chitinase and HexNAc'ase (I, IV). It is thought that the categorization presented could be of general applicability in fungi as well as in higher plants to specify enzyme-wall associations in a straightforward, comparable manner, thus avoiding some of the ambiguous terms prevailing in the literature, such as "weakly", "strongly" or "tightly" wall bound. The results are discussed in more detail for several of the more economically important enzymes studied.
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PMID:A system of categorizing enzyme-cell wall associations in Agaricus bisporus, using operational criteria. 1160 7

In tyrosinase-positive amelanotic melanoma cells, inactive tyrosinase accumulates in the endoplasmic reticulum. Based on studies described here, we propose that aberrant vacuolar proton ATPase (V-ATPase)-mediated proton transport in melanoma cells disrupts tyrosinase trafficking through the secretory pathway. Amelanotic but not melanotic melanoma cells or normal melanocytes display elevated proton export as observed by the acidification of the extracellular medium and their ability to maintain neutral intracellular pH. Tyrosinase activity and transit through the Golgi were restored by either maintaining the melanoma cells in alkaline medium (pH 7.4-7.7) or by restricting glucose uptake. The translocation of tyrosinase out of the endoplasmic reticulum and the induction of cell pigmentation in the presence of the ionophore monensin or the specific V-ATPase inhibitors concanamycin A and bafilomycin A1 supported a role for V-ATPases in this process. Because it was previously shown that V-ATPase activity is increased in solid tumors in response to an acidified environment, the appearance of hypopigmented cells in tyrosinase-positive melanoma tumors may indicate the onset of enhanced glycolysis and extracellular acidification, conditions known to favor metastatic spread and resistance to weak base chemotherapeutic drugs.
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PMID:Abnormal acidification of melanoma cells induces tyrosinase retention in the early secretory pathway. 1181 90

Changes in pigmentation are frequently encountered in primary and metastatic melanocytic lesions. Pigmentation is determined by the activity of tyrosinase (TYR), the rate-limiting enzyme in melanin synthesis. Tyrosinase activity can be modulated at the genetic and/or epigenetic level. In this commentary I suggest that pigmentation can serve as an indicator for genetic and metabolic changes as follows. In TYR-negative, amelanotic melanomas cells, downregulation of TYR and other melanocyte-specific gene expression is likely to be mediated by dominantly acting oncogenes with impact on the transcriptional activity of the melanocyte-specific transcription factor Mitf. Ras and c-myc, shown to be active and upregulated in subclasses of melanoma tumors, have the potential to induce these changes. TYR-positive highly pigmented melanoma tumors are likely to reside in aerobic, well-vascularized microenvironment. In contrast, hypo- or amelanotic TYR-positive lesions suffer from reduced TYR activity due to an acidified microenvironment. These lesions might have encountered anaerobic conditions, and have adapted to the reduced oxygen by enhanced glycolysis, leading to extracellular acidification and activation of V-ATPase.
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PMID:Pigmentation in melanomas: changes manifesting underlying oncogenic and metabolic activities. 1220 72


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