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

---

Query: EC:2.5.1.18 (glutathione S-transferase)
22,582 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Buthionine sulfoximine (BSO), a specific inhibitor of glutathione synthesis, showed variable growth-inhibitory activity in different tumor cell lines with a high degree of inhibitory activity against melanoma-derived cell lines. A correlation between BSO growth-inhibitory effects and cellular glutathione peroxidase activity was observed. In contrast, no correlation was demonstrated between the response to BSO and cellular tyrosinase, gamma-glutamylcysteine synthetase, glutathione transferase, gamma-glutamyl transpeptidase, or glutathione reductase activities. BSO enhanced 3,4-dihydroxybenzylamine (3,4-DHBA) (fourfold) and melphalan (threefold) in vitro cytotoxic activity as determined by inhibition of DNA synthesis in human melanoma cells and this enhancement was dependent on the duration of exposure to drug. BSO demonstrated in vivo antitumor activity in B16 melanoma-bearing mice prolonging survival by 29% and in combination with 3,4-DHBA resulted in a slight (48% versus 38%) increase in life span as compared to 3,4-DHBA alone. The combination of BSO and melphalan, however, increased the life span of B16 melanoma-bearing mice by 170%, as compared to melphalan alone (80%). These studies demonstrate a unique in vivo antimelanoma activity of BSO.
...
PMID:Melanoma cytotoxicity of buthionine sulfoximine (BSO) alone and in combination with 3,4-dihydroxybenzylamine and melphalan. 151 64

The actions of glutathione S-transferase and tyrosinase on the in vitro production of glutathionyl-3,4-dihydroxyphenylalanine and the dopachrome level in the presence of GSH and L-3,4-dihydroxyphenylalanine were studied. No clear evidence of complementarity between tyrosinase and glutathione S-transferase was observed; on the contrary, in the presence of glutathione S-transferase the glutathionyl-3,4-dihydroxyphenylalanine yield was lower than with tyrosinase only, as measured by HPLC. It is concluded that the spontaneous conjugation of GSH with dopaquinone should probably be high enough to scavenge the toxic quinone and to produce precursors for phaeomelanogenesis.
...
PMID:A study on the in vitro interaction between tyrosinase and glutathione S-transferase. 310 90

The irreversible and reversible inhibition of glutathione S-transferases (GSTs) by eugenol was studied in rat, mouse and man. Using liver cytosol of human, rat and mouse, species differences were found in the rate of irreversible inhibition of GSTs by eugenol in the presence of the enzyme tyrosinase. Tyrosinase was used to oxidize eugenol. No inhibition was observed in the absence of tyrosinase. The rate of irreversible inhibition of GSTs was highest in mouse cytosol, and lowest in rat cytosol. In addition, the irreversible inhibition of human and rat GSTs by eugenol was studied using purified isoenzymes of man and rat. The human GST isoenzymes A1-1, M1a-1a and P1-1 and the rat GST isoenzymes 1-1, 2-2, 3-3, 4-4 and 7-7 were irreversibly inhibited by eugenol in the presence of tyrosinase. In this respect human GST P1-1 and rat GST 7-7 were by far the most sensitive enzymes; human GST A2-2 was not inhibited. Indications were found that human GST P1-1 may be inhibited via three mechanisms: in addition to the well documentated nucleophilic addition of quinones and oxidation of cysteine residues, a covalent subunit cross-linking was also observed. The reversible inhibition of human and rat GST by eugenol, eugenol methyl ether, isoeugenol methyl ether, 2-allylphenol and 4-propylphenol was also studied using purified isoenzymes. The reversible inhibition of human and rat GSTs, using 1-chloro-2,4-dinitrobenzene as substrate, was expressed as I25. All compounds caused moderate reversible inhibition (I25 ranged from 0.2 to 5.4 mM for human GSTs and from 0.4 to 4.9 mM for rat GSTs). In rat, eugenol methyl ether was the strongest inhibitor. In human, the overall inhibiting capacities of eugenol, eugenol methyl ether, isoeugenol methyl ether and 4-propyl phenol were more or less similar; 2-allylphenol was the poorest inhibitor.
...
PMID:Inhibition of rat, mouse, and human glutathione S-transferase by eugenol and its oxidation products. 862 May 81

The risk factors for women developing breast and endometrium cancers are all associated with a lifetime of estrogen exposure. Estrogen replacement therapy (ERT) in particular has been correlated with a slight increased cancer risk, although the numerous benefits of ERT may negate this harmful side effect. Equilenin and equilin are equine estrogens which make up between 30% and 45% of the most widely prescribed estrogen replacement formulation, Premarin (Wyeth-Ayerst). In this study we have synthesized the catechol metabolites of equilenin [4-hydroxyequilenin (4-OHEN)] and equilin [4-hydroxyequilin (4-OHEQ)] and examined how changing unsaturation in the B ring affects the formation of o-quinone GSH conjugates and the ability of the o-quinones and/or GSH conjugates to inhibit glutathione S-transferase (GST). Interestingly, both 4-OHEN and 4-OHEQ autoxidized to o-quinones without the need of oxidative enzyme catalysis. 4-OHEN-o-quinone reacts with GSH to give two mono-GSH conjugates and one diadduct. The behavior of 4-OHEQ was found to be more complex than 4-OHEN as conjugates resulting from 4-OHEN were detected in addition to the 4-OHEQ GSH adducts. Both 4-OHEN and 4-OHEQ were found to be potent inhibitors of GST-catalyzed conjugation of GSH with 1-chloro-2,4-dinitrobenzene. In contrast, the endogenous catechol estrogens, 4-hydroxyestrone (4-OHE) and 2-hydroxyestrone (2-OHE), were without effect unless tyrosinase was present to convert the catechols to o-quinones. Scavengers of reactive oxygen species and metal chelators had no effect on GST inhibition by catechol estrogens with the exception of the catalase which protected GST activity. Kinetic studies showed that 4-OHEN was a potent irreversible inactivator of GST. Preincubation of the enzyme with 4-OHEN showed a time-dependent increase in inhibitory effect, and gel filtration did not restore GST activity confirming the irreversible nature of the enzyme inactivation. Analysis of the Kitz-Wilson plot gave a dissociation constant of the reversible enzyme-inhibitor complex (Ki = 620 microM) and a rate constant of conversion of the reversible enzyme-inhibitor complex to the irreversibly inhibited enzyme (k2 = 7.3 x 10(-)3 s-1). These data suggest that 4-OHEN is an irreversible inactivator with relatively low affinity for GST; however, once formed the 4-OHEN enzyme complex is rapidly converted to the irreversibly inhibited enzyme. The inhibition mechanism likely involves oxidation of the catechol estrogens to o-quinones and covalent modification and/or oxidation of critical amino acid residues on GST. In addition, hydrogen peroxide generated through redox cycling of the o-quinone and/or semiquinone radical and GSH could cause oxidative damage to GST.
...
PMID:Inhibition of glutathione S-transferase activity by the quinoid metabolites of equine estrogens. 967 38

The activities of antioxidant enzymes, and the expression of p21(WAF1) and p53 proteins were studied at different times after subculture during proliferation and differentiation phases. Two human melanoma cell lines were used: IPC182, which is a non-differentiating cell line, and IGR221, which spontaneously differentiates at the end of the exponential growth phase, as evidenced by a marked increase of melanin content and tyrosinase activity. In the two cell lines, the slowing of proliferation coincided with an increase in the activity and amount of immunoreactive superoxide dismutases (SOD1 and SOD2), and a decrease of catalase and glutathione peroxidase activities, and of the glutathione content. The levels of p21WAF1 and p53 proteins were found to be lower in confluent than in proliferative cells. Several parameters were modified only during the differentiation phase of IGR221 cells; in these cells the increase of tyrosinase activity was highly correlated with the increase in SOD2, GST, glutathione reductase, and G6PD activities. The level of glutathione was found to be lower in differentiated IGR221 than in non-differentiated IPC182 cells. These results suggest that p21WAF1 and p53 proteins are not involved in the spontaneous differentiation process of melanoma cells, and that abnormal regulation of the cell cycle inhibition pathway occurred in these cells. The results sustain the hypothesis that alterations of antioxidant enzyme expression are involved in the control of proliferation and differentiation of melanoma cells. Alterations of SOD2 activity may be of particular importance, since variations are observed with both cell growth and cell differentiation.
...
PMID:Modulation of antioxidant enzymes p21WAF1 and p53 expression during proliferation and differentiation of human melanoma cell lines. 1023 48

In the present study, the inhibition of human glutathione S-transferase P1-1 (GSTP1-1) by the flavonoid quercetin has been investigated. The results show a time- and concentration-dependent inhibition of GSTP1-1 by quercetin. GSTP1-1 activity is completely inhibited upon 1 h incubation with 100 microM quercetin or 2 h incubation with 25 microM quercetin, whereas 1 and 10 microM quercetin inhibit GSTP1-1 activity to a significant extent reaching a maximum of 25 and 42% inhibition respectively after 2 h. Co-incubation with tyrosinase greatly enhances the rate of inactivation, whereas co-incubation with ascorbic acid or glutathione prevents this inhibition. Addition of glutathione upon complete inactivation of GSTP1-1 partially restores the activity. Inhibition studies with the GSTP1-1 mutants C47S, C101S and the double mutant C47S/C101S showed that cysteine 47 is the key residue in the interaction between quercetin and GSTP1-1. HPLC and LC-MS analysis of trypsin digested GSTP1-1 inhibited by quercetin did not show formation of a covalent bond between Cys 47 residue of the peptide fragment 45-54 and quercetin. It was demonstrated that the inability to detect the covalent quercetin-peptide adduct using LC-MS is due to the reversible nature of the adduct-formation in combination with rapid and preferential dimerization of the peptide fragment once liberated from the protein. Nevertheless, the results of the present study indicate that quinone-type oxidation products of quercetin likely act as specific active site inhibitors of GSTP1-1 by binding to cysteine 47.
...
PMID:Inhibition of human glutathione S-transferase P1-1 by the flavonoid quercetin. 1268 90

The rationale fo the development of prodrugs relies upon delivery of higher concentrations of a drug to target cells compared to administration of the drug itself. In the last decades, numerous prodrugs that are enzymatically activated into anti-cancer agents have been developed. This review describes the most important enzymes involved in prodrug activation notably with respect to tissue distribution, up-regulation in tumor cells and turnover rates. The following endogenous enzymes are discussed: aldehyde oxidase, amino acid oxidase, cytochrome P450 reductase, DT-diaphorase, cytochrome P450, tyrosinase, thymidylate synthase, thymidine phosphorylase, glutathione S-transferase, deoxycytidine kinase, carboxylesterase, alkaline phosphatase, beta-glucuronidase and cysteine conjugate beta-lyase. In relation to each of these enzymes, several prodrugs are discussed regarding organ- or tumor-selective activation of clinically relevant prodrugs of 5-fluorouracil, axazaphosphorines (cyclophosphamide, ifosfamide, and trofosfamide), paclitaxel, etoposide, anthracyclines (doxorubicin, daunorubicin, epirubicin), mercaptopurine, thioguanine, cisplatin, melphalan, and other important prodrugs such as menadione, mitomycin C, tirapazamine, 5-(aziridin-1-yl)-2,4-dinitrobenzamide, ganciclovir, irinotecan, dacarbazine, and amifostine. In addition to endogenous enzymes, a number of nonendogenous enzymes, used in antibody-, gene-, and virus-directed enzyme prodrug therapies, are described. It is concluded that the development of prodrugs has been relatively successful; however, all prodrugs lack a complete selectivity. Therefore, more work is needed to explore the differences between tumor and nontumor cells and to develop optimal substrates in terms of substrate affinity and enzyme turnover rates fo prodrug-activating enzymes resulting in more rapid and selective cleavage of the prodrug inside the tumor cells.
...
PMID:Enzyme-catalyzed activation of anticancer prodrugs. 1500 63

The effect of catechol-O-methyltransferase (COMT) deficiency on methamphetamine-induced hydroxyl radical production in the brain was assessed by the salicylate trapping method. Methamphetamine-induced hyperthermia was also studied. Furthermore, the effect of COMT deficiency on the activities of glutathione S-transferase, quinone reductase and liver mono-oxygenases was assessed with and without l-dopa challenge. Finally, two alternative pathways of l-dopa metabolism were evaluated. Methamphetamine increased 2,3-dihydroxybenzoic acid levels only slightly (n.s.) at the lowest dose level (2.5 mg/kg x 4 i.p.). This was accompanied by a simultaneous increase in salicylate levels so that the 2,3-dihydroxybenzoic acid/salicylate ratio decreased correspondingly. Most importantly, no COMT genotype-dependent changes were observed. However, hyperthermia was induced even at the lowest methamphetamine dose, the COMT-deficient mice being most sensitive. COMT deficiency did not significantly change the activities of liver glutathione S-transferase, quinone reductase or 7-ethoxyresorufin and 7-pentoxyresorufin O-dealkylation. In COMT-deficient female mice, l-dopa (30-80 mg/kg b.i.d. for 2 days) did not induce any significant changes in liver or brain glutathione S-transferase and quinone reductase activity or liver 7-ethoxyresorufin O-deethylation activity. The levels of l-dopa conjugates in urine were also negligible in COMT-deficient mice. Skin tyrosinase activity was increased in 7- to 8-day-old hairless COMT-deficient pups. The present results suggest that despite the increased hyperthermic response, COMT deficiency does not increase methamphetamine-induced hydroxyl radical production or change significantly the activity of certain enzymes involved in defense against reactive oxygen species. In conclusion, we found no evidence of increased oxidative stress in the liver or brain of adult mice lacking COMT activity.
...
PMID:Lack of increased oxidative stress in catechol-O-methyltransferase (COMT)-deficient mice. 1537 29

Recently, genes encoding TatA, TatB, and TatC homologues were identified in Streptomyces lividans and the functionality of the twin-arginine translocation (Tat) pathway was demonstrated. Previously, we have shown that TatC is indispensable for Tat-dependent secretion in S. lividans. In the present work, we demonstrate that as TatB, S. lividans TatA is important but not essential for efficient secretion of xylanase C and tyrosinase. The results presented here indicate that in the presence of TatC, still partially functional translocation systems composed of TatAC or TatBC can be formed, suggesting that TatA and TatB have at least partially overlapping activities. However, the dissimilar effect caused by a tatA deletion or a tatB deletion on Tat-dependent secretion together with the fact that TatA cannot fully functionally substitute TatB and vice versa indicates that in S. lividans TatA and TatB are not functionally equivalent. Interestingly, soluble GST-tagged TatA and TatB were able to specifically bind Tat-dependent preproteins. The ability to bind Tat-dependent preproteins together with their cytoplasmic localization in S. lividans strongly suggests that both TatA and TatB, independently or associated, serve to recruit Tat-dependent preproteins to the translocase.
...
PMID:Functional analysis of TatA and TatB in Streptomyces lividans. 1611 62

We isolated a cDNA homolog of Neurospora crassa wc-2 from the basidiomycetous mushroom Lentinula edodes and termed it phrB cDNA. The deduced PHRB (313 amino acid residues) contained a PAS domain and a zinc-finger motif. Random binding-site selection analysis of the PHRB produced in Escherichia coli revealed that it bound to a 7-bp sequence with the consensus sequence 5'GATA/TTG/T/AC3'. Electrophoretic mobility-shift assay showed that it also bound to the consensus sequence 5'GATATTC3' in the promoter region of the L. edodes tyrosinase gene (Le.tyr). In vitro GST-pulldown immunoblot analysis disclosed that PHRB interacts with a putative blue-light photoreceptor of L. edodes (PHRA), the homolog of N. crassa WC-1, through the PAS B- and/or PAS C domain of PHRA. The expression of phrB and Le.tyr genes in pre-primordial mycelia of L. edodes is induced by light exposure, suggesting that PHRB can regulate the expression of the Le.tyr gene in a light-dependent manner.
...
PMID:The basidiomycetous mushroom Lentinula edodes white collar-2 homolog PHRB, a partner of putative blue-light photoreceptor PHRA, binds to a specific site in the promoter region of the L. edodes tyrosinase gene. 1934 89


1 2 3 Next >>

---