Browse
Submit Data
Databases
API
Help

Dataset Information

35 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Glutathione Transferase (GST)-Activated Prodrugs.

ABSTRACT: Glutathione transferase (formerly GST) catalyzes the inactivation of various electrophile-producing anticancer agents via conjugation to the tripeptide glutathione. Moreover, several data link the overexpression of some GSTs, in particular GSTP1-1, to both natural and acquired resistance to various structurally unrelated anticancer drugs. Tumor overexpression of these proteins has provided a rationale for the search of GST inhibitors and GST activated cytotoxic prodrugs. In the present review we discuss the current structural and pharmacological knowledge of GST-activated cytotoxic compounds.

SUBMITTER: Ruzza P

PROVIDER: S-EPMC3834953 | biostudies-literature | 2013 Apr

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Publications

Glutathione Transferase (GST)-Activated Prodrugs.

Ruzza Paolo P Calderan Andrea A

Pharmaceutics 20130402 2

Glutathione transferase (formerly GST) catalyzes the inactivation of various electrophile-producing anticancer agents via conjugation to the tripeptide glutathione. Moreover, several data link the overexpression of some GSTs, in particular GSTP1-1, to both natural and acquired resistance to various structurally unrelated anticancer drugs. Tumor overexpression of these proteins has provided a rationale for the search of GST inhibitors and GST activated cytotoxic prodrugs. In the present review we ...[more]

PMID: 24300447

Similar Datasets

Glutathione-S-transferase (GST) polymorphisms are associated with relapse after radical prostatectomy.

Project description:BackgroundOrgan confined prostate cancer (PCa) can be cured by radical retropubic prostatectomy (RRP); however, some tumors will still recur. Current tools fail to identify patients at risk of recurrence. Glutathione-S-transferases (GSTs) are involved in the metabolism of carcinogens, hormones and drugs. Thus, genetic polymorphisms that modify the GST activities may modify the risk of PCa recurrence.MethodsWe retrospectively recruited Argentine PCa patients treated with RRP to study the association between GST polymorphisms and PCa biochemical relapse after RRP. We genotyped germline DNA in 105 patients for: GSTP1 c.313A>G (p.105 Ile>Val, rs1695) by PCR-RFLP; and GSTT1 null and GSTM1 null polymorphisms by multiplex PCR. Kaplan-Meier curves and Cox proportional hazard models were used to evaluate these associations.ResultsPatients with GSTP1 c.313GG genotype showed shorter biochemical relapse-free survival (BRFS) (P = 0.003) and higher risk for recurrence in unadjusted (Hazard ratio (HR) = 3.16, 95% confidence interval (95% CI) = 1.41-7.06, P = 0.005) and multivariate models (HR = 3.01, 95% CI = 1.13-8.02, P = 0.028). We did not find significant associations for GSTT1 and GSTM1 genotypes. In addition, we found shorter BRFS (P = 0.010) and increased risk for recurrence for patients having two or more risk alleles when we combined the genotypes of the three GSTs in multivariate models (HR = 3.06, 95% CI = 1.20-7.80, P = 0.019).ConclusionsOur results give support to the implementation of GSTs genotyping for personalized therapies as a novel alternative for PCa management for patients who undergo RRP. To the best of our knowledge, this is the first study that examined GST polymorphisms in PCa progression in Argentine men. Replication of our findings in larger cohort is warranted.

| S-EPMC3626169 | biostudies-literature

Glutathione Transferase Photoaffinity Labeling Displays GST Induction by Safeners and Pathogen Infection.

Project description:Glutathione transferases (GSTs) represent a large and diverse enzyme family involved in the detoxification of small molecules by glutathione conjugation in crops, weeds and model plants. In this study, we introduce an easy and quick assay for photoaffinity labeling of GSTs to study GSTs globally in various plant species. The small-molecule probe contains glutathione, a photoreactive group and a minitag for coupling to reporter tags via click chemistry. Under UV irradiation, this probe quickly and robustly labels GSTs in crude protein extracts of different plant species. Purification and mass spectrometry (MS) analysis of labeled proteins from Arabidopsis identified 10 enriched GSTs from the Phi(F) and Tau(U) classes. Photoaffinity labeling of GSTs demonstrated GST induction in wheat seedlings upon treatment with safeners and in Arabidopsis leaves upon infection with avirulent bacteria. Treatment of Arabidopsis with salicylic acid (SA) analog benzothiadiazole (BTH) induces GST labeling independent of NPR1, the master regulator of SA. Six Phi- and Tau-class GSTs that are induced upon BTH treatment were identified, and their labeling was confirmed upon transient overexpression. These data demonstrate that GST photoaffinity labeling is a useful approach to studying GST induction in crude extracts of different plant species upon different types of stress.

| S-EPMC10799724 | biostudies-literature

Glutathione S-transferase (GST) of American Cockroach, Periplaneta americana: Classes, Isoforms, and Allergenicity.

Project description:Insect glutathione S-transferases (GSTs) play important roles in insecticide/drug resistance and stress response. Medically, GSTs of house dust mites (Dermatophagoides pteronyssinus and Blomia tropicalis) and German cockroach (Blattella germanica) are human allergens. In this study, classes, isoforms and B-cell and allergenic epitopes of GST of American cockroach, Periplaneta americana, the predominant species in the tropics and subtropics were investigated for the first time. Enzymatically active native and recombinant P. americana-GSTs bound to IgE in sera of all P. americana allergic patients that were tested. By gel-based proteomics and multiple sequence alignments, the native GST comprises three isoforms of delta and sigma classes. All isoforms interacted with serum IgE of the cockroach allergic subjects. Molecularly, the protein contains six B-cell epitopes; two epitopes located at ?1-?1 and ?4-?3 regions bound to patients' serum IgE, indicating that they are allergenic. P. americana are ubiquitous and their GST can sensitize humans to allergic diseases; thus, the protein should be included in the allergen array for component resolved diagnosis (CRD) of allergic patients, either by skin prick test or specific IgE determination. The GST is suitable also as a target of environmental allergen detection and quantification for intervention of cockroach sensitization and allergic morbidity.

| S-EPMC5764987 | biostudies-literature

A glutathione transferase from Agrobacterium tumefaciens reveals a novel class of bacterial GST superfamily.

Project description:In the present work, we report a novel class of glutathione transferases (GSTs) originated from the pathogenic soil bacterium Agrobacterium tumefaciens C58, with structural and catalytic properties not observed previously in prokaryotic and eukaryotic GST isoenzymes. A GST-like sequence from A. tumefaciens C58 (Atu3701) with low similarity to other characterized GST family of enzymes was identified. Phylogenetic analysis showed that it belongs to a distinct GST class not previously described and restricted only in soil bacteria, called the Eta class (H). This enzyme (designated as AtuGSTH1-1) was cloned and expressed in E. coli and its structural and catalytic properties were investigated. Functional analysis showed that AtuGSTH1-1 exhibits significant transferase activity against the common substrates aryl halides, as well as very high peroxidase activity towards organic hydroperoxides. The crystal structure of AtuGSTH1-1 was determined at 1.4 Å resolution in complex with S-(p-nitrobenzyl)-glutathione (Nb-GSH). Although AtuGSTH1-1 adopts the canonical GST fold, sequence and structural characteristics distinct from previously characterized GSTs were identified. The absence of the classic catalytic essential residues (Tyr, Ser, Cys) distinguishes AtuGSTH1-1 from all other cytosolic GSTs of known structure and function. Site-directed mutagenesis showed that instead of the classic catalytic residues, an Arg residue (Arg34), an electron-sharing network, and a bridge of a network of water molecules may form the basis of the catalytic mechanism. Comparative sequence analysis, structural information, and site-directed mutagenesis in combination with kinetic analysis showed that Phe22, Ser25, and Arg187 are additional important residues for the enzyme's catalytic efficiency and specificity.

| S-EPMC3319563 | biostudies-literature

Association Between Glutathione S-Transferase (GST) Polymorphisms and Schizophrenia in a Chinese Han Population.

Project description:Background:Glutathione S-transferase (GST) is an important antioxidant enzyme in the body. The weakening of the antioxidant system causes damage to the cells and tissues that make up the organism, adversely affects the function of the nervous system, and ultimately leads to schizophrenia (SCZ). Previous studies have yielded inconsistent results across different ethnic populations. Purpose:This case-control study was carried out to investigate whether genetic polymorphisms in GST could be associated with SCZ in the Chinese Han population. Patients and Methods:A total of 794 participants, including 379 SCZ patients (case group) and 415 healthy individuals (control group), were genotyped by polymerase chain reaction-restriction fragment length for polymorphisms in GST genes. Results:The study found that the frequency of the GSTM1 null genotype was higher in case group than control group (p=0.003). The frequency of the GSTM1 and GSTT1 double null genotype was also higher in case group than control group (p=0.008). Conclusion:We conclude that the GSTM1 null genotype and the GSTM1 and GSTT1 double null genotype may be related to the onset of SCZ in Chinese Han population.

| S-EPMC7038391 | biostudies-literature

Glutathione-S-transferase (GST) P1, GSTM1, exercise, ozone and asthma incidence in school children.

Project description:BackgroundBecause asthma has been associated with exercise and ozone exposure, an association likely mediated by oxidative stress, we hypothesised that glutathione-S-transferase (GST)P1, GSTM1, exercise and ozone exposure have interrelated effects on the pathogenesis of asthma.MethodsAssociations of the well characterised null variant of GSTM1 and four single nucleotide polymorphisms (SNPs) that characterised common variation in the GSTP1 locus with new onset asthma in a cohort of 1610 school children were examined. Children's exercise and ozone exposure were classified using participation in team sports and community annual average ozone levels, respectively.ResultsA two SNP model involving putatively functional variants (rs6591255, rs1695 (Ile105Va)) best captured the association between GSTP1 and asthma. The risk of asthma was lower for those with the Val allele of Ile105Val (hazard ratio (HR) 0.60, 95% CI 0.4 to 0.8) and higher for the variant allele of rs6591255 (HR 1.40, 95% CI 1.1 to 1.9). The risk of asthma increased with level of exercise among ile(105) homozygotes but not among those with at least one val(105) allele (interaction p value = 0.02). The risk was highest among ile(105) homozygotes who participated in >or=3 sports in the high ozone communities (HR 6.15, 95% CI 2.2 to 7.4). GSTM1 null was independently associated with an increased risk of asthma and showed little variation with air pollution or GSTP1 genotype. These results were consistent in two independent fourth grade cohorts recruited in 1993 and 1996.ConclusionChildren who inherit a val(105) variant allele may be protected from the increased risk of asthma associated with exercise, especially in high ozone communities. GSTM1 null genotype was associated with an increased risk of asthma.

| S-EPMC2738935 | biostudies-literature

Analysis of the glutathione S-transferase (GST) gene family.

Project description:The glutathione S-transferase (GST) gene family encodes genes that are critical for certain life processes, as well as for detoxication and toxification mechanisms, via conjugation of reduced glutathione (GSH) with numerous substrates such as pharmaceuticals and environmental pollutants. The GST genes are upregulated in response to oxidative stress and are inexplicably overexpressed in many tumours, leading to problems during cancer chemotherapy. An analysis of the GST gene family in the Human Genome Organization-sponsored Human Gene Nomenclature Committee database showed 21 putatively functional genes. Upon closer examination, however, GST-kappa 1 (GSTK1), prostaglandin E synthase (PTGES) and three microsomal GSTs (MGST1, MGST2, MGST3) were determined as encoding membrane-bound enzymes having GST-like activity, but these genes are not evolutionarily related to the GST gene family. It is concluded that the complete GST gene family comprises 16 genes in six subfamilies--alpha (GSTA), mu (GSTM), omega (GSTO), pi (GSTP), theta (GSTT) and zeta (GSTZ).

| S-EPMC3500200 | biostudies-other

X-ray structures of Na-GST-1 and Na-GST-2 two glutathione S-transferase from the human hookworm Necator americanus.

Project description:BackgroundHuman hookworm infection is a major cause of anemia and malnutrition of adults and children in the developing world. As part of on-going efforts to control hookworm infection, The Human Hookworm Vaccine Initiative has identified candidate vaccine antigens from the infective L3 larval stages and adult stages of the parasite. Adult stage antigens include the cytosolic glutathione-S-transferases (GSTs). Nematode GSTs facilitate the inactivation and degradation of a variety of electrophilic substrates (drugs) via the nucleophilic addition of reduced glutathione. Parasite GSTs also play significant roles in multi-drug resistance and the modulation of host-immune defense mechanisms.ResultsThe crystal structures of Na-GST-1 and Na-GST-2, two major GSTs from Necator americanus the main human hookworm parasite, have been solved at the resolution limits of 2.4 A and 1.9 A respectively. The structure of Na-GST-1 was refined to R-factor 18.9% (R-free 28.3%) while that of Na-GST-2 was refined to R-factor 17.1% (R-free 21.7%). Glutathione usurped during the fermentation process in bound in the glutathione binding site (G-site) of each monomer of Na-GST-2. Na-GST-1 is uncomplexed and its G-site is abrogated by Gln 50. These first structures of human hookworm parasite GSTs could aid the design of novel hookworm drugs.ConclusionThe 3-dimensional structures of Na-GST-1 and Na-GST-2 show two views of human hookworm GSTs. While the GST-complex structure of Na-GST-2 reveals a typical GST G-site that of Na-GST-1 suggests that there is some conformational flexibility required in order to bind the substrate GST. In addition, the overall binding cavities for both are larger, more open, as well as more accessible to diverse ligands than those of GSTs from organisms that have other major detoxifying mechanisms. The results from this study could aid in the design of novel drugs and vaccine antigens.

| S-EPMC1924862 | biostudies-literature

Structural modifications modulate stability of glutathione-activated arylated diazeniumdiolate prodrugs.

Project description:JS-K, a diazeniumdiolate-based nitric oxide (NO)-releasing prodrug, is currently in late pre-clinical development as an anti-cancer drug candidate. This prodrug was designed to be activated by glutathione (GSH) to release NO. To increase the potency of JS-K, we are investigating the effect of slowing the reaction of the prodrugs with GSH. Herein, we report the effect of replacement of nitro group(s) by other electron-withdrawing group(s) in JS-K and its homo-piperazine analogues on GSH activation and the drugs' biological activity. We show that nitro-to-cyano substitution increases the half-life of the prodrug in the presence of GSH without compromising the compound's in vivo antitumor activity.

| S-EPMC3590845 | biostudies-literature

SKN-1-independent transcriptional activation of glutathione S-transferase 4 (GST-4) by EGF signaling.

Project description:In C. elegans research, transcriptional activation of glutathione S-transferase 4 (gst-4) is often used as a read-out for SKN-1 activity. While many heed an assumed non-exclusivity of the GFP reporter signal driven by the gst-4 promoter to SKN-1, this is also often ignored. We here show that gst-4 can also be transcriptionally activated by EOR-1, a transcription factor mediating effects of the epidermal growth factor (EGF) pathway. Along with enhancing exogenous oxidative stress tolerance, EOR-1 inde-pendently of SKN-1 increases gst-4 transcription in response to augmented EGF signaling. Our findings caution researchers within the C. elegans community to always rely on sufficient experimental controls when assaying SKN-1 transcriptional activity with a gst-4p::gfp reporter, such as SKN-1 loss-of-function mutants and/or additional target genes next to gst-4.

| S-EPMC5190145 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data