Glycation of Glutamate Cysteine Ligase by 2-Deoxy-d-Ribose and its Potential Impact on Chemoresistance in Glioblastoma

  title={Glycation of Glutamate Cysteine Ligase by 2-Deoxy-d-Ribose and its Potential Impact on Chemoresistance in Glioblastoma},
  author={Donald S. Backos and Kristofer S. Fritz and Debbie G. McArthur and Jadwiga K. Kepa and Andrew M. Donson and Dennis R. Petersen and Nicholas K. Foreman and Christopher C. Franklin and Philip Reigan},
  journal={Neurochemical Research},
The antioxidant glutathione (GSH) plays a critical role in maintaining intracellular redox homeostasis but in tumors the GSH biosynthetic pathway is often dysregulated, contributing to tumor resistance to radiation and chemotherapy. Glutamate-cysteine ligase (GCL) catalyzes the first and rate-limiting reaction in GSH synthesis, and enzyme function is controlled by GSH feedback inhibition or by transcriptional upregulation of the catalytic (GCLC) and modifier (GCLM) subunits. However, it has… 
2'-Deoxyribose mediated glycation leads to alterations in BSA structure via generation of carbonyl species.
A significant modification was evident in 2'-Deoxyribose-glycated BSA which was confirmed through increased hyperchromicity, keto amine moieties, carbonyl and hydroxymethyl furfural content, fluorescent AGEs, altered secondary structure conformers (α helix and β sheets), band shift in the amide-I region and diminished free lysine and free arginine content.
Thymidine catabolism promotes NADPH oxidase-derived reactive oxygen species (ROS) signalling in KB and yumoto cells
It is demonstrated that TP promotes NADPH oxidase-derived ROS signalling in cancer cells and thymidine catabolism increases the intracellular NADPH level via the PPP, which enhances the production of ROS by NADPH oxidation and activates its downstream signalling.
System χc- overexpression prevents 2-deoxy-d-ribose-induced β-cell damage.
It is shown that 2-deoxy-d-ribose (dRib) induces oxidative damage through GSH depletion in pancreatic β-cells and depletes intracellular GSH content through inhibition of cystine transport via system χc- inβ-cells.
Emerging regulatory paradigms in glutathione metabolism.
This review will discuss the enzymes and pathways affecting glutathione flux in cancer and summarize current models for regulating cellular glutATHione through both de novo synthesis and efficient salvage, and examine the integration of glutathion metabolism with other altered fates of intermediary metabolites.
Evaluation of Thymidine Phosphorylase Inhibitors in Glioblastoma and Their Capacity for Temozolomide Potentiation.
It is supported that TP inhibitors could be used as chemosensitizing agents in GBM to improve the efficacy of TMZ and enhance the cytotoxicity of temozolomide (TMZ).
Design of Novel Inhibitors of Human Thymidine Phosphorylase: Synthesis, Enzyme Inhibition, in Vitro Toxicity, and Impact on Human Glioblastoma Cancer.
To the best of the knowledge, this active compound is the most potent in vitro hTP inhibitor with a kinetic profile that cannot be reversed by the accumulation of any enzyme substrates.
Strategies to Target Glucose Metabolism in Tumor Microenvironment on Cancer by Flavonoids
The roles of flavonoids in regulating glucose metabolism and cancer cell growth in TME, such as proliferation advantage, cell mobility, and chemoresistance to cancer, as well as modifiers of thermal sensitivity are focused on.
Pleiotropic consequences of metabolic stress for the major histocompatibility complex class II molecule antigen processing and presentation machinery.
Hyperglycemia and hyperlipidemia are often observed in individuals with type II diabetes (T2D) and related mouse models. One dysmetabolic biochemical consequence is the non-enzymatic reaction between
Thymidine phosphorylase in cancer aggressiveness and chemoresistance
This review provides comprehensive understanding of the molecular mechanism of TP function in cancer and describes recent advancement in understanding, with a focus on cancer cell biology and the pharmacology of pyrimidine analogue anticancer agents.
A combination of curcumin and oligomeric proanthocyanidins offer superior anti-tumorigenic properties in colorectal cancer
A case is made for the clinical co-administration of curcumin and OPCs as a treatment therapy for patients with colorectal cancer by delineating the cooperative mechanisms of action.


Posttranslational modification and regulation of glutamate-cysteine ligase by the α,β-unsaturated aldehyde 4-hydroxy-2-nonenal.
It is demonstrated that 4-HNE can alter GCL holoenzyme formation and activity via direct posttranslational modification of the GCL subunits in vitro, which could significantly affect cellular GSH homeostasis and GSH-dependent detoxification during periods of oxidative stress.
Variable regulation of glutamate cysteine ligase subunit proteins affects glutathione biosynthesis in response to oxidative stress.
It is demonstrated that alterations in cellular GSH are clearly correlated with GCLC to a greater extent than GCLM, suggesting that the regulatory role of G CLM is minimal under physiologically relevant conditions of oxidative stress.
Rapid Activation of Glutamate Cysteine Ligase following Oxidative Stress*
It is suggested that a dynamic equilibrium exists between low and high activity forms of GCL and is altered by transient oxidative stress, which provides a mechanism for the rapid post-translational activation of G CL and maintenance of cellular GSH homeostasis.
Structure, function, and post-translational regulation of the catalytic and modifier subunits of glutamate cysteine ligase.
Variability in GCL expression is associated with several disease phenotypes and transgenic mouse and rat models promise to be highly useful for investigating the relationships between GCL activity, GSH synthesis, and disease in humans.
2-deoxy-d-ribose induces apoptosis by inhibiting the synthesis and increasing the efflux of glutathione.
It is concluded that dRib interferes with GSH homeostasis and that likely cellular oxidative stress is a consequence of GSH depletion.
Regulation of glutathione synthesis.
  • Shelly C. Lu
  • Biology, Medicine
    Molecular aspects of medicine
  • 2009
Dysregulation of GSH synthesis is increasingly being recognized as contributing to the pathogenesis of many pathological conditions, including diabetes mellitus, pulmonary fibrosis, cholestatic liver injury, endotoxemia and drug-resistant tumor cells.
The enzymes of glutathione synthesis: gamma-glutamylcysteine synthetase.
  • O. Griffith, R. Mulcahy
  • Chemistry, Medicine
    Advances in enzymology and related areas of molecular biology
  • 1999
The key step in glutathione synthesis, namely the ATP-dependent synthesis of gamma-glutamylcysteine, is the topic of this review and attention is focused on post-translational regulation.
Interaction between the catalytic and modifier subunits of glutamate-cysteine ligase.
The results suggest that the heterodimer formation may not be dependent on primary amino-acid sequence but, instead, involves a complex formation of the tertiary structure of both proteins.
Manipulation of cellular GSH biosynthetic capacity via TAT-mediated protein transduction of wild-type or a dominant-negative mutant of glutamate cysteine ligase alters cell sensitivity to oxidant-induced cytotoxicity.
It is demonstrated that TAT-mediated transduction of wild-type or dominant-inhibitory mutants of the GCL subunits is a viable means of manipulating cellular GCL activity to assess the effects of altered GSH biosynthetic capacity.
Covalent coupling of reduced glutathione with ribose: loss of cosubstrate ability to glutathione peroxidase.
The coupling of GSH with a monosaccharide such as ribose might contribute to the decreased cell GSH and glutathione peroxidase activity observed in diabetics.