Green Tea Polyphenols Modulate Insulin Secretion by Inhibiting Glutamate Dehydrogenase
The Children's Hospital of Philadelphia, Filadelfia, Pennsylvania, United States Journal of Biological Chemistry
(Impact Factor: 4.57).
05/2006; 281(15):10214-21. DOI: 10.1074/jbc.M512792200
Insulin secretion by pancreatic beta-cells is stimulated by glucose, amino acids, and other metabolic fuels. Glutamate dehydrogenase (GDH) has been shown to play a regulatory role in this process. The importance of GDH was underscored by features of hyperinsulinemia/hyperammonemia syndrome, where a dominant mutation causes the loss of inhibition by GTP and ATP. Here we report the effects of green tea polyphenols on GDH and insulin secretion. Of the four compounds tested, epigallocatechin gallate (EGCG) and epicatechin gallate were found to inhibit GDH with nanomolar ED(50) values and were therefore found to be as potent as the physiologically important inhibitor GTP. Furthermore, we have demonstrated that EGCG inhibits BCH-stimulated insulin secretion, a process that is mediated by GDH, under conditions where GDH is no longer inhibited by high energy metabolites. EGCG does not affect glucose-stimulated insulin secretion under high energy conditions where GDH is probably fully inhibited. We have further shown that these compounds act in an allosteric manner independent of their antioxidant activity and that the beta-cell stimulatory effects are directly correlated with glutamine oxidation. These results demonstrate that EGCG, much like the activator of GDH (BCH), can facilitate dissecting the complex regulation of insulin secretion by pharmacologically modulating the effects of GDH.
Available from: Richard I. Morimoto
- "In contrast to inhibitors that bind the N-terminus, novobiocin derivatives that target the C-terminal domain slow the growth of cancer cells and promote degradation of HSP90 clients without inducing the heat shock response, which is an important and somewhat unexpected distinction . Other non-ATP-competitive HSP90 inhibitors are known, but most are non-selective, which limits their in vivo use; examples include epigallocatechin gallate  (inhibits several nonchaperone targets     ), cisplatin  (damages DNA ), and silybin  (inhibits P-glycoprotein  and cytochrome P450 ). A particularly interesting class of small molecules is capable of modulating co-chaperone access to the EEVD motif in the HSP90 C-terminus. "
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ABSTRACT: Protein homeostasis (proteostasis) is inextricably tied to cellular health and organismal lifespan. Aging, exposure to physiological and environmental stress, and expression of mutant and metastable proteins can cause an imbalance in the protein folding landscape, resulting in the formation of non-native protein aggregates that challenge the capacity of the proteostasis network (PN), increasing the risk for diseases associated with misfolding, aggregation and aberrant regulation of cell stress responses. Molecular chaperones have central roles in each of the arms of the PN (protein synthesis, folding, disaggregation, and degradation), leading to the proposal that modulation of chaperone function could have therapeutic benefits for the large and growing family of diseases of protein conformation including neurodegeneration, metabolic diseases, and cancer. In this review, we will discuss the current strategies used to tune the PN through targeting molecular chaperones and assess the potential of the chemical biology of proteostasis.
Copyright © 2015. Published by Elsevier Ltd.
Journal of Molecular Biology 05/2015; 427(18). DOI:10.1016/j.jmb.2015.05.010 · 4.33 Impact Factor
Available from: Fadlo R Khuri
- "Currently, the only reported GDH1 inhibitor is epigallocatechin gallate (EGCG), a polyphenol flavonoid isolated from green tea. However, EGCG targets a group of enzymes that use NADPH as a cofactor (Li et al., 2006, 2011a, 2011b). We thus designed a series of screening assays to identify GDH1-selective inhibitors . "
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ABSTRACT: How mitochondrial glutaminolysis contributes to redox homeostasis in cancer cells remains unclear. Here we report that the mitochondrial enzyme glutamate dehydrogenase 1 (GDH1) is commonly upregulated in human cancers. GDH1 is important for redox homeostasis in cancer cells by controlling the intracellular levels of its product alpha-ketoglutarate and subsequent metabolite fumarate. Mechanistically, fumarate binds to and activates a reactive oxygen species scavenging enzyme glutathione peroxidase 1. Targeting GDH1 by shRNA or a small molecule inhibitor R162 resulted in imbalanced redox homeostasis, leading to attenuated cancer cell proliferation and tumor growth.
Copyright © 2015 Elsevier Inc. All rights reserved.
Cancer Cell 02/2015; 27(2):257-70. DOI:10.1016/j.ccell.2014.12.006 · 23.52 Impact Factor
Available from: Alfred J Meijer
- "In retrospect , the participation of glutamate dehydrogenase in the control of autophagy is in agreement with the obser - vation that autophagy was stimulated pharmacologically by the green tea component epigallocatechin gallate ( Li et al . 2011 ; Zhou et al . 2014 ) . This compound is a powerful inhib - itor of glutamate dehydrogenase ( Li et al . 2006 ) , but the link between these phenomena was not made . Involvement of GDH in amino acid sensing has serious consequences for the use of chloroquine in the measure - ment of autophagic flux . This compound not only increases the intralysosomal pH and in this way affects the intralysosomal amino acid pool , as discussed above ( cf . sect"
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ABSTRACT: Amino acids not only participate in intermediary metabolism but also stimulate insulin-mechanistic target of rapamycin (MTOR)-mediated signal transduction which controls the major metabolic pathways. Among these is the pathway of autophagy which takes care of the degradation of long-lived proteins and of the elimination of damaged or functionally redundant organelles. Proper functioning of this process is essential for cell survival. Dysregulation of autophagy has been implicated in the etiology of several pathologies. The history of the studies on the interrelationship between amino acids, MTOR signaling and autophagy is the subject of this review. The mechanisms responsible for the stimulation of MTOR-mediated signaling, and the inhibition of autophagy, by amino acids have been studied intensively in the past but are still not completely clarified. Recent developments in this field are discussed.
Amino Acids 06/2014; 47(10). DOI:10.1007/s00726-014-1765-4 · 3.29 Impact Factor
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