Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.4.3.11 (glutamate dehydrogenase)
 4,437 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Insulin secretion in humans is usually induced by mixed meals, which upon ingestion, increase the plasma concentration of glucose, fatty acids, amino acids, and incretins like glucagon-like peptide 1. Beta-cells can stay in the off-mode, ready-mode or on-mode; the mode-switching being determined by the open state probability of the ATP-sensitive potassium channels, and the activity of enzymes like glucokinase, and glutamate dehydrogenase. Mitochondrial metabolism is critical for insulin secretion. A sound understanding of the intermediary metabolism, electrophysiology, and cell signaling is essential for comprehension of the entire spectrum of the stimulus-secretion coupling. Depolarization brought about by inhibition of the ATP sensitive potassium channel, together with the inward depolarizing currents through the transient receptor potential (TRP) channels, leads to electrical activities, opening of the voltage-gated calcium channels, and exocytosis of insulin. Calcium- and cAMP-signaling elicited by depolarization, and activation of G-protein-coupled receptors, including the free fatty acid receptors, are intricately connected in the form of networks at different levels. Activation of the glucagon-like peptide 1 receptor augments insulin secretion by amplifying calcium signals by calcium induced calcium release (CICR). In the treatment of type 2 diabetes, use of the sulfonylureas that act on the ATP sensitive potassium channel, damages the beta cells, which eventually fail; these drugs do not improve the cardiovascular outcomes. In contrast, drugs acting through the glucagon-like peptide-1 receptor protect the beta-cells, and improve cardiovascular outcomes. The use of the glucagon-like peptide 1 receptor agonists is increasing and that of sulfonylurea is decreasing. A better understanding of the stimulus-secretion coupling may lead to the discovery of other molecular targets for development of drugs for the prevention and treatment of type 2 diabetes.
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PMID:Stimulus-Secretion Coupling in Beta-Cells: From Basic to Bedside. 3164 40

Chagas disease is a neglected tropical disease and a leading cause of heart failure in Latin America caused by a protozoan called Trypanosoma cruzi. This parasite presents a complex multi-stage life cycle. Anti-Chagas drugs currently available are limited to benznidazole and nifurtimox, both with severe side effects. Thus, there is a need for alternative and more efficient drugs. Genome-scale metabolic models (GEMs) can accurately predict metabolic capabilities and aid in drug discovery in metabolic genes. This work developed an extended GEM, hereafter referred to as iIS312, of the published and validated T. cruzi core metabolism model. From iIS312, we then built three stage-specific models through transcriptomics data integration, and showed that epimastigotes present the most active metabolism among the stages (see S1-S4 GEMs). Stage-specific models predicted significant metabolic differences among stages, including variations in flux distribution in core metabolism. Moreover, the gene essentiality predictions suggest potential drug targets, among which some have been previously proven lethal, including glutamate dehydrogenase, glucokinase and hexokinase. To validate the models, we measured the activity of enzymes in the core metabolism of the parasite at different stages, and showed the results were consistent with model predictions. Our results represent a potential step forward towards the improvement of Chagas disease treatment. To our knowledge, these stage-specific models are the first GEMs built for the stages Amastigote and Trypomastigote. This work is also the first to present an in silico GEM comparison among different stages in the T. cruzi life cycle.
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PMID:Genome-scale metabolic models highlight stage-specific differences in essential metabolic pathways in Trypanosoma cruzi. 3302 77


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