Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:6.4.1.1 (pyruvate carboxylase)
 1,516 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

It has been shown previously that glucose-induced insulin release is completely absent in rat pancreatic islets that had been cultured for 1 day at low glucose (1 mM) and that it is restored by culturing islets for a 2nd day at high (20 mM) glucose (MacDonald, M. J., Fahien, L. A., McKenzie, D. I., and Moran, S. M. (1991) Am. J. Physiol. 259, E548-E554). It has been suggested that the incapacitation of glucose's insulinotropism is due to down-regulation of the synthesis of enzymes that process glucose's metabolic signal for insulin release. In the current study, results of metabolic, enzymic, and molecular biologic experiments were each consistent with (an) intramitochondrial site(s) of down-regulation in islets cultured at low glucose. Glucose metabolism was inhibited 80% in islets cultured at 1 mM glucose. The suppression of release of 14CO2 from [6-14C]glucose greater than from [U-14C]glucose greater than [3,4-14C]glucose greater than from [1-14C]glucose in islets cultured at low glucose indicated a mitochondrial site of down-regulation because C-6 of glucose can only be converted to CO2 in the citric acid cycle, whereas C-1 can be released as CO2 in the 6-phosphogluconate dehydrogenase [corrected] reaction, and C-6 of glucose dwells in the citric acid cycle longer than carbons 2-5 of glucose. Since carbons 3 and 4 of glucose can be decarboxylated in the pyruvate dehydrogenase reaction, incomplete suppression of CO2 formation from these carbons is consistent with suppression of pyruvate carboxylation as well as decarboxylation. Formation of 3HOH from [5-3H]glucose was equal in the two groups of islets, indicating that glycolysis as far as phosphoenolpyruvate was intact. This idea was supported by assays which showed that activities of enzymes of the glycolytic pathway between glucokinase/hexokinase and pyruvate kinase were equal in both types of islets. Additional studies indicated that regulation by glucose was at transcription of genes coding for some mitochondrial enzymes. Glucokinase, malic enzyme, and fumarase mRNAs were not affected by glucose, whereas the pyruvate dehydrogenase E1 alpha subunit and pyruvate carboxylase mRNAs were decreased 85-90% in islets cultured at 1 mM glucose. Pyruvate dehydrogenase enzyme activity was decreased to a similar extent in these islets. About 24 h was required for maximal (de)induction of pyruvate dehydrogenase E1 alpha and pyruvate carboxylase mRNAs, and the amounts of transcripts were proportional to the concentrations of glucose between 1 and 20 mM.(ABSTRACT TRUNCATED AT 400 WORDS)
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PMID:Pyruvate dehydrogenase and pyruvate carboxylase. Sites of pretranslational regulation by glucose of glucose-induced insulin release in pancreatic islets. 193 63

Pancreatic islets were cultured for 1 day in the presence of 1 to 20 mM glucose and islet proteins were separated on polyacrylamide gels and transferred to nitrocellulose. Pyruvate carboxylase and an unidentified biotin-containing protein were visualized with [125I]streptavidin followed by autoradiography. The amount of pyruvate carboxylase was proportional to the concentration of glucose. Estimates of the amount of the enzyme in islets were made by comparing the density of the islet pyruvate carboxylase band with a standard curve of various amounts of authentic pyruvate carboxylase. This indicated that the enzyme comprised 0.4% of total islet protein. Net synthesis of the enzyme was increased by cAMP and methyl succinate. A nuclear run-on assay showed that glucose caused increases in pyruvate carboxylase and pyruvate dehydrogenase E1 alpha subunit transcripts and decreases in branched chain ketoacid dehydrogenase E1 alpha transcripts in rat insulinoma (RINm5F) cells. Pancreatic islets cultured in the presence of 1 mM glucose for 1 day cannot respond to glucose with insulin release. Previous studies demonstrated that carbon flux into the citric acid cycle intermediates via both carboxylation and decarboxylation is decreased in glucose-incapacitated islets (M. J. MacDonald, 1993, Arch. Biochem. Biophys. 300, 205-214), 1993). The current results support the idea that carboxylation of glucose-derived pyruvate, as well as decarboxylation of pyruvate, is important for glucose-induced insulin secretion.
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PMID:Influence of glucose on pyruvate carboxylase expression in pancreatic islets. 777 76