Phosphoenolpyruvate carboxykinase inhibition

Phosphoenolpyruvate carboxykinase (PEP-CK), a key enzyme in gluconeogenesis, is regulated by several hormones, all of which affect the transcription of the PEP-CK gene. Cortisol, glucagon, and thyroxin induce PEP-CK, while insulin inhibits its induction (see p. 158). 

A patient presented with a bacterial infection that produced an endotoxin that inhibits phosphoenolpyruvate carboxykinase. 

Insulin inhibits transcription of the enzyme phosphoenolpyruvate carboxykinase (PEPCK). PEPCK is a key enzyme in gluconeogenesis and transcription is the primary means of regulating it. By inhibiting PEPCK transcription, insulin can depress glucose production tremendously. (Conversely, the hormone glucagon, which increases blood glucose levels, stimulates PEPCK transcription.)... 

Phosphoenolpyruvate carboxykinase (PEPCK) - This enzyme has no known allosteric regulators. The enzyme is controlled by hormonal regulation of its synthesis. The hormone, glucagon, activates transcription of the structural gene for the enzyme. Insulin, on the other hand, inhibits transcription of the gene. 

Glucagon brings about the inhibition of pyruvate kinase (PK) in the liver, causing phosphoenolpyruvate (PEP) to accumulate. The level of pyruvate decreases, both because its synthesis from PEP is blocked and because it continues to be converted to PEP, via the pyruvate carboxylase and phosphoenolpyruvate carboxykinase reactions. Accumulation of PEP promotes gluconeogenesis, while the inhibition of pyruvate kinase diminishes the glycolytic flux rate. 

Some effects of insulin occur within seconds or minutes, including the activation of glucose and ion transport systems, the covalent modification of enzymes (i.e., phosphorylation or dephosphorylation), and some effects on gene transcription (i.e., inhibition of the phosphoenolpyruvate carboxykinase gene). Effects on protein synthesis and gene transcription require hours, while those on cell proliferation and differentiation may take days. 

REGULATION OF GENE TRANSCRIPTION A major action of insulin is the regulation of transcription of more than 100 specific genes. InsuMn inhibits the transcription of phosphoenolpyruvate carboxykinase, contributing to insulin s inhibition of gluconeogenesis this effect of insulin may explain why the liver overproduces glucose in the insuhn-resistant state that is characteristic of type 2 DM. 

Iron is also an essential constituent of several non-porphyrin enzymes, e.g. aconitase, aldolase, and succinic dehydrogenase. Inhibition of the synthesis of glucose by tryptophan in animal cells depends on chelation. The tryptophan is metabolized to pyridine-2,3-dicarboxylic acid, which complexes the divalent iron necessary for the action of phosphoenolpyruvate carboxykinase (a key enzyme in the neogenesis of glucose) (Veneziale et al., 1967). 

Phosphoenolpyruvate carboxykinase (PEPCK) in the cytosol needs GTP, is stimulated by glucagon and inhibited by insulin. 

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