Pyruvate kinase stimulation

The key regulatory enzymes in glycolysis are phosphory-lase, hexokinase, phosphofructokinase and pyruvate kinase, the activities of which are stimulated by the increase in the concentrations of AMP and phosphate and the decrease in that of phosphocreatine. These mechanisms are discussed in Chapters 6 and 9 Figures 6.16 and 9.27. 

Mertens E, Van Schaftingen E, Muller M (1992) Pyruvate kinase from Trichomonas vaginalis, an allosteric enzyme stimulated by ribose 5-phosphate and glycerate 3-phos-phate. Mol Biochem Parasitol 54 13-20... 

Insulin stimulates the synthesis of hexokinases II and IV, PFK-1, pyruvate kinase, and several enzymes involved in lipid synthesis. Insulin stimulates glycogen synthesis in muscle and liver. 

Pyruvate kinase catalyzes the third irreversible step in glycolysis. It is activated by fructose 1,6-bisphosphate. ATP and the amino acid alanine allosterically inhibit the enzyme so that glycolysis slows when supplies of ATP and biosynthetic precursors (indicated by the levels of Ala) are already sufficiently high. In addition, in a control similar to that for PFK (see above), when the blood glucose concentration is low, glucagon is released and stimulates phosphorylation of the enzyme via a cAMP cascade (see Topic J7). This covalent modification inhibits the enzyme so that glycolysis slows down in times of low blood glucose levels. 

Pyruvate kinase is also stimulated by fructose 1,6-bisphosphate (see Topic J3 feedforward activation) so that its activity rises when needed, as glycolysis speeds up. 

The enzyme that catalyzes the conversion of PEP to pyruvate is pyruvate kinase. Liver pyruvate kinase is stimulated allosterically by fructose-1,6-diphosphate, AMP, ADP, and glyceraldehyde-3-phosphate. It is inhibited by alanine, ATP, NADH, and, more importantly, by cAMP- and Ca2 calmodulin-controlled phosphorylation. High blood glucagon levels thus inhibit the activities of both PFK II and pyruvate kinase in the liver through phosphorylation. Transcription of pyruvate kinase is also decreased by glucagon and increased by insulin. Muscle pyruvate kinase is not subject to cAMP or Ca2+ regulation. The pyruvate kinase reaction is practically irreversible. 

Insulin stimulates phosphatases that dephosphoiylate and activate pyruvate kinase. 

A. Insulin stimulates activation of pyruvate kinase, pyruvate dehydrogenase, and phospho-fructokinase 2 (PFK2). PFK2 then catalyzes formation of fructose 2,6-bisphosphate, which is an activator of PFK1 and an inhibitor of fructose 1,6-bisphosphatase, a gluconeogenic enzyme. 

Pyruvate kinase activity Stimulation Casein kinase II Biphasic... 

By decreasing the activity of glycolytic enzymes competing for the same substrate in this case, by inactivating pyruvate kinase in the cytosol and pyruvate dehydrogenase in the mitochondria (via cAMP stimulation of protein kinase). 

---