Allosterism pyruvate kinase

Pyruvate kinase possesses allosteric sites for numerous effectors. It is activated by AMP and fructose-1,6-bisphosphate and inhibited by ATP, acetyl-CoA, and alanine. (Note that alanine is the a-amino acid counterpart of the a-keto acid, pyruvate.) Furthermore, liver pyruvate kinase is regulated by covalent modification. Flormones such as glucagon activate a cAMP-dependent protein kinase, which transfers a phosphoryl group from ATP to the enzyme. The phos-phorylated form of pyruvate kinase is more strongly inhibited by ATP and alanine and has a higher for PEP, so that, in the presence of physiological levels of PEP, the enzyme is inactive. Then PEP is used as a substrate for glucose synthesis in the pathway (to be described in Chapter 23), instead... 

Acetyl-CoA is a potent allosteric effector of glycolysis and gluconeogenesis. It allosterically inhibits pyruvate kinase (as noted in Chapter 19) and activates pyruvate carboxylase. Because it also allosterically inhibits pyruvate dehydrogenase (the enzymatic link between glycolysis and the TCA cycle), the cellular fate of pyruvate is strongly dependent on acetyl-CoA levels. A rise in... 

M15. Mattevi, A., Bolognesi, M and Valentini, G., The allosteric regulation of pyruvate kinase. FEBS Lett. 389, 15-19(1996). 

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... 

Three glycolytic enzymes are subject to allosteric regulation hexoldnase IV, phosphofructokinase-1 (PFK-1), and pyruvate kinase. 

Pyruvate kinase is allosterically inhibited by ATP, and the liver isozyme is inhibited by cAMP-dependent phosphorylation. 

Figure 10.4 The abolition of positive cooperativity on the binding of allosteric effectors to some enzymes. Note the dramatic increases in activity at low substrate concentrations on the addition of adenosine monophosphate to isocitrate dehydrogenase, of deoxycytosine diphosphate to deoxythymidine kinase, and of fructose 1,6-diphosphate to pyruvate kinase this shows how the activity may be switched on by an allosteric effector (PEP = phosphoenolpyruvate). [From J. A. Hathaway and D. E. Atkinson, J. Biol. Chem. 238,2875 (1963) R. Okazaki and A. Kornbcrg, J. Biol. Chem. 239,275 (1964) R. Haeckel, B. Hess, W. Lauterhom, and K.-H. Wurster, Hoppe-Seyler s Z. Physiol. Chem. 349, 699 (1968).]...

Muscle pyruvate kinase (PK) responds hyperbolically to its substrate, PEP, but the liver form of the enzyme responds sigmoidally. Fructose-1,6-bisphos-phate is an allosteric activator of liver pyruvate kinase, but it apparently has no effect on the muscle enzyme. 

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. 

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. 

Section 24,2.2) also allosterically inhihits the pyruvate kinases—in this case, to signal that building blocks are abundant. 

Figure 16.21. Control of the Catalytic Activity of Pyruvate Kinase. Pyruvate kinase is regulated by allosteric effectors and covalent modification.

A. Mattevi, G. Valentini, M. Rizzi, M L. Speranza, M. Bolognesi, and A. Coda. 1995. Crystal structure oiEscherichia coli pyruvate kinase type I Molecular basis of the allosteric transition Structure 3 729-741. (PubMed)... 

Two other allosteric enzyme regulatory reactions also help to regulate glycolysis the conversion of fructose 6-phosphate to fructose 1,6-diphosphate by phos-phofructokinase and the conversion of phosphoenolpyru-vate to pyruvate by pyruvate kinase. 

Mattevi A, Valentini G, Rizzi M> Speranza ML, Bolog-nesi M, Coda A. Crystal structure of Escherichia coh pyruvate kinase type I molecular basis of the allosteric transition. Structure 1995 3 729-41. 

A. Mattevi, M. Bolognesi, and G. Valentini The allosteric regulation of pyruvate kinase. FEES Letters 389,15 (1996). 

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