Positive allosteric effectors

The most potent positive allosteric effector of phospho-ffuctokinase-1 and inhibitor of fructose-1,6-bisphos-phatase in liver is fructose 2,6-bisphosphate. It relieves inhibition of phosphofructokinase-1 by ATP and increases affinity for fructose 6-phosphate. It inhibits fructose-1,6-bisphosphatase by increasing the for fructose 1,6-bisphosphate. Its concentration is under both substrate (allosteric) and hormonal control (covalent modification) (Figure 19-3). 

Carbamoyl phosphate synthetase I produces carbamoyl phosphate in the mitochondria from CO2, NH3, and two ATP molecules. The enzyme, which has an absolute requirement for its positive allosteric effector, N-acetylglutamate, is the rate-limiting step in the cycle. 

PFK is activated by AMP (the precursor for ADP and ATP) and by F26BP (which also acts as a positive allosteric effector ) but is inhibited by ATP, citrate and lowered pH ( end products of the pathway), ATP and citrate acting as negative allosteric effectors . In contrast FBPase is activated by citrate (a positive allosteric effector ) and inhibited by the plenty signal F26BP (a negative allosteric effector ). 

Short-term regulation of the cycle occurs principally at carbamoyl phosphate synthetase-I, which is relatively inactive in the absence of its allosteric activator N-acetylglutamate. The steady-state concentration of N-acetylglutamate is set by the concentration of its components, acetyl-CoA and glutamate, and by arginine, which is a positive allosteric effector of... 

E) IV-acetylglutamate is a positive allosteric effector of ornithine transcarbamoylase... 

Figure 24-2 The urea cycle pathway. CPS I, Carbamyl phosphate synthetase I N-acetyigiutamate as positive allosteric effector OTC, ornithine transcarbamyiase MS, argininosuccinate synthetase Ai, argininosuccinate iyase AR, arginase ADP, adenosine diphosphate, ATf adenosine triphosphate, P, inorganic phosphate.

The activity of pyruvate carboxylase is dependent upon the positive allosteric effector... 

Oxidation and decarboxylation of isocitrate to a-ketoglutarate. Isocitrate dehydrogenase is also an allosteric enzyme however, the enz)une is controlled by the positive allosteric effector, ADP. ADP is a signal that the levels of ATP must be low, and therefore the rate of the citric acid cycle should be increased. Interestingly, isocitrate dehydrogenase is also inhibited by high levels of NADH and ATP. 

Homotropic effect refers to allosteric effects produced by enzyme s own substrate and heterotropic effects are due to metabohtes that are not stmcturaUy related to enzyme s substrates. Positive effects are related to enzyme activation and negative effects to enzyme inhibition. Thus, fmctose-diphosphate is a positive allosteric effector of pymvate kinase. 

Studies with the acetyl-CoA carboxylases from avian [128,178] and rat liver [188] and from bovine adipose tissue [129] show that the K values for the substrates of the reaction (ATP, HCOj" and acetyl-CoA) are not materially affected by tricarboxylic acid activators, whereas large effects are observed. Direct binding experiments demonstrate that the affinity of the avian liver carboxylase for acetyl-CoA is not altered by citrate [180]. Thus, these tricarboxylic acids appear to act by increasing the rate of reaction of enzyme-bound substrate rather than by altering substrate affinity, and hence, according to the classification of Monod, Wyman, and Changeux, are positive allosteric effectors of the type [195]. 

Overexpression of pyruvate kinase and phosphofructokinase did not influence the activities of other enzymes in the pathway, nor did it change intermediary metabolite levels, and as a result, CA production was not increased. The activity of overexpressed phosphofructokinase was decreased through a reduction in the level of fructose 2,6-bisphosphate, a positive allosteric effector of phosphofructokinase. Another study found that overexpression of citrate synthase did not increase the rate of CA production. These studies support the calculations of Torres, who concluded that at least seven glycolytic enzymes needed to be overexpressed to achieve a significant increase in flux toward citrate. - ... 

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