Is isocitrate dehydrogenase an allosteric enzyme

covalent enzyme modification

covalent enzyme modification, Enzyme modulation, Enzyme interconversion. Oligomeric (i.e. multi-chain) enzymes can exist in two or more forms, which can be converted into one another by enzyme-catalyzed covalent modification, and differ, for example, in terms of activity, substrate affinity or dependence on effectors. Usually the difference in activity is that one form is active and the other is inactive. The activity of the converting enzymes is regulated by other enzymes, metabolites and / or effectors. The k. In addition to the allostery, E. is important for physiological regulation. While allostery allows the speed of metabolic reactions to be fine-tuned, k. E. An on / off switch for the cell functions, which is very sensitive to environmental influences.

The most common type of k. E. appears to be a cycle of phosphorylation / dephosphorylation. Many cell membrane receptor molecules are kinases, as are the products of some oncogenes.

The possibility of such systems to react drastically to small changes in the concentration of the effector molecules is based on their kinetic behavior, which can be described with the Michaelis-Menten equation. In the steady state, the rate constant of the activation and inactivation reaction P depends

on the proportion of the active form (P * / Ptotal) protein P present. If the substrate concentration (the regulated protein) is less than the KmValue of the regulating enzyme, the kinetics are first-order. The following applies to the forward reaction: vH = (VmH/ KmH) P, and for the reverse reaction: vR. = (vmR/ KmR) P*. If the two reactions are shown graphically as in Fig. 1, then the proportion of the activated enzyme in the stationary state appears at the intersection of the graphs of the two enzymes. A small change in activity (V.m) with one of the two enzymes does not have a major effect on the active part of the substrate protein.

On the other hand, if the concentration of the regulated protein is high enough to saturate the two modifying enzymes, a zero order reaction results. In this case, a relatively small change in V causesmValue of one of the two shows a large change in the proportion of the regulated protein that is in the active form (Fig. 1B). This makes the system very sensitive to changes in the concentration of an allosteric regulator for one of the modifying enzymes. An example of a system that obeys zero order regulation is isocitrate dehydrogenase from E. coli [D.C. LaPorte and D.E. Koshland, Jr. Nature305 (1983) 286-290]. This enzyme determines the distribution of acetyl-CoA between the tricarboxylic acid cycle and the glyoxylate cycle. Isocitrate dehydrogenase, which belongs to the tricarboxylic acid cycle, is inactivated by phosphorylation. The phosphatase, which removes the phosphate groups and thereby activates the dehydrogenase, is in turn activated by 3-phosphoglycerate, a metabolic precursor of acetyl-CoA. If 3-phosphoglycerate is present, the active isocitrate dehydrogenase allows the acetyl-CoA to enter the tricarboxylic acid cycle, where it becomes CO2 is oxidized. However, if the bacteria grow on an excess of acetate, the relative lack of 3-phosphoglycerate causes the inactivation of phosphatase and thus dehydrogenase. The tricarboxylic acid cycle is then shut down and the glyoxylate switch provides carbon for the synthesis of cell substances. The Km The behavior of the phosphatase in relation to the concentration of the isocitrate dehydrogenase is such that a slight change in the concentration of the 3-phosphoglycerate shifts the equilibrium of the isocitrate dehydrogenase from almost completely active to almost completely inactive and vice versa.

Phosphorylase, which catalyzes glycogen breakdown, is an example of a k. E. represents cyclic AMP (hormones) as a reaction to the concentration of the secondary messenger substance. The inactive form (b) of phosphorylase is activated by phosphorylation of a serine residue. In muscle phosphorylase, the dimeric b-form of the enzyme is caused to aggregate into a tetramer, the active a-form (in the liver the a- and b-forms have the same M.r). The enzyme that is responsible for the activation, the phosphorylase b-kinase, must in turn be activated by a specific kinase.

Other enzymes that are regulated by phosphorylation and dephosphorylation are pyruvate dehydrogenase, glycogen synthetase, phosphofructokinase and glutamate dehydrogenase. A K. E., which by changing the M.r is accompanied, i.e. an association and dissociation, occurs in phosphoribosyl pyrophosphate amidotransferase, pancreatic lipase (F- and S-lipase), human glucose-6-phosphate dehydrogenase and pyruvate kinase in the rat kidney (ADP ribosylation) [OM Rosen and E.G. Cancer (ed.) Protein phosphorylation, Cold Spring Harbor Laboratory, Cold Spring Harbor, N.Y. (1982), Vol. 8, A and B].