Allosteric modification

This has particular relevance to allosteric modification of receptors. As described in Chapter 7, the fraction of receptor bound to an agonist [A], expressed in terms of the presence of an allosteric modulator [B], is given as... 

Each interaction (reactions and allosteric modifications) is associated with a rate equation and kinetic parameters. 

Protein substrates are degraded in the cell at specific times in response to physiological stimuli. In addition, degradation of substrates is probably spatially restricted within a cell. Based on accumulated evidence, it appears that the vulnerability or resistance to ubiquitin—proteasome-mediated degradation is regulated usually by a posttranslational modification. The protein substrates are modified in two main ways (1) by phosphorylation or (2) by allosteric modifications. 

Ubiquitin ligases largely control the substrate specificity of ubiquitin-conjugation reaction. The temporal specificity of ubiquitin conjugation to substrates by these enzymes is provided by regulation of the ligase activity. Activity of ubiquitin ligases can be modulated by posttranslational modification such as phosphorylation and by allosteric modification of the enzyme, or by attachment to UbL proteins. 

Allosteric probe dependence, as well as offering a positive avenue of therapeutic advancement as discussed previously, can have negative effects. For example, allosteric modification of an endogenous signaling system requires... 

Enzyme activity can be regulated by covalent modification or by noncovalent (allosteric) modification. A few enzymes can undergo both forms of modification (e.g., glycogen phosphorylase and glutamine synthetase). Some covalent chemical modifications are phosphorylation and dephosphorylation, acetylation and deacetylation, adeny-lylation and deadenylylation, uridylylation and deuridyly-lation, and methylation and demethylation. In mammalian systems, phosphorylation and dephosphorylation are most commonly used as means of metabolic control. Phosphorylation is catalyzed by protein kinases and occurs at specific seryl (or threonyl) residues and occasionally at tyrosyl residues these amino acid residues are not usually part of the catalytic site of the enzyme. Dephosphorylation is accomplished by phosphoprotein phosphatases ... 

Although the MM equation is a powerful kinetic form to which the vast majority of enzyme kinetics has been fitted, one should not forget the assumptions and limitations of the model. As a basic example, feedback inhibition, whereby the product of the reaction inhibits the enzyme-substrate cooperativity, multiple-substrate reactions, allosteric modifications, and other deviations from the reaction scheme in equation (1) are treated only adequately by the MM formalism under certain experimental conditions. In other words, enzyme kinetics are often bent to conform to the MM formalism for the sake of obtaining a set of parameters easily recognizable by most biochemists. The expUcit mathematical and experimental treatment of reaction mechanisms more complex than that shown in equation (1) is highly involved, although a mathematical automated kinetic equation derivation framework for an arbitrary mechanism has been described in the past (e.g., ref. 6). 

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