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Enzyme Kinetics and Drugs as Enzyme Inhibitors
Published in Peter Grunwald, Pharmaceutical Biocatalysis, 2019
Allosteric regulation (or control) means the influence of an effector molecule on an enzyme and plays a role in cell signaling (long-range allosteric effects); it binds at a site other than the enzyme’s active site, the allosteric site. This is often accompanied by conformational changes involving protein dynamics. Effector molecules either cause positive allosteric modulation (allosteric activation) or negative allosteric modulation (allosteric inhibition) and are in a broader sense of importance for conformational perturbations on cellular functions and disease states; in other words the allosteric change in one protein may affect the behavior of other proteins downstream. Non-competitive inhibition always means allosteric inhibition but not all allosteric inhibitors act non-competitive. For models explaining the allosteric effect see Monod et al. (1965; concerted model) and Koshland et al. (1966, sequential model).
The Mannitol Enzyme II of the Bacterial Phosphotransferase System: A Functionally Chimaeric Protein with Receptor, Transport, Kinase, and Regulatory Activities
Published in James F. Kane, Multifunctional Proteins: Catalytic/Structural and Regulatory, 2019
Milton H. Saier, John E. Leonard
Recent studies have revealed that many enzymes catalyze more than a single chemical reaction and that their activities may be subject to allosteric regulation by ligands or proteins which are not structurally related to the substrates or products of the enzyme catalyzed reactions. The allosteric effectors bind to sites on the protein which are topologically distinct from the active sites involved in catalysis.1 Additionally, a few of these proteins in bacteria function in the regulation of their own syntheses either at the transcriptional or the trans-lational level. Several examples of such proteins are discussed in this volume. In general, these enzymes are cytoplasmic constituents which can freely diffuse to the bacterial chromosome or to the appropriate messenger RNA molecules where they exert their regulatory roles.
General concepts for applied exercise physiology
Published in Nick Draper, Helen Marshall, Exercise Physiology, 2014
While allosteric regulation quickly moderates the rate of enzymatic activity, covalent modification can, within seconds, switch enzyme activity on or off. This regulatory modification occurs through the usually reversible bonding of a substrate to specific amino acids within the enzyme such as serine, histidine, tyrosine and threonine. One of the most common modifiers is inorganic phosphate which is attached to an enzyme through ATP hydrolysis. Interestingly, this enzyme phosphorylation, to regulate its activity, requires an enzyme itself, known as a protein kinase, to catalyse the reaction. The reverse process, dephosphorylation, is catalysed by another set of enzymes known as protein phosphatases. Covalent modification serves to activate some enzymes while it can inactivate other enzymes. By reversing the process, where possible, an enzyme can return to its pre-modified state. Enzymatic phosphorylation provides an important mechanism for controlling the rate of metabolism and is closely linked with the third regulatory mechanism, nervous-endocrine control. As was described in Chapter 3, hormones such as adrenaline are released during exercise to increase metabolism. The release of adrenaline serves to stimulate an increase in glycogen catabolism within muscle fibres (cells). This increase is brought about through the covalent modification of glycogen phosphorylase, the enzyme that catalyses the reaction to remove glucose, in the form of glucose-1-phosphate, from glycogen.
Hidden allosteric sites and De-Novo drug design
Published in Expert Opinion on Drug Discovery, 2022
Ashfaq Ur Rehman, Shaoyong Lu, Abdul Aziz Khan, Beenish Khurshid, Salman Rasheed, Abdul Wadood, Jian Zhang
Allostery is a notion that was proposed ~50 years ago and describes how an effector can modulate protein activity by binding to an allosteric site that is topographically different from the orthosteric site [8–10]. The balance between distinct conformational states is critical for protein function. Many extrinsic stimuli that regulate protein function, including localized perturbations, can shift this balance. When the perturbation site is not directly adjacent to the site of altered activity, the regulation is referred to as allosteric. A classic case of allosteric regulation is cooperative ligand binding of many oligomeric proteins in which binding of substrate to one subunit impacts ligand affinity in other identical subunits [10].
Computational approaches for the design of modulators targeting protein-protein interactions
Published in Expert Opinion on Drug Discovery, 2023
Ashfaq Ur Rehman, Beenish Khurshid, Yasir Ali, Salman Rasheed, Abdul Wadood, Ho-Leung Ng, Hai-Feng Chen, Zhiqiang Wei, Ray Luo, Jian Zhang
Enzymes modulate their function using allosteric regulation [51]. A small molecule binds at one site and stimulates a structural change at a remote region, modifying the active site’s conformation. Some PPIs may also use this mechanism. Thus, an inhibitor that binds to an allosteric site could in-principal disturb the major PPI, inhibiting its contact with the other protein (Figure 1). Allosteric modulation has many advantages [34]. It could offer better PPI modulation and improve specificity. It may be easier than hot-spot modulation, as accessible binding sites (e.g. grooves) may be present at several spots on a protein.