Glycogen phosphorylase molecul

An enzyme that, once activated, produces activated forms of the next enzyme in the pathway, and so on, produces a cascade. Thus the initial signal of glucagon binding is greatly amplified. Specifically, each molecule of protein kinase A, once activated and before it is deactivated, can phosphorylate and activate hundreds of phosphorylase kinase molecules that, in turn, can activate many hundreds of molecules of glycogen phosphorylase. Thus, just a few molecules of glucagon can rapidly stimulate the action of thousands of glycogen phosphorylase molecules. 

Muscle glycogen phosphorylase is one of the most well studied enzymes and was also one of the first enzymes discovered to be controlled by reversible phosphorylation (by E.G. Krebs and E. Fischer in 1956). Phosphorylase is also controlled allosterically by ATP, AMP, glucose and glucose-6-phosphate. Structurally, muscle glycogen phosphorylase is similar to its hepatic isoenzyme counterpart composed of identical subunits each with a molecular mass of approximately 110 kDa. To achieve full activity, the enzyme requires the binding of one molecule of pyridoxal phosphate, the active form of vitamin B6, to each subunit. 

The next key point is to realize that each enzyme in the pathway exists in both active and inactive forms. cAMP initiates a cascade of reactions by activating protein kinase A (PK-A)," the active form of which activates the next enzyme in the sequence, and so on. At the end of the day, glycogen phosphorylase is activated and glucose or ATP is produced. This signaling pathway is a marvelous amplification system. A few molecules of glucagon or adrenaline may induce formation of many molecules of cAMP, which may activate many of PK-A, and so on. The catalytic power of enzymes is magnified in cascades of this sort. 

All aminotransferases have the same prosthetic group and the same reaction mechanism. The prosthetic group is pyridoxal phosphate (PLP), the coenzyme form of pyridoxine, or vitamin B6. We encountered pyridoxal phosphate in Chapter 15, as a coenzyme in the glycogen phosphorylase reaction, but its role in that reaction is not representative of its usual coenzyme function. Its primary role in cells is in the metabolism of molecules with amino groups. 

Additionally, computational chemists often use the resulting output alignment of the molecules as input for 3D-QSAR modeling. As already stated, most field-based 3D-QSAR approaches (such as CoMFA) need a pre-aligned set of molecules and the pharmacophore method is certainly one of the best ways to obtain an objective alignment of the compounds. Klabunde et al., for instance, have recently reported the use of a pharmacophore model of human liver glycogen phosphorylase inhibitors together with 3D information from inhibitor-enzyme complexes to derive a predictive CoMFA model [98]. 

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