Phosphorylase mechanisms

Figure 21.8. Phosphorylase Mechanism. A bound HP042- group (red) favors the cleavage of the glycosidic bond by donating a proton to the departing glucose (black). This reaction results in the formation of a carbocation and is favored by the transfer of a proton from the protonated phosphate group of the bound pyridoxal phosphate PLP group (blue). The combination of the carbocation and the orthophosphate results in the formation of glucose 1-phosphate.

Many LactobaciUus species have an absolute growth requirement for a purine, a pyrimidine, and a single deoxyribonudeoside of any sort because the entire complement of cellular deoxyribonucleotides is derived from these materials, there is an evident requirement for the capability of transferring the deoxyribosyl function between bases in these cells. However, in lactobacilli deoxyribosyl transfer is not accomplished by the phosphorylase mechanisms outlined above in this connection it may be noted that lactobacilli are devoid of thymidine phosphorylase (4). A specific enzyme activity, deoxyribosyl transfer in these bacteria this is accomplished without the intermediate formation of deoxyribose 1-phosphate, is readily reversible, and takes place in the absence of inorganic phosphate ... 

Kornberg has hypothesized that UDPG might arise from a p3rro-phosphorylase mechanism analogous to the synthesis of FAD from ATP and riboflavin phosphate. Thus, uridine triphosphate plus glucose-l-phos-... 

Maltose phosphorylase cannot carry out a similar reaction. The P exchange reaction of sucrose phosphorylase is accounted for by a double-displacement mechanism where E = E-glucose ... 

Maltose phosphorylase proceeds via a single-displacement reaction that necessarily requires the formation of a ternary maltose E Pi (or glucose E glucose-l-phosphate) complex for any reaction to occur. Exchange reactions are a characteristic of enzymes that obey double-displacement mechanisms at some point in their catalysis. 

FIGURE 15.17 The mechanism of covalent modification and allosteric regnlation of glycogen phosphorylase. The T states are bine and the R states bine-green. 

Stimulation of glycogen breakdown involves consumption of molecules of ATP at three different steps in the hormone-sensitive adenylyl cyclase cascade (Figure 15.19). Note that the cascade mechanism is a means of chemical amplification, because the binding of just a few molecules of epinephrine or glucagon results in the synthesis of many molecules of cyclic / MP, which, through the action of c/ MP-dependent protein kinase, can activate many more molecules of phosphorylase kinase and even more molecules of phosphorylase. For example, an extracellular level of 10 to 10 M epinephrine prompts the for-... 

The principal enzymes controlling glycogen metabolism—glycogen phosphorylase and glycogen synthase— are regulated by allosteric mechanisms and covalent modifications due to reversible phosphorylation and... 

Muscle phosphorylase is distinct from that of Hver. It is a dimer, each monomer containing 1 mol of pyridoxal phosphate (vitamin Bg). It is present in two forms phos-phoiylase a, which is phosphorylated and active in either the presence or absence of 5 -AMP (its allosteric modifier) and phosphorylase h, which is dephosphorylated and active only in the presence of 5 -AMP. This occurs during exercise when the level of 5 -AMP rises, providing, by this mechanism, fuel for the muscle. Phosphorylase a is the normal physiologically active form of the enzyme. 

Villar-Palasi C On the mechanism of inactivation of muscle glycogen phosphorylase by insulin. Biochim Biophys Acta 1994 1224 384. 

The biosynthesis of purines and pyrimidines is stringently regulated and coordinated by feedback mechanisms that ensure their production in quantities and at times appropriate to varying physiologic demand. Genetic diseases of purine metabolism include gout, Lesch-Nyhan syndrome, adenosine deaminase deficiency, and purine nucleoside phosphorylase deficiency. By contrast, apart from the orotic acidurias, there are few clinically significant disorders of pyrimidine catabolism. 

Fig. 14.3 5 -FU catabolism, anabolism and mechanism of action. 5-FUH2, 5-fluoro-5,6-dihydrouracil 5-FdUMP, 5-fluorodeoxyuridine monophosphate TP, thymidine phosphorylase TK, thymidine kinase TS, thymidylate synthase CH2THF, 5,10-methylenetetrahydrofolate.

As is often the case, tissue-specific control mechanisms operate to optimise adaptation to particular conditions. For example, muscle contraction requires an increase in cytosolic calcium ion concentration (see Section 7.2.1, Figure 7.4). During exercise when energy generation needs to be increased, or from a more accurate metabolic point of view, when the ATP-to-ADP ratio falls rapidly, and the accompanying rise in [Ca2 + ] activate (i) glycogen phosphorylase which initates catabolism of... 

Reversible phosphorylation is the main control mechanism of liver phosphorylase allosteric effects being much less pronounced. This is in contrast with muscle phosphorylase, which is also controlled by phosphorylation, stimulated by an adrenaline-... 

A well-known example, indeed the first enzyme that was shown to be regulated by the phosphorylation/ dephosphorylation mechanism, is glycogen phosphorylase, which catalyses the breakdown of glycogen (Box 3.7). 

It is important to point ont that these four mechanisms are not mntuaUy exclnsive. Indeed, it is probable that, for some reactions, aU fonr mechanisms play a role in regnlation of flnx and this combination conld provide an enormons increase in sensitivity. An example is the regulation of the enzyme phosphorylase in mnscle and liver, and hence the process of glycogenolysis (Chapters 6 and 12). 

Figure 6.31 (a) An increase in the intracellular concentration of glucose in the liver results in an increased activity of glycogen synthase and a decreased activity of glycogen phosphorylase. The mechanisms for these effects are shown in (b). 

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