Glycogen Active

The end product of the intermediary metabolism of fatty acids with an uneven number of carbons differs sharply from those formed after the breakdown of the even-chain fatty acids. Whereas glycogen is produced from the fatty acids having an uneven number of carbon atoms, those fatty acids with an even number of carbon atoms have no glycogenic activity, but, with the possible exception of acetic acid, they are all ketogenic and possess no ketolytic activity. 

Greenberg, E., Preiss, J. E., VanBoldrick, M., and Preiss, J. 1983. Biosynthesis of bacterial glycogen Activator specificity of the ADPglucose pyrophosphorylase of Rhodopseudomo-nads. Arch. Biochem. Biophys. 220, 594-604. 

Glycogen, activated with cyanogen Inromide, has been covalently bound to phosphorylase Z>. The product showed a higher afiinity than the native en me... 

C. It is secreted along with noradrenaline by the adrenal medulla, from which it may be obtained. It may be synthesized from catechol. It is used as the acid tartrate in the treatment of allergic reactions and circulatory collapse. It is included in some local anaesthetic injections in order to constrict blood vessels locally and slow the disappearance of anaesthetic from the site of injection. Ultimately it induces cellular activation of phosphorylase which promotes catabolism of glycogen to glucose. 

Physiological response glycogen breakdown visual excitation histamine secretion in all allergic reactions slowing of pacemaker activity that controls the rate of the heartbeat... 

PHOSPHOPROTEINS. These proteins have phosphate groups esterified to the hydroxyls of serine, threonine, or tyrosine residues. Casein, the major protein of milk, contains many phosphates and serves to bring essential phosphorus to the growing infant. Many key steps in metabolism are regulated between states of activity or inactivity, depending on the presence or absence of phosphate groups on proteins, as we shall see in Chapter 15. Glycogen phospho-rylase a is one well-studied example. 

Muscle glycogen phosphorylase is a dimer of two identical subunits (842 residues, 97.44 kD). Each subunit contains a pyridoxal phosphate cofactor, covalently linked as a Schiff base to Lys °. Each subunit contains an active site (at the center of the subunit) and an allosteric effector site near the subunit interface (Eigure 15.15). In addition, a regulatory phosphorylation site is located at Ser on each subunit. A glycogen-binding site on each subunit facilitates prior association of glycogen phosphorylase with its substrate and also exerts regulatory control on the enzymatic reaction. 

Glycogen phosphorylase conforms to the Monod-Wyman-Changeux model of allosteric transitions, with the active form of the enzyme designated the R state and the inactive form denoted as the T state (Figure 15.17). Thus, AMP promotes the conversion to the active R state, whereas ATP, glucose-6-P, and caffeine favor conversion to the inactive T state. 

As early as 1938, it was known that glycogen phosphorylase existed in two forms the less active phosphorylase b and the more active phosphorylase a. In 1956, Edwin Krebs and Edmond Eischer reported that a converting enzyme could convert phosphorylase b to phosphorylase a. Three years later, Krebs and Eischer demonstrated that the conversion of phosphorylase b to phosphorylase a involved covalent phosphorylation, as in Eigure 15.17. 

FIGURE 15.19 The hormone-activated enzymatic cascade that leads to activation of glycogen phosphorylase. 

The cAMP formed by adenylyl cyclase (Figure 15.20) does not persist because 5 -phosphodiesterase activity prevalent in cells hydrolyzes cAMP to give 5 -AMP. Caffeine inhibits 5 -phosphodi-esterase activity. Describe the effects on glycogen phosphorylase activity that arise as a consequence of drinking lots of caffeinated coffee. 

Enzymes have evolved such that their values (or A o.s values) for substrate(s) are roughly equal to the in vivo concentration(s) of the substrate (s). Assume that glycogen phosphorylase is assayed at [P[] = A o.s in the absence and presence of AMP or ATP. Estimate from Figure 15.15 the relative glycogen phosphorylase activity when (a) neither AMP or ATP is present, (b) AMP is present, and (c) ATP is present. 

John.son, L. N., and Barford, D., 1993. The effects of pho.sphorylation on the. structure and function of proteins. Annual Review of Biophysics and Biomolecular Structure 22 199-232. A review of protein pho.sphorylation and its role in regrdation of enzymatic activity, with particular empha.sis on glycogen pho.sphoryla.se. 

We are familiar with several examples of chemical activation as a strategy for group transfer reactions. Acetyl-CoA is an activated form of acetate, biotin and tetrahydrofolate activate one-carbon groups for transfer, and ATP is an activated form of phosphate. Luis Leloir, a biochemist in Argentina, showed in the 1950s that glycogen synthesis depended upon sugar nucleotides, which may be... 

Glycogen synthase also exists in two distinct forms which can be interconverted by the action of specific enzymes active, dephosphorylated glycogen synthase I (glucose-6-P-independent) and less active phosphorylated glycogen synthase D (glucose-6-P-dependent). The nature of phosphorylation is more complex with glycogen synthase. As many as nine serine residues on the enzyme appear to be subject to phosphorylation, each site s phosphorylation having some effect on enzyme activity. 

Dephosphorylation of both glycogen phosphorylase and glycogen synthase is carried out by phosphoprotein phosphatase 1. The action of phosphopro-tein phosphatase 1 inactivates glycogen phosphorylase and activates glycogen synthase. 

For all these activities, breakdown of muscle glycogen provides much of the needed glucose. The rate of glycogen con-... 

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-... 

---