Diabetes is a condition in which blood glucose levels are never lowered to their physiological standard state. Glycogen Phosphorylase B catalyzes the reaction release of glucose from glycogen. It is an important reaction determining metabolic homeostasis. Many metabolic pathways are regulated not only their end products but by other compounds that indicate levels of various other intermediates. Compounds that effect the ability of an enzyme that are not involved in the active site are called allosteric effectors. It is known that NAD+ interferes with AMP’s ability to act as an allosteric activator of glycogen phosphorylase b. 1-Methylnicotinamide is a structural analog that mimics the structure of the nicotinamide in NADH. 1-Methylnicotinamide’s ability to inhibit Glycogen phosphorylase b can be determined with enzyme kinetic experiments. These experiments indicate that 1-Methylnicotinamide interferes with the AMP binding site and provides additional means to inhibit the release of glucose.
Introduction ok but need sources for quotes
Glycogen phosphorylase is a key enzyme in the regulation of glycogen metabolism. In muscle, glycogen phosphorylase creates fueling energy for the cell but in the l
iver creates free glucose. The enzyme exists in two forms; Glycogen phosphorylase a (active) and Glycogen phosphorylase b (inactive). In the body glycogen phosphorylase b can be activated by non- covalent cooperative binding of AMP binding of NADH. X-ray diffraction studies have shown the conformational changes that take place following activation of the muscle enzyme on conversion from the T- to R-state by phosphorylation or AMP. Inactivation of Glycogen phosphorylase b involves dramatic conformational change so that the N-terminal residues, 10 to 22, swing through 120° with respect to their position in Glycogen phosphorylase a(active). When AMP binds to its effector site it allosterically activates glycogen phosphorylase b. Previous kinetic studies demonstrated that NADH inhibits the AMP activation of glycogen phosphorylase b. Crystallographic binding studies at 3.5 Å resolution show that NADH binds to the same sites on the enzyme as AMP. This site is close to the subunit-subunit interface which is 12 Å from the catalytic site. The nucleoside inhibitor site is also 12 Å from the catalytic site. The two sites bind both NADH but nucleoside inhibitor binds the adenosine from NADH and AMP site binds only the nicotine head group. The conformations of the two sites are different but both bind NADH. When AMP binds to its effector site it allosterically activates glycogen phosphorylase b.
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