5. (a) Hexokinase IV is known as glucokinase (GCK) and is a central metabolic enzyme that participates in glucose homeostatic maintenance by governing the rates of glucose catabolism in pan- creatic B-cells and glycogen storage in hepatocytes (liver cells). In contrast to the regulatory mecha- nisms of hexokinase I or Il in other tissues, GCk is regulated by binding to the Glucokinase Regulatory Protein (GRP) located in the cell nucleus. When glucose in hepatocytes is low, GCK is sequestered in the nucleus by binding to the GRP. High glucose, for instance, after ingestion of a meal, disrupts the GRP-GCK complex, allowing the GCK to diffuse into the cytoplasm to convert glucose into glucose-6- phosphate. Contrast the properties of hexokinases I and IV with respect to oligomeric structure, mech- anism of regulation of their activity, KM value, and dependence of catalytic activity on cellular location. Hexokinase l is found in, for instance, muscle tissue. Property subunit structutre hexokínase I/I hexokinase IV mechanism of regulation KM value cellular location (b) Diabetes mellitus is a disease characterized by reduced sehsitivity of cellular membranes of muscle and adipose tissue to insulin facilitating uptake of glucosę. The resultant efféct is that gluçose in the błood stream Tises to higher lev- els and decreases more slowly than in unaf- feeted individuals. Recently a synthetic pipera- H2N zine derivative, Compound Y, shown on the right, has been shown to function by causing dis- sociation of theGRE GCK complex. Administra- tion of Compound Yto diabetic rats after feed- ing had the effect shown by the graph on the right CF3 `s-N N CF3 Compound Y 500 Legend for sym- bols: •, vehicle; V, Cmpd Y; O, GCK activator; x, metformin (a widely prescribed drug used to treat diabetes melli- 400- 300- * *** *** 200- *** R61) formulas (except for nucleotides, etc.) catalyzed by hexokinase IV or glucokinase. Write the reaction using structural 100 *** 4 7 Time after dose (h) (b2) cose level in diabetic rats. Why is there no effect of the piperazine derivative in other tissues except for pancreatic B-cells and hepatocytes? Explain the basis by which the drug, Compound Y, facilitates lowering of the blood glu- (ь3) concentration with time, has the velocity of the reaction catalyzed by GCK changed or has the turnover rate of the enzyme been increased? Which kinetic parameter describes the molecular basis of the effect? Why? For the effect illustrated in the diagram above showing the decrease in the blood glucose If we consider the resting blood glucose level in diabetic rats according to the graph as ap- (b4) proximately 275 mg/dl (at 0 hr), that is then lowered to about 150 mg/dl by the drug. What are the corresponding concentrations expressed in millimolar units? Blood glucose (mg dl-1)