From x-ray crystallography, molecular recognition and site directed mutagenesis studies the binding of glucose 1-phosphate and its derivatives in ground state and transition state is well characterised. However, present knowledge about substrate binding sites of glucosyl residues in phosphorylases is still incomplete. Īn alternate way to look for potent inhibitors other than glucose compounds would be to design analogs derived from the oligosaccharide substrate. Since there are only weak physiological inhibitors known, a variety of glucose compounds with better inhibitory properties were designed, synthesised and tested by L. One class of phosphorylase inhibitors consists of glucose analogs which stabilise the inactive T-form of the enzyme. Such inhibitors may be of use for therapy of the non-insulin dependent form of diabetes (NIDDM or Type II diabetes). Therefore, suppression of glucose output from the liver may be achieved by inhibition of glycogen phosphorylase. In muscle glucose 1-phosphate is further metabolised via glycolysis to provide energy, and in liver phosphorylase helps to maintain a constant blood glucose level via the action of glucose 6-phosphatase. Glucose n + P i ↔ glucose n − 1 + glucose 1 ‐ phosphate The role played by pyridoxal phosphate is that of a proton shuttle or buffer to stabilize the oxycarbonium–phosphate ion pair, allowing covalent binding of the phosphate to the oxycarbonium ion, to form glucose-1-phosphate. The resultant oxycarbonium ion is stabilized by the inorganic phosphate. The initial stage in the phosphorolysis of glycogen is protonation of the glycosidic oxygen of the polysaccharide by inorganic phosphate. The catalytic region of the coenzyme is the 5'-phosphate group. Unlike other pyridoxal phosphate-dependent enzymes, in which the carbonyl group is essential for catalysis, the internal Schiff base between pyridoxal phosphate and lysine in glycogen phosphorylase is not broken during the reaction. Glycogen phosphorylase catalyzes the sequential phosphorolysis of glycogen to release glucose-1-phosphate it is thus the key enzyme in the utilization of muscle and liver reserves of glycogen. Bender, in Encyclopedia of Human Nutrition (Third Edition), 2013 The Role of Pyridoxal Phosphate in Glycogen Phosphorylase 19,20 Natural five-membered ring iminosugar 1,4-dideoxy-1,4-imino-arabinitol (DAB, 20) shows strong inhibition of GP with K i values in the nanomolar range ( Figure 3). Bols, unpublished results) 19 however, N-substitution could not improve the binding. 18 Iminosugars such as isofagomine ( 17, IC 50 = 0.7 μM), azafagomine ( 18, IC 50 = 0.7 μM), and the recently prepared noeuromycin ( 19, IC 50 = 4 μM) were found to inhibit GP (N. 17,17a Modification of 15 allowed the preparation of N-acyl- N′-β- d-glucopyranosyl urea derivative 16 ( K i = 0.4 μM) as one of the best glucose analog inhibitors to date. 16 Molecular design, organic synthesis, protein crystallography, and biological assays led to glucopyranosylidene- spiro-hydantoin ( 15, K i = 3.4 μM) as an efficient GP inhibitor. 15 One of the approaches to modulate the action of GP is the use of glucose derivatives as inhibitors. GP is the main regulatory enzyme in the liver, being responsible for the control of blood glucose level, and for that reason it is considered as a new target for the treatment of diabetes type 2.
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