Summary
α-D-glucose is a weak inhibitor (Ki=1.7 mM) of glycogen phosphorylase (GP) and acts as physiological regulator of hepatic glycogen metabolism; it binds to GP at the catalytic site and stabilizes the inactive T state of the enzyme promoting the action of protein phosphatase 1 and stimulating glycogen synthase. The three-dimensional structures of T state rabbit muscle GPb and the GPb-α-D-glucose complex have been exploited in the design of better regulators of GP that could shift the balance between glycogen synthesis and glycogen degradation in favour of the former. Close examination of the catalytic site with α-D-glucose bound shows that there is an empty pocket adjacent to the β-1-C position. β-D-glucose is a poorer inhibitor (Ki=7.4 mM) than α-D-glucose, but mutarotaion has prevented the binding of β-D-glucose in T state GP crystals. A series of β-D-glucose analogues has been designed and tested in kinetic and crystallographic experiments. Several compounds have been discovered that have an increased affinity for GP than the parent compound.
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DeFronzo, R.A. (1988). The triumvirate beta-cell, muscle, liver. A collusion responsible for NIDDM. Diabetes 37, 667–687.
Martin, J.L., Veluraja, K., Ross, K., Johnson, L.N., Fleet, G.W.J., Ramsden, N.G., Bruce, I., Orchard, M.G., Oikonomakos, N.G., Papageorgiou, A.C., Leonidas, D.D. & Tsitoura, H.S. (1991). Glucose analogue inhibitors of glycogen phosphorylase: The design of potential drugs for diabetes. Biochemistry 30, 10101–10116.
Bollen, M. & Stalmans, W. (1992). The structure, role, and regulation of type-1 protein phosphatases. Crit. Rev. Biochem. Mol. Biol. 27, 227–281.
Acharya, K.R., Stuart, D.I., Varvil, K.M. & Johnson, L.N. (1991). Glycogen Phosphorylase b: Description of the Protein Structure, pp. 1–123. World Scientific Publishing Co. Pte. Ltd., Singapore.
Leonidas, D.D., Oikonomakos, N.G., Papageorgiou, A.C. & Sotiroudis, T.G. (1992). Kinetic properties of tetrameric glycogen phosphorylase b in solution and in the crystalline state. Protein Sci. 1, 1123–1132.
Oikonomakos, N.G., Melpidou, A.E. & Johnson, L.N. (1985). Crystallization of pig skeletal phosphorylase b. Purification, physical and catalytic characterization. Biochim. Biophys. Acta 832, 248–256.
Leonidas, D.D., Oikonomakos, N.G., Papageorgiou, A.C., Acharya, K.R., Barford, D. & Johnson, L.N. (1992). Control of phosphorylase b by a modified cofactor: Crystallographic studies on R-state glycogen phosphorylase reconstituted with pyridoxal 5′-diphosphate. Protein Sci. 1, 1112–1122.
Watson, K.A., Mitchell, E.P., Johnson, L.N., Son, J.C., Bichard, C.J.F., Orchard, M.G., Fleet, G.W.J., Oikonomakos, N.G., Leonidas, D.D., Kontou, M. & Papageorgiou, A.C. (1994). The design of inhibitors of glycogen phosphorylase: A study of α and β-c-glucosides and 1-thio-β-D-glucose compounds. Biochemistry 33, 5745–5758.
Barford, D., Schwabe, J.W.R., Oikonomakos, N.G., Acharya, K.R., Hajdu, J., Papageorgiou, A.C., Martin, J.L., Knott, J.C.A., Vasella, A. & Johnson, L.N. (1988). Channels at the catalytic site of glycogen phosphorylase b: binding and kinetic studies with the β-glycosidase inhibitor, D-gluconohydroximo-1,5-lactone- N-phenylurethane. Biochemistry 27, 6733–6641.
Pigman, W. & Isbell, H.S. (1968). Mutarotation of sugars in solution: Part I. History, basic kinetics, and composition of sugar solutions. Advan. Carbohydrate Chem. 23, 11–57.
Segel, I.H. (1975) Enzyme Kinetics, pp. 465–504, Wiley-Interscience, New York.
Sprang S.R., Goldsmith, E.J., Fletterick, R.J., Withers, S.G. & Madsen, N.B. (1982). Catalytic site of glycogen phosphorylase: structure of the T state and specificity for α-D-glucose. Biochemistry 21, 5364–5371.
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Oikonomakos, N.G., Kontou, M., Zographos, S.E. et al. The design of potential antidiabetic drugs: experimental investigation of a number of β-D-glucose analogue inhibitors of glycogen phosphorylase. Eur. J. Drug Metab. Pharmacokinet. 19, 185–192 (1994). https://doi.org/10.1007/BF03188920
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DOI: https://doi.org/10.1007/BF03188920