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Iminosugars as potential inhibitors of glycogenolysis: Structural insights into the molecular basis of glycogen phosphorylase inhibition

Lookup NU author(s): Professor Loranne Agius


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Iminosugars DAB (5), isofagomine (9), and several N-substituted derivatives have been identified as potent inhibitors of liver glycogen phosphorylase a (IC50 = 0.4-1.2 μM) and of basal and glucagon-stimulated glycogenolysis (IC50 = 1-3 μM). The X-ray structures of 5, 9, and its N-3-phenylpropyl analogue 8 in complex with rabbit muscle glycogen phosphorylase (GPb) shows that iminosugars bind tightly at the catalytic site in the presence of the substrate phosphate and induce conformational changes that characterize the R-state conformation of the enzyme. Charged nitrogen N1 is within hydrogen-bonding distance with the carbonyl oxygen of His377 (5) and in ionic contact with the substrate phosphate oxygen (8 and 9). Our findings suggest that the inhibitors function as oxocarbenium ion transition-state analogues. The conformational change to the R state provides an explanation for previous findings that 5, unlike inhibitors that favor the T state, promotes phosphorylation of GPb in hepatocytes with sequential inactivation of glycogen synthase. © 2006 American Chemical Society.

Publication metadata

Author(s): Oikonomakos NG, Tiraidis C, Leonidas DD, Zographos SE, Kristiansen M, Jessen CU, Norskov-Lauritsen L, Agius L

Publication type: Article

Publication status: Published

Journal: Journal of Medicinal Chemistry

Year: 2006

Volume: 49

Issue: 19

Pages: 5687-5701

ISSN (print): 0022-2623

ISSN (electronic): 1520-4804

Publisher: American Chemical Society


DOI: 10.1021/jm060496g

PubMed id: 16970395


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