Iminosugars as Potential Inhibitors of Glycogenolysis: Structural Insights into the Molecular Basis of Glycogen Phosphorylase Inhibition
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- 作者：Nikos G. Oikonomakos ; Costas Tiraidis ; Demetres D. Leonidas ; Spyros E. Zographos ; Marit Kristiansen ; Claus U. Jessen ; Leif N
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- 刊名：Journal of Medicinal Chemistry
- 出版年：2006
- 出版时间：September 21, 2006
- 年：2006
- 卷：49
- 期：19
- 页码：5687 - 5701
- 全文大小：1527K
- 年卷期：v.49,no.19(September 21, 2006)
- ISSN：1520-4804
文摘
Iminosugars DAB (5), isofagomine (9), and several N-substituted derivatives have been identified as potentinhibitors of liver glycogen phosphorylase a (IC50 = 0.4-1.2 
M) and of basal and glucagon-stimulatedglycogenolysis (IC50 = 1-3 M). The X-ray structures of 5, 9, and its N-3-phenylpropyl analogue 8 incomplex with rabbit muscle glycogen phosphorylase (GPb) shows that iminosugars bind tightly at the catalyticsite in the presence of the substrate phosphate and induce conformational changes that characterize theR-state conformation of the enzyme. Charged nitrogen N1 is within hydrogen-bonding distance with thecarbonyl oxygen of His377 (5) and in ionic contact with the substrate phosphate oxygen (8 and 9). Ourfindings suggest that the inhibitors function as oxocarbenium ion transition-state analogues. The conformationalchange to the R state provides an explanation for previous findings that 5, unlike inhibitors that favor theT state, promotes phosphorylation of GPb in hepatocytes with sequential inactivation of glycogen synthase.
M) and of basal and glucagon-stimulatedglycogenolysis (IC50 = 1-3 M). The X-ray structures of 5, 9, and its N-3-phenylpropyl analogue 8 incomplex with rabbit muscle glycogen phosphorylase (GPb) shows that iminosugars bind tightly at the catalyticsite in the presence of the substrate phosphate and induce conformational changes that characterize theR-state conformation of the enzyme. Charged nitrogen N1 is within hydrogen-bonding distance with thecarbonyl oxygen of His377 (5) and in ionic contact with the substrate phosphate oxygen (8 and 9). Ourfindings suggest that the inhibitors function as oxocarbenium ion transition-state analogues. The conformationalchange to the R state provides an explanation for previous findings that 5, unlike inhibitors that favor theT state, promotes phosphorylation of GPb in hepatocytes with sequential inactivation of glycogen synthase.