Structural insight into the mechanism of streptozotocin inhibition of O-GlcNAcase
Structural insight into the mechanism of streptozotocin inhibition of O-GlcNAcase
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DOI：
10.1016/j.carres.2008.12.007
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发表时间：
2009-03-31
影响因子：
3.1
通讯作者：
Davies, Gideon J.
中科院分区：
文献类型：
--
作者：
He, Yuan;Martinez-Fleites, Carlos;Davies, Gideon J.
尽管链脲佐菌素 (STZ) 在糖尿病研究中的应用已有数十年，但链脲佐菌素 (STZ) 对胰腺 P 胰岛细胞的细胞毒性机制仍然是一个讨论的话题。尽管 STZ 毒性可能与其促进 DNA 烷基化的能力有关，但有人提出 STZ 通过抑制 O-GlcNAcase 诱导胰腺 p 细胞死亡。在本报告中，我们探讨了 STZ 与人 O-GlcNAcase 的密切同源物（来自 Bacteroides thetaiotaomicron 的 BtGH84）的结合模式。我们的结果表明，STZ 以其完整形式结合在酶活性位点，不形成共价加合物，这与 BtGH84 和人 O-GlcNAcase 的溶液研究以及产气荚膜梭菌同源物的结构研究一致。 BtGH84 的活性位点在 STZ 结合后发生显着变形，因此催化机制从结合腔中排出。 (C) 2008 Elsevier Ltd. 保留所有权利。
Despite decades of its use in diabetes research, the mechanism of cytotoxicity of streptozotocin (STZ) toward pancreatic P-islet cells has remained a topic of discussion. Although STZ toxicity is likely a function of its capacity to promote DNA alkylation, it has been proposed that STZ induces pancreatic p-cell death through O-GlcNAcase inhibition. In this report, we explore the binding mode of STZ to a close homolog of human O-GlcNAcase, BtGH84 from Bacteroides thetaiotaomicron. Our results show that STZ binds in the enzyme active site in its intact form, without the formation of a covalent adduct, consistent with solution studies on BtGH84 and human O-GlcNAcase, as well as with structural work on a homolog from Clostridium perfringens. The active site of the BtGH84 is considerably deformed upon STZ binding and as a result the catalytic machinery is expelled from the binding cavity. (C) 2008 Elsevier Ltd. All rights reserved.