X-ray Crystal Structure and Binding Mode Analysis of Human S-Adenosylhomocysteine Hydrolase Complexed with Novel Mechanism-Based Inhibitors, Haloneplanocin A Analogues

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• 作者：Kang Man Lee ; Won Jun Choi ; Yoonji Lee ; Hyun Joo Lee ; Long Xuan Zhao ; Hyuk Woo Lee ; Jae Gyu Park ; Hea Ok Kim ; Kwang Yeon Hwang ; Yong-Seok Heo ; Sun Choi ; Lak Shin Jeong
• 刊名：Journal of Medicinal Chemistry
• 出版年：2011
• 出版时间：February 24, 2011
• 年：2011
• 卷：54
• 期：4
• 页码：930-938
• 全文大小：1038K
• 年卷期：v.54,no.4(February 24, 2011)
• ISSN：1520-4804

文摘

The X-ray crystal structure of human S-adenosylhomocysteine (AdoHcy) hydrolase was first determined as a tetrameric form bound with the novel mechanism-based inhibitor fluoroneplanocin A (4b). The crystallized enzyme complex showed the closed conformation and turned out to be the intermediate of mechanism-based inhibition. It confirmed that the cofactor depletion by 3鈥?oxidation of fluoroneplanocin A contributes to the enzyme inhibition along with the irreversible covalent modification of AdoHcy hydrolase. In addition, a series of haloneplanocin A analogues (4b鈭?b>e and 5b鈭?b>e) were designed and synthesized to characterize the binding role and reactivity of the halogen substituents and the 4鈥?CH₂OH group. The biological evaluation and molecular modeling studies identified the key pharmacophores and structural requirements for the inhibitor binding of AdoHcy hydrolase. The inhibitory activity was decreased as the size of the halogen atom increased and/or if the 4鈥?CH₂OH group was absent. These results could be utilized to design new therapeutic agents operating via AdoHcy hydrolase inhibition.