X-ray crystal structure and binding mode analysis of human S-adenosylhomocysteine hydrolase complexed with novel mechanism-based inhibitors, haloneplanocin A analogues

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

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

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′-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-e and 5b-e) were designed and synthesized to characterize the binding role and reactivity of the halogen substituents and the 4′-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′-CH2OH group was absent. These results could be utilized to design new therapeutic agents operating via AdoHcy hydrolase inhibition.

Original languageEnglish
Pages (from-to)930-938
Number of pages9
JournalJournal of Medicinal Chemistry
Volume54
Issue number4
DOIs
Publication statusPublished - 2011 Feb 24

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery

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