title: X-ray crystal structure and binding mode analysis of human S-adenosylhomocysteine hydrolase complexed with novel mechanism-based inhibitors, haloneplanocin A analogues.
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'-CH(2)OH 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'-CH(2)OH group was absent. These results could be utilized to design new therapeutic agents operating via AdoHcy hydrolase inhibition.
authors.affiliation: College of Pharmacy, Ewha Womans University, Seoul 120-750, Korea.
authors.forename: Kang Man
authors.initials: KM
authors.lastname: Lee
authors.forename: Won Jun
authors.initials: WJ
authors.lastname: Choi
authors.forename: Yoonji
authors.initials: Y
authors.lastname: Lee
authors.forename: Hyun Joo
authors.initials: HJ
authors.lastname: Lee
authors.forename: Long Xuan
authors.initials: LX
authors.lastname: Zhao
authors.forename: Hyuk Woo
authors.initials: HW
authors.lastname: Lee
authors.forename: Jae Gyu
authors.initials: JG
authors.lastname: Park
authors.forename: Hea Ok
authors.initials: HO
authors.lastname: Kim
authors.forename: Kwang Yeon
authors.initials: KY
authors.lastname: Hwang
authors.forename: Yong-Seok
authors.initials: YS
authors.lastname: Heo
authors.forename: Sun
authors.initials: S
authors.lastname: Choi
authors.forename: Lak Shin
authors.initials: LS
authors.lastname: Jeong
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D043383:Adenosylhomocysteinase / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000378:metabolism*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D056004:Molecular Dynamics Simulation; D009904:Optical Rotation; D016339:Spectrometry, Mass, Fast Atom Bombardment
chemical_list: D004791:Enzyme Inhibitors; D043383:Adenosylhomocysteinase; D000241:Adenosine