The Structure of Murine N1-Acetylspermine Oxidase Reveals Molecular Details of Vertebrate Polyamine Catabolism

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• 作者：Tove SjögrenCarola M. Wassvik ; Arjan Snijder ; Anna Aagaard ; Taichi Kumanomidou ; Louise Barlind ; Tim P. Kaminski ; Akiko Kashima ; Takehiro Yokota ; Ola Fjellström
• 刊名：Biochemistry
• 出版年：2017
• 出版时间：January 24, 2017
• 年：2017
• 卷：56
• 期：3
• 页码：458-467
• 全文大小：492K
• ISSN：1520-4995

文摘

N¹-Acetylspermine oxidase (APAO) catalyzes the conversion of N¹-acetylspermine or N¹-acetylspermidine to spermidine or putrescine, respectively, with concomitant formation of N-acetyl-3-aminopropanal and hydrogen peroxide. Here we present the structure of murine APAO in its oxidized holo form and in complex with substrate. The structures provide a basis for understanding molecular details of substrate interaction in vertebrate APAO, highlighting a key role for an asparagine residue in coordinating the N¹-acetyl group of the substrate. We applied computational methods to the crystal structures to rationalize previous observations with regard to the substrate charge state. The analysis suggests that APAO features an active site ideally suited for binding of charged polyamines. We also reveal the structure of APAO in complex with the irreversible inhibitor MDL72527. In addition to the covalent adduct, a second MDL72527 molecule is bound in the active site. Binding of MDL72527 is accompanied by altered conformations in the APAO backbone. On the basis of structures of APAO, we discuss the potential for development of specific inhibitors.