The Structure of Murine N1-Acetylspermine Oxidase Reveals Molecular Details of Vertebrate Polyamine Catabolism
| Autor: | Akiko Kashima, Carola M. Wassvik, Louise Barlind, Anna Aagaard, Tove Sjögren, Tim Kaminski, Ola Fjellström, Arjan Snijder, Takehiro Yokota, Taichi Kumanomidou |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
chemistry.chemical_classification Oxidase test Substrate Interaction APAO 030102 biochemistry & molecular biology biology Stereochemistry Active site Biochemistry 03 medical and health sciences Polyamine Catabolism chemistry.chemical_compound 030104 developmental biology Protein structure chemistry Oxidoreductase Covalent bond biology.protein |
| Zdroj: | Biochemistry. 56:458-467 |
| ISSN: | 1520-4995 0006-2960 |
| DOI: | 10.1021/acs.biochem.6b01140 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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