title: The Structure of Murine N1-Acetylspermine Oxidase Reveals Molecular Details of Vertebrate Polyamine Catabolism.
abstract: 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.
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca , Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Tove
authors.identifier: 0000-0002-6703-4200
authors.initials: T
authors.lastname: Sjögren
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca , Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Carola M
authors.initials: CM
authors.lastname: Wassvik
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca , Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Arjan
authors.initials: A
authors.lastname: Snijder
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca , Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Anna
authors.initials: A
authors.lastname: Aagaard
authors.affiliation: Discovery Technology Laboratories, Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation , 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors.forename: Taichi
authors.initials: T
authors.lastname: Kumanomidou
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca , Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Louise
authors.initials: L
authors.lastname: Barlind
authors.affiliation: Discovery Sciences, Innovative Medicines and Early Development, AstraZeneca , Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Tim P
authors.initials: TP
authors.lastname: Kaminski
authors.affiliation: Discovery Technology Laboratories, Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation , 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors.forename: Akiko
authors.initials: A
authors.lastname: Kashima
authors.affiliation: Discovery Technology Laboratories, Sohyaku, Innovative Research Division, Mitsubishi Tanabe Pharma Corporation , 1000, Kamoshida-cho, Aoba-ku, Yokohama, Kanagawa 227-0033, Japan.
authors.forename: Takehiro
authors.initials: T
authors.lastname: Yokota
authors.affiliation: Cardiovascular and Metabolic Diseases, Innovative Medicines and Early Development, AstraZeneca , Pepparedsleden 1, SE-431 83 Mölndal, Sweden.
authors.forename: Ola
authors.initials: O
authors.lastname: Fjellström
mesh_terms: D000447:Aldehydes / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D020134:Catalytic Domain; D015870:Gene Expression; D006861:Hydrogen Peroxide / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D051379:Mice; D008958:Models, Molecular; D010084:Oxidation-Reduction; D010088:Oxidoreductases / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D011437:Propylamines / Q000737:chemistry / Q000378:metabolism; D017433:Protein Structure, Secondary; D011700:Putrescine / Q000031:analogs & derivatives / Q000737:chemistry* / Q000378:metabolism; D013095:Spermidine / Q000031:analogs & derivatives* / Q000737:chemistry* / Q000378:metabolism; D013096:Spermine / Q000031:analogs & derivatives* / Q000737:chemistry / Q000378:metabolism
chemical_list: D000447:Aldehydes; D011437:Propylamines; C017988:N(1)-acetylspermidine; C044445:MDL 72527; C029452:N'-acetylspermine; D013096:Spermine; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; D013095:Spermidine; D011700:Putrescine