title: Molecular basis for the binding of competitive inhibitors of maize polyamine oxidase.
abstract: Maize polyamine oxidase (MPAO), the only member of the polyamine oxidase (PAO) family whose three-dimensional structure is known, is characterized by a 30 A long U-shaped catalytic tunnel located between the substrate binding domain and the FAD. To shed light on the MPAO ligand binding mode, we studied the inhibition properties of linear diamines, agmatine, prenylagmatine (G3), G3 analogues, and guazatine, and analyzed the structural determinants of their biological activity. Linear diamines competitively inhibited MPAO, with the inhibitory activity increasing as a function of the number of methylene groups. With regard to the guanidino competitive inhibitors, including agmatine, G3, and G3 analogues, the presence of a hydrophobic substituent constitutes the principal factor influencing MPAO inhibition, as the addition of a hydrophobic substituent to the guanidino group of both G3 and G3 analogues greatly increases the inhibitory activity. Moreover, results obtained by a molecular modeling procedure indicated that in their preferred orientation, G3 analogues point the ammonium group toward the narrow entrance of the tunnel, while the terminal hydrophobic group is located within the large entrance. The high binding affinity for MPAO exhibited by G3 and G3 analogues bearing a prenyl group as a substituent on the guanidino moiety is in agreement with the observation that the prenyl group binds in a well-defined hydrophobic pocket, mainly formed by aromatic residues. Finally, docking simulations performed with the charged and uncharged forms of MPAO inhibitors indicate that the stereoelectronic properties of the MPAO active site are consistent with the binding of inhibitors in the protonated form.
authors.affiliation: Dipartimento di Biologia, Università Roma Tre, Viale Guglielmo Marconi 446, I-00146 Roma, Italy.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Cona
authors.forename: Fabrizio
authors.initials: F
authors.lastname: Manetti
authors.forename: Rosalida
authors.initials: R
authors.lastname: Leone
authors.forename: Federico
authors.initials: F
authors.lastname: Corelli
authors.forename: Paraskevi
authors.initials: P
authors.lastname: Tavladoraki
authors.forename: Fabio
authors.initials: F
authors.lastname: Polticelli
authors.forename: Maurizio
authors.initials: M
authors.lastname: Botta
mesh_terms: D000376:Agmatine / Q000031:analogs & derivatives / Q000737:chemistry; D001667:Binding, Competitive; D002384:Catalysis; D020134:Catalytic Domain; D003198:Computer Simulation; D003959:Diamines / Q000737:chemistry; D004791:Enzyme Inhibitors / Q000737:chemistry; D006146:Guanidines / Q000737:chemistry; D008958:Models, Molecular; D000587:Oxidoreductases Acting on CH-NH Group Donors / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D010940:Plant Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry*; D011485:Protein Binding; D011522:Protons; D013379:Substrate Specificity; D003313:Zea mays / Q000201:enzymology*; D000097667:Polyamine Oxidase
chemical_list: D000376:Agmatine; D003959:Diamines; D004791:Enzyme Inhibitors; D006146:Guanidines; D000587:Oxidoreductases Acting on CH-NH Group Donors; D010940:Plant Proteins; D011522:Protons; D000097667:Polyamine Oxidase; C008697:octamethylenediamine; C012343:guazatine