title: Role of the sulfonium center in determining the ligand specificity of human s-adenosylmethionine decarboxylase.
abstract: S-Adenosylmethionine decarboxylase (AdoMetDC) is a key enzyme in the polyamine biosynthetic pathway. Inhibition of this pathway and subsequent depletion of polyamine levels is a viable strategy for cancer chemotherapy and for the treatment of parasitic diseases. Substrate analogue inhibitors display an absolute requirement for a positive charge at the position equivalent to the sulfonium of S-adenosylmethionine. We investigated the ligand specificity of AdoMetDC through crystallography, quantum chemical calculations, and stopped-flow experiments. We determined crystal structures of the enzyme cocrystallized with 5'-deoxy-5'-dimethylthioadenosine and 5'-deoxy-5'-(N-dimethyl)amino-8-methyladenosine. The crystal structures revealed a favorable cation-pi interaction between the ligand and the aromatic side chains of Phe7 and Phe223. The estimated stabilization from this interaction is 4.5 kcal/mol as determined by quantum chemical calculations. Stopped-flow kinetic experiments showed that the rate of the substrate binding to the enzyme greatly depends on Phe7 and Phe223, thus supporting the importance of the cation-pi interaction.
authors.affiliation: Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA.
authors.forename: Shridhar
authors.initials: S
authors.lastname: Bale
authors.forename: Wesley
authors.initials: W
authors.lastname: Brooks
authors.forename: Jeremiah W
authors.initials: JW
authors.lastname: Hanes
authors.forename: Arnold M
authors.initials: AM
authors.lastname: Mahesan
authors.forename: Wayne C
authors.initials: WC
authors.lastname: Guida
authors.forename: Steven E
authors.initials: SE
authors.lastname: Ealick
mesh_terms: D012437:Adenosylmethionine Decarboxylase / Q000737:chemistry / Q000378:metabolism*; D018360:Crystallography, X-Ray; D006801:Humans; D007700:Kinetics; D008024:Ligands; D011487:Protein Conformation; D011789:Quantum Theory; D013379:Substrate Specificity; D013452:Sulfonium Compounds / Q000378:metabolism*; D013816:Thermodynamics
chemical_list: D008024:Ligands; D013452:Sulfonium Compounds; D012437:Adenosylmethionine Decarboxylase