Download MendeleyRole of the sulfonium center in determining the ligand specificity of human s-adenosylmethionine decarboxylase.
Bale, S., Brooks, W., Hanes, J.W., Mahesan, A.M., Guida, W.C., Ealick, S.E.(2009) Biochemistry 48: 6423-6430
- PubMed: 19527050
- DOI: https://doi.org/10.1021/bi900590m
- Primary Citation of Related Structures:
3H0V, 3H0W - PubMed 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.
Organizational Affiliation:
Department of Chemistry and Chemical Biology, Cornell University, Ithaca, New York 14853, USA.
