Role of the Sulfonium Center in Determining the Ligand Specificity of Human S-Adenosylmethionine Decarboxylase
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- 作者：Shridhar Bale ; Wesley Brooks ; Jeremiah W. Hanes ; Arnold M. Mahesan ; Wayne C. Guida ; Steven E. Ealick
- 刊名：Biochemistry
- 出版年：2009
- 出版时间：July 14, 2009
- 年：2009
- 卷：48
- 期：27
- 页码：6423-6430
- 全文大小：844K
- 年卷期：v.48,no.27(July 14, 2009)
- ISSN：1520-4995
文摘
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−π 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−π interaction.