Role of the sulfonium center in determining the ligand specificity of human s-adenosylmethionine decarboxylase.
Role of the sulfonium center in determining the ligand specificity of human s-adenosylmethionine decarboxylase.
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DOI：
10.1021/bi900590m
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发表时间：
2009-07-14
期刊：
影响因子：
2.9
通讯作者：
Ealick, Steven E.
中科院分区：
文献类型：
--
作者：
Bale, Shridhar;Brooks, Wesley;Hanes, Jeremiah W.;Mahesan, Arnold M.;Guida, Wayne C.;Ealick, Steven E.
S-腺苷蛋氨酸脱羧酶(ADO-MetDC)是多胺生物合成途径中的一个关键酶。抑制这一途径并随后耗尽多胺水平是癌症化疗和寄生虫病治疗的可行策略。底物类似物抑制剂在相当于S-腺苷蛋氨酸的硫的位置上显示出绝对的正电荷要求。我们通过结晶学、量子化学计算和停流实验研究了ADOMetDC的配体专一性。测定了5‘-脱氧-5’-二甲基硫代腺苷和5‘-脱氧-5’-(N-二甲基)氨基-8-甲基腺苷共结晶酶的晶体结构。晶体结构表明，配体与Phe7和Phe223的芳香族侧链之间存在良好的阳离子-π相互作用。根据量子化学计算，这种相互作用的稳定性估计为4.5千卡/摩尔。停流动力学实验表明底物与酶的结合速率很大程度上依赖于Phe7和Phe223，从而支持了阳离子-π相互作用的重要性。
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-methyl adenosine. 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.
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影响因子：
15
作者：
Biot, C;Buisine, E;Rooman, M
通讯作者：
Rooman, M
影响因子：
5.7
作者：
Ekstrom, JL;Mathews, II;Ealick, SE
通讯作者：
Ealick, SE
影响因子：
7.3
作者：
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通讯作者：
ABDELMONEM, MM
DOI：
10.1107/s0907444904019158
发表时间：
2004-12-01
影响因子：
2.2
作者：
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通讯作者：
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影响因子：
15
作者：
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