Isozyme Specific Allosteric Regulation of Human Sulfotransferase 1A1.
Isozyme Specific Allosteric Regulation of Human Sulfotransferase 1A1.
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DOI：
10.1021/acs.biochem.6b00401
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发表时间：
2016-07-26
期刊：
影响因子：
2.9
通讯作者：
Leyh TS
中科院分区：
文献类型：
--
作者：
Wang T;Cook I;Leyh TS
人胞质硫基转移酶（SULT）是一个由13个成员组成的酶家族，通过将PAPS（3 '-磷酸腺苷5'-磷酸硫酸酯）上的硫酰基（-SO 3）区域特异性地转移到受体的羟基和胺上，调节数百甚至数千个信号小分子的活性。受磺化调节的信号分子包括许多类固醇和甲状腺激素、肾上腺素、血清素和多巴胺。SULT 1A 1是一种主要的II相代谢SULT亚型，在肝脏中浓度很高，最近发现它具有两个变构结合位点，每个位点结合一种单独的复杂化合物-儿茶素（天然存在的多酚）和NSAIDS。在儿茶素类中，表没食子儿茶素没食子酸酯（epigallocatechin gallate，EGCG）对SULT 1A 1显示出高亲和力和特异性。与这两个位点相关的变构网络尚未定义。在这里，使用平衡结合和presteady状态的研究，网络被证明涉及14个不同的复合物。ECGG结合SULT 1A 1的变构位点和相对较弱的活性位点。它不是SULT 1A 1底物，但被SULT 2A 1磺化。当酶的活性位点帽被核苷酸的结合关闭时，EGCG的结合紧密17倍。当核苷酸饱和时，EGCG以两个相结合。在第一种情况下，它与帽开放型构象异构体结合;在第二种情况下，它将帽捕获在闭合构型中。封帽封装核苷酸，防止其释放;因此，EGCG诱导的帽稳定化减缓核苷酸释放，抑制周转。最后，提出了一个综合的定量模型的网络。
The human cytosolic sulfotransferases (SULTs) comprise a 13-member enzyme family that regulates the activities of hundreds, perhaps thousands of signaling small molecules via regiospecific transfer of the sulfuryl-moiety (-SO3) from PAPS (3’-phosphoadenosine 5’-phosphosulfate) to the hydroxyls and amines of acceptors. Signaling molecules regulated by sulfonation include numerous steroid and thyroid hormones, epinephrine, serotonin, and dopamine. SULT1A1, a major phase II metabolism SULT isoform, is found at high concentration in liver and has recently been show to harbor two allosteric-binding sites, each of which binds a separate and complex class of compounds - the catechins (naturally occurring polyphenols) and NSAIDS. Among catechins, epigallocatechin gallate (EGCG) displays high affinity and specificity toward SULT1A1. The allosteric network associated with either site has yet to be defined. Here, using equilibrium binding and presteady state studies, the network is shown to involve fourteen distinct complexes. ECGG binds both the allosteric site and, relatively weakly, the active site of SULT1A1. It is not a SULT1A1 substrate, but is sulfonated by SULT2A1. EGCG binds 17-fold more tightly when the active-site cap of the enzyme is closed by the binding of nucleotide. When nucleotide is saturating, EGCG binds in two phases. In the first, it binds to the cap-open conformer; in the second, it traps the cap in the closed configuration. Cap-closure encapsulates the nucleotide, preventing its release; hence, the EGCG-induced cap stabilization slows nucleotide release, inhibiting turnover. Finally, a comprehensive quantitative model of the network is presented.
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