3'-Phosphoadenosine 5'-phosphosulfate allosterically regulates sulfotransferase turnover.
3'-Phosphoadenosine 5'-phosphosulfate allosterically regulates sulfotransferase turnover.
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DOI：
10.1021/bi501120p
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发表时间：
2014-11-11
期刊：
影响因子：
2.9
通讯作者：
Leyh, Thomas S.
中科院分区：
文献类型：
--
作者：
Wang, Ting;Cook, Ian;Leyh, Thomas S.
人胞质磺基转移酶 (SULT) 通过将硫酰基部分 (-SO3) 从 3'-磷酸腺苷 5'-磷酸硫酸盐 (PAPS) 转移到受体的羟基和伯胺来调节数千种小分子（代谢物、药物和其他外源物质）的活性。 SULT1A1 是肝脏中最丰富的 SULT，并且具有所有 SULT 中最广泛的底物谱。在这里，我们发现了一种新形式的 SULT1A1 变构调节，可以在 130 倍的动态范围内调节酶的催化效率。详细探讨了该调节的分子基础，并显示其根源于 SULT1A1 二聚体中相邻亚基活性位点帽之间的能量耦合。第一个结合的核苷酸导致其所结合的帽闭合，同时将相邻亚基中的帽稳定在打开位置。第二个核苷酸的结合导致两个帽打开。封盖在空间上控制核苷酸和受体的活性位点进入；因此，作为核苷酸占据函数而发生的帽结构变化导致底物亲和力和酶周转的变化。多种器官组织中的 PAPS 水平表明，该酶的催化效率在不同组织之间存在 130 倍的差异，并且在那些经历最大外源“负荷”的组织中效率最高。
Human cytosolic sulfotransferases (SULTs) regulate the activities of thousands of small molecules—metabolites, drugs, and other xenobiotics—via the transfer of the sulfuryl moiety (-SO3) from 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to the hydroxyls and primary amines of acceptors. SULT1A1 is the most abundant SULT in liver and has the broadest substrate spectrum of any SULT. Here we present the discovery of a new form of SULT1A1 allosteric regulation that modulates the catalytic efficiency of the enzyme over a 130-fold dynamic range. The molecular basis of the regulation is explored in detail and is shown to be rooted in an energetic coupling between the active-site caps of adjacent subunits in the SULT1A1 dimer. The first nucleotide to bind causes closure of the cap to which it is bound and at the same time stabilizes the cap in the adjacent subunit in the open position. Binding of the second nucleotide causes both caps to open. Cap closure sterically controls active-site access of the nucleotide and acceptor; consequently, the structural changes in the cap that occur as a function of nucleotide occupancy lead to changes in the substrate affinities and turnover of the enzyme. PAPS levels in tissues from a variety of organs suggest that the catalytic efficiency of the enzyme varies across tissues over the full 130-fold range and that efficiency is greatest in those tissues that experience the greatest xenobiotic “load”.
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