Asymmetric catalysis at a distance: catalytic, site-selective phosphorylation of teicoplanin.
Asymmetric catalysis at a distance: catalytic, site-selective phosphorylation of teicoplanin.
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DOI：
10.1021/ja406067v
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发表时间：
2013-08-21
影响因子：
15
通讯作者：
Miller SJ
中科院分区：
文献类型：
--
作者：
Han S;Miller SJ
我们报告了三种不同的基于肽的催化剂，能够对复杂糖肽抗生素替考拉宁A2-2中的三个不同羟基进行位点选择性磷酸化。其中两种催化剂的设计利用了模拟替考拉宁生物作用机制的催化剂-底物相互作用。这些催化剂基于已知以特定方式靶向替考拉宁结构的DXaa-DXaa肽基序。第三个是通过评价为历史上不同的项目开发的一套催化剂来确定的。每种催化剂都含有额外的功能，旨在将催化部分（亲核烷基咪唑）置于糖肽结构的不同区域。质谱法和2D-NMR光谱法的组合允许不同磷酸化替考拉宁衍生物的结构归属。机制研究也报告，支持的假设，导致发现的催化剂。以这种方式，已经实现了小分子催化剂，其允许基于替考拉宁A2-2的X射线晶体结构在相隔11.6 nm、16.5 nm和近17.7 nm的位点处对反应进行合理的催化控制。最后，我们报告了新的磷酸化替考拉宁类似物的生物活性，并将结果与天然产物本身进行了比较。
We report three distinct, peptide-based catalysts that enable site-selective phosphorylation of three distinct hydroxyl groups within the complex glycopeptide antibiotic teicoplanin A2-2. Two of the catalysts are based on a design that capitalizes on a catalyst-substrate interaction that mimics the biological mechanism of action for teicoplanin. These catalysts are based on a DXaa-DXaa peptide motif that is known to target the teicoplanin structure in a specific manner. The third was identified through evaluation of a set of catalysts that had been developed for historically distinct projects. Each catalyst contains additional functionality designed to dispose a catalytic moiety (a nucleophilic alkylimidazole) at a different region of the glycopeptide structure. A combination of mass spectrometry and 2D-NMR spectroscopy allowed structural assignment of the distinct phosphorylated teicoplanin derivatives. Mechanistic studies are also reported that support the hypotheses that led to the discovery of the catalysts. In this manner, small molecule catalysts have been achieved that allow rational, catalytic control over reactions at sites that are separated by 11.6 Å, 16.5 Å and nearly 17.7 Å, based on the X-ray crystal structure of teicoplanin A2-2. Finally, we report the biological activity of the new phosphorylated teicoplanin analogs, and compare the results to the natural product itself.
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影响因子：
15
作者：
Fisk, JD;Powell, DR;Gellman, SH
通讯作者：
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影响因子：
21.8
作者：
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DOI：
10.1107/s0907444912050469
发表时间：
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影响因子：
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作者：
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通讯作者：
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影响因子：
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作者：
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