Chemoenzymatic Synthesis of C6-Modified Sugar Nucleotides To Probe the GDP-D-Mannose Dehydrogenase from Pseudomonas aeruginosa
Chemoenzymatic Synthesis of C6-Modified Sugar Nucleotides To Probe the GDP-D-Mannose Dehydrogenase from Pseudomonas aeruginosa
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DOI：
10.1021/acs.orglett.9b00967
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发表时间：
2019-06-21
期刊：
影响因子：
5.2
通讯作者：
Miller, Gavin J.
中科院分区：
文献类型：
--
作者：
Ahmadipour, Sanaz;Pergolizzi, Giulia;Miller, Gavin J.
描述了一系列 C6 修饰的 GDP-AD-Man 糖核苷酸的化学酶合成。这为从铜绿假单胞菌中生产 GDP-D-甘露糖脱氢酶 (GMD) 的 GDP-D-ManA 提供了第一个结构功能工具。使用常见的 C6 醛官能化策略，化学合成引入了氘富集，同时在 C6 上进行了一系列甘露糖 1-磷酸的单碳同系化。这些材料被证明是来自肠沙门氏菌的 GDP-甘露糖焦磷酸化酶的底物，提供修饰的 GDP-D-Mans 所需的工具箱。 C6-CH3 修饰的糖核苷酸能够可逆地阻止 GMD 产生 GDP-ManA。通过高分辨率质谱法鉴定 C6-CH3 修饰类似物氧化产生的酮产物。
The chemoenzymatic synthesis of a series of C6-modified GDP-AD-Man sugar nucleotides is described. This provides the first structure-function tools for the GDP-D-ManA producing GDP-D-mannose dehydrogenase (GMD) from Pseudomonas aeruginosa. Using a common C6 aldehyde functionalization strategy, chemical synthesis introduces deuterium enrichment, alongside one-carbon homologation at C6 for a series of mannose 1-phosphates. These materials are shown to be substrates for the GDP-mannose pyrophosphorylase from Salmonella enterica, delivering the required toolbox of modified GDP-D-Mans. C6-CH3 modified sugar-nucleotides are capable of reversibly preventing GDP-ManA production by GMD. The ketone product from oxidation of a C6-CH3 modified analogue is identified by high-resolution mass spectrometry.