MS/MS fragmentation-guided search of TMG-chitooligomycins and their structure-activity relationship in specific β-N-acetylglucosaminidase inhibition.
MS/MS fragmentation-guided search of TMG-chitooligomycins and their structure-activity relationship in specific β-N-acetylglucosaminidase inhibition.
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DOI：
10.1039/c0ob01090a
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发表时间：
2011-04
影响因子：
3.2
通讯作者：
H. Usuki;Yukihiro Yamamoto;Yuya Kumagai;T. Nitoda;H. Kanzaki;T. Hatanaka
中科院分区：
文献类型：
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作者：
H. Usuki;Yukihiro Yamamoto;Yuya Kumagai;T. Nitoda;H. Kanzaki;T. Hatanaka
还原性四糖TMG-壳三霉素（1）是β-N-乙酰氨基葡萄糖苷酶（GlcNAcase）的抑制剂，由放线菌环状链霉菌NBRC 13369产生。该抑制剂显示出独特的抑制谱，即对来自含几丁质的生物如昆虫和真菌的酶的选择性。然而，其结构-选择性关系仍有待澄清。在这项研究中，我们进行了结构导向搜索的类似物1，以获得不同的N，N，N-三甲基氨基葡萄糖（TMG）含有壳寡糖。在该方法中，1在ESI-MS/MS分析上的特异性裂解谱用于选择性检测所需化合物。结果，从产1链霉菌的培养滤液中分离得到两个新的类似物，分别命名为TMG-壳单霉素（3）和TMG-壳双霉素（2）。它们的酶抑制活性表明，效力和选择性取决于还原性末端GlcNAc单元的聚合度。此外，计算建模研究激发了TMG相关化合物作为GH 20酶的米氏复合物中底物的模拟物的抑制机制。这项研究是一个成功的应用MS/MS实验的天然产物的结构导向分离的例子。
The reducing tetrasaccharide TMG-chitotriomycin (1) is an inhibitor of β-N-acetylglucosaminidase (GlcNAcase), produced by the actinomycete Streptomyces anulatus NBRC13369. The inhibitor shows a unique inhibitory spectrum, that is, selectivity toward enzymes from chitin-containing organisms such as insects and fungi. Nevertheless, its structure-selectivity relationship remains to be clarified. In this study, we conducted a structure-guided search of analogues of 1 in order to obtain diverse N,N,N-trimethylglucosaminium (TMG)-containing chitooligosaccharides. In this approach, the specific fragmentation profile of 1 on ESI-MS/MS analysis was used for the selective detection of desired compounds. As a result, two new analogues, named TMG-chitomonomycin (3) and TMG-chitobiomycin (2), were obtained from a culture filtrate of 1-producing Streptomyces. Their enzyme-inhibiting activity revealed that the potency and selectivity depended on the degree of polymerization of the reducing end GlcNAc units. Furthermore, a computational modeling study inspired the inhibitory mechanism of TMG-related compounds as a mimic of the substrate in the Michaelis complex of the GH20 enzyme. This study is an example of the successful application of a MS/MS experiment for structure-guided isolation of natural products.