An O-GlcNAcase-specific inhibitor and substrate engineered by the extension of the N-acetyl moiety
An O-GlcNAcase-specific inhibitor and substrate engineered by the extension of the N-acetyl moiety
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DOI：
10.1021/ja0582915
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发表时间：
2006-04-05
影响因子：
15
通讯作者：
Hanover, JA
中科院分区：
文献类型：
--
作者：
Kim, EJ;Perreira, M;Hanover, JA
合成了一种新型PUGNAc类似物（一种有效的O-GlcNAcase抑制剂），并将其作为O-GlcNAcase、氨基己糖苷酶A和氨基己糖苷酶B的抑制剂进行了分析。虽然PUGNAc未显示出对这些相关酶的选择性抑制，但乙酰基部分延伸至较长丁基链提供了对O-GlcNAc酶具有抑制作用的化合物，并且未观察到对氨基己糖苷酶A或氨基己糖苷酶B的抑制。此外，我们将这种在theN-乙酰基上的底物识别知识应用于我们最近报道的用于监测O-GlcNAc酶活性的荧光底物。令人欣慰的是，这种改变的小分子被证明是O-GlcNAc酶的有效底物，而对氨基己糖苷酶A没有活性。该试剂首次提供了一种独立于相关酶氨基己糖苷酶A和氨基己糖苷酶B的监测O-GlcNAcase活性的方法。
A novel analogue of PUGNAc, a potent O-GlcNAcase inhibitor, was synthesized and analyzed as an inhibitor of O-GlcNAcase, hexosaminidase A, and hexosaminidase B. While PUGNAc does not demonstrate selective inhibition of these related enzymes, the extension of the acetyl moiety to the longer butyl chain provided a compound with depressed inhibition of O-GlcNAcase and no observed inhibition of either hexosaminidase A or hexosaminidase B. Further, we applied this knowledge of substrate recognition at theN-acetyl group to our recently reported fluorogenic substrate for monitoring O-GlcNAcase activity. Gratifyingly, this altered small molecule was demonstrated to be a potent substrate for O-GlcNAcase while possessing no activity at hexosaminidase A. This reagent provides, for the first time, a means for monitoring O-GlcNAcase activity independent of the related enzymes hexosaminidase A and hexosaminidase B.