State Key Laboratory of Bio-organic and Natural Products Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 354 Fenglin Road, 200032 Shanghai, P. R. China.
Chembiochem. 2011 Feb 11;12(3):457-67. doi: 10.1002/cbic.201000561. Epub 2010 Dec 23.
GH20 β-N-acetyl-D-hexosaminidases are enzymes involved in many vital processes. Inhibitors that specifically target GH20 enzymes in pests are of agricultural and economic importance. Structural comparison has revealed that the bacterial chitindegrading β-N-acetyl-D-hexosaminidases each have an extra +1 subsite in the active site; this structural difference could be exploited for the development of selective inhibitors. N,N,Ntrimethyl-D-glucosamine (TMG)-chitotriomycin, which contains three GlcNAc residues, is a natural selective inhibitor against bacterial and insect β-N-acetyl-D-hexosaminidases. However, our structural alignment analysis indicated that the two GlcNAc residues at the reducing end might be unnecessary. To prove this hypothesis, we designed and synthesized a series of TMG-chitotriomycin analogues containing one to four GlcNAc units. Inhibitory kinetics and molecular docking showed that TMG-(GlcNAc)(2), is as active as TMG-chitotriomycin [TMG-(GlcNAc)(3)]. The selective inhibition mechanism of TMG-chitotriomycin was also explained.
GH20β-N-乙酰-D-己糖苷酶参与许多重要的生理过程。特异性靶向害虫 GH20 酶的抑制剂具有农业和经济重要性。结构比较表明，细菌来源的壳聚糖降解β-N-乙酰-D-己糖苷酶在活性位点各有一个额外的+1 亚位点；这种结构差异可用于开发选择性抑制剂。含有三个 GlcNAc 残基的 N,N,N-三甲基-D-葡萄糖胺（TMG）-壳三霉素是一种天然的选择性抑制剂，可抑制细菌和昆虫的β-N-乙酰-D-己糖苷酶。然而，我们的结构比对分析表明，还原端的两个 GlcNAc 残基可能是不必要的。为了验证这一假设，我们设计并合成了一系列含有一个至四个 GlcNAc 单元的 TMG-壳三霉素类似物。抑制动力学和分子对接表明，TMG-(GlcNAc)(2)与 TMG-壳三霉素[TMG-(GlcNAc)(3)]一样具有活性。还解释了 TMG-壳三霉素的选择性抑制机制。
