Department of Microbiology and Immunobiology, Harvard Medical School, Boston, Massachusetts, USA.
Nat Chem Biol. 2011 Nov 13;8(1):72-7. doi: 10.1038/nchembio.711.
Glycosyltransferases (Gtfs) catalyze the formation of a diverse array of glycoconjugates. Small-molecule inhibitors to manipulate Gtf activity in cells have long been sought as tools for understanding Gtf function. Success has been limited because of challenges in designing inhibitors that mimic the negatively charged diphosphate substrates. Here we report the mechanism of action of a small molecule that inhibits O-linked N-acetylglucosamine transferase (OGT), an essential human enzyme that modulates cell signaling pathways by catalyzing a unique intracellular post-translational modification, β-O-GlcNAcylation. The molecule contains a five-heteroatom dicarbamate core that functions as a neutral diphosphate mimic. One dicarbamate carbonyl reacts with an essential active site lysine that anchors the diphosphate of the nucleotide-sugar substrate. A nearby cysteine then reacts with the lysine adduct to form a carbonyl crosslink in the OGT active site. Though this unprecedented double-displacement mechanism reflects the unique architecture of the OGT active site, related dicarbamate scaffolds may inhibit other enzymes that bind nucleotide-containing substrates.
糖基转移酶（Gtfs）催化形成各种各样的糖缀合物。长期以来，人们一直寻求小分子抑制剂来操纵细胞中的 Gtf 活性，将其作为研究 Gtf 功能的工具。但由于设计模拟带负电荷二磷酸底物的抑制剂具有挑战性，因此成功有限。在这里，我们报告了一种小分子抑制 O-连接 N-乙酰氨基葡萄糖转移酶（OGT）的作用机制。OGT 是一种必需的人类酶，通过催化独特的细胞内翻译后修饰——β-O-GlcNAcylation，调节细胞信号通路。该分子含有一个包含五个杂原子的二氨基甲酸盐核心，作为中性二磷酸模拟物。一个二氨基甲酸盐羰基与锚定核苷酸糖底物二磷酸的必需活性位点赖氨酸反应。然后，附近的半胱氨酸与赖氨酸加合物反应，在 OGT 活性位点形成羰基交联。尽管这种前所未有的双置换机制反映了 OGT 活性位点的独特结构，但相关的二氨基甲酸盐支架可能会抑制其他结合含核苷酸底物的酶。
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