Yamaguchi Takao, Blázquez Blas, Hesek Dusan, Lee Mijoon, Llarrull Leticia I, Boggess Bill, Oliver Allen G, Fisher Jed F, Mobashery Shahriar
Department Chemistry and Biochemistry, University of Notre Dame, Notre Dame, Indiana 46556, United States.
ACS Med Chem Lett. 2012 Mar 8;3(3):238-242. doi: 10.1021/ml2002746. Epub 2012 Jan 19.
Gram-negative bacteria have evolved an elaborate process for the recycling of their cell wall, which is initiated in the periplasmic space by the action of lytic transglycosylases. The product of this reaction, β-D-N-acetylglucosamine-(1→4)-1,6-anhydro-β-D-N-acetylmuramyl-L-Ala-γ-D-Glu-meso-DAP-D-Ala-D-Ala (compound 1), is internalized to begin the recycling events within the cytoplasm. The first step in the cytoplasmic recycling is catalyzed by the NagZ glycosylase, which cleaves in a hydrolytic reaction the N-acetylglucosamine glycosidic bond of metabolite 1. The reactions catalyzed by both the lytic glycosylases and NagZ are believed to involve oxocarbenium transition species. We describe herein the synthesis and evaluation of four iminosaccharides as possible mimetics of the oxocarbenium species, and disclose one as a potent (compound 3, K(i) = 300 ± 15 nM) competitive inhibitor of NagZ.
革兰氏阴性菌已经进化出一种复杂的细胞壁循环利用过程，该过程由溶菌转糖基酶在周质空间的作用引发。此反应的产物，β-D-N-乙酰葡糖胺-(1→4)-1,6-脱水-β-D-N-乙酰胞壁酰-L-丙氨酸-γ-D-谷氨酸-内消旋二氨基庚二酸-D-丙氨酸-D-丙氨酸（化合物1），被内化以在细胞质内开始循环利用过程。细胞质循环利用的第一步由NagZ糖基酶催化，该酶在水解反应中裂解代谢物1的N-乙酰葡糖胺糖苷键。溶菌糖基酶和NagZ催化的反应都被认为涉及氧鎓离子过渡态。我们在此描述了四种亚氨基糖作为氧鎓离子物种可能模拟物的合成与评估，并公开了一种作为NagZ的强效竞争性抑制剂（化合物3，K(i)=300±15 nM）。
