Department Zernike Institute for Advanced Materials, University of Groningen, Nijenborgh 4, 9747 AG, Groningen, The Netherlands.
Stratingh Institute for Chemistry, University of Groningen, Nijenborgh 7, 9747 AG, Groningen, The Netherlands.
Chembiochem. 2018 Jan 4;19(1):58-65. doi: 10.1002/cbic.201700402. Epub 2017 Dec 11.
Enzymes of the 2-C-methyl-d-erythritol-4-phosphate pathway for the biosynthesis of isoprenoid precursors are validated drug targets. By performing phage display on 1-deoxy-d-xylulose-5-phosphate synthase (DXS), which catalyzes the first step of this pathway, we discovered several peptide hits and recognized false-positive hits. The enriched peptide binder P12 emerged as a substrate (d-glyceraldehyde-3-phosphate)-competitive inhibitor of Deinococcus radiodurans DXS. The results indicate possible overlap of the cofactor- and acceptor-substrate-binding pockets and provide inspiration for the design of inhibitors of DXS with a unique and novel mechanism of inhibition.
2-C-甲基-D-赤藓醇-4-磷酸途径的酶是异戊烯基前体生物合成的有效药物靶点。通过对催化该途径第一步反应的 1-脱氧-D-木酮糖-5-磷酸合酶（DXS）进行噬菌体展示，我们发现了几个肽类结合物，并识别出了假阳性结合物。富含肽结合物的 P12 是耐辐射球菌 DXS 的底物（D-甘油醛-3-磷酸）竞争性抑制剂。研究结果表明，辅因子和受体底物结合口袋可能存在重叠，并为设计具有独特新颖抑制机制的 DXS 抑制剂提供了启示。
