Expanding the structural diversity of drimentines by exploring the promiscuity of two N-methyltransferases
Expanding the structural diversity of drimentines by exploring the promiscuity of two N-methyltransferases
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通过探索两种 N-甲基转移酶的混杂性扩大德里门汀的结构多样性
DOI：
10.1016/j.isci.2020.101323
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发表时间：
2020
期刊：
影响因子：
5.8
通讯作者：
Wenli Li
中科院分区：
文献类型：
--
作者：
Tingting Yao;Jing Liu;Enjing Jin;Zengzhi Liu;Huayue Li;Qian Che;Tianjiao Zhu;Dehai Li;Wenli Li
甲基化被认为是合理改善先导化合物关键药代动力学特征的一种有前途的方法。尽管各种剪裁酶被发现与环二肽合成酶(CDPS)聚集在一起，以对二酮基哌嗪(DKP)环进行进一步的修饰反应，生成含有DKP的复杂化合物，但到目前为止，与CDPS共生的甲基转移酶(MTS)已经被实验表征。在这里，我们通过鉴定和鉴定DmtMT2-1(来自Streptomycessp)来破译DMTs生物合成过程中的甲基化步骤。NRRL F-5123)和DmtMT1(产自苏菲链霉菌OUC6819)。DmtMT2-1催化前DMT和DMT的N4甲基化；相反，DmtMT1识别DKP环，在萜类部分组装之前发挥作用。值得注意的是，这两种MT都表现出广泛的衬底混杂。它们与不同链霉菌的dmt1基因的组合表达成功地产生了8个非天然的dmt类似物。我们的结果丰富了MT工具箱，为探索用于药物开发的DKP衍生物的结构多样性奠定了基础。
Methylation is envisioned as a promising way to rationally improve key pharmacokinetic characteristics of lead compounds. Although diverse tailoring enzymes are found to be clustered with cyclodipeptide synthases (CDPSs) to perform further modification reactions on the diketopiperazine (DKP) rings generating complex DKP-containing compounds, so far, a limited number of methyltransferases (MTs) co-occurring with CDPS have been experimentally characterized. Herein, we deciphered the methylation steps during drimentines (DMTs) biosynthesis with identification and characterization of DmtMT2-1 (fromStreptomycessp. NRRL F-5123) and DmtMT1 (fromStreptomyces youssoufiensisOUC6819). DmtMT2-1 catalyzesN4-methylation of both pre-DMTs and DMTs; conversely, DmtMT1 recognizes the DKP rings, functioning before the assembly of the terpene moiety. Notably, both MTs display broad substrate promiscuity. Their combinatorial expression with thedmt1genes in differentStreptomycesstrains successfully generated eight unnatural DMT analogs. Our results enriched the MT tool-box, setting the stage for exploring the structural diversity of DKP derivatives for drug development.