Robust Chemoenzymatic Synthesis of Keratinimicin Aglycone Analogues Facilitated by the Structure and Selectivity of OxyB.
Robust Chemoenzymatic Synthesis of Keratinimicin Aglycone Analogues Facilitated by the Structure and Selectivity of OxyB.
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DOI：
10.1021/acschembio.3c00192
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发表时间：
2023-07-21
影响因子：
4
通讯作者：
Seyedsayamdost MR
中科院分区：
文献类型：
--
作者：
Hauser N;Ireland KA;Chioti VT;Forneris CC;Davis KM;Seyedsayamdost MR
耐多药病原体的出现对公众健康构成威胁，需要新的抗菌剂。作为治疗革兰氏阳性菌的典型糖肽抗生素(GPA)，万古霉素提供了一个很有前途的起点。万古霉素支架的外围改造使新的GPA得以开发。然而，由于该复合物族的大小和复杂性，修改核心仍然具有挑战性。最近成功地用化学酶法合成了万古霉素，表明该方法具有广泛的应用前景。在这里，我们描述了通过生产角蛋白A的苷元类似物，将化学酶策略扩展到包含所有芳香族氨基酸的II型GPA，角蛋白A是一种比万古霉素对艰难梭菌有效5倍的GPA。在这些研究过程中，我们发现细胞色素P450酶OxyBker具有广泛的底物耐受性和显著的选择性，可以在线性多肽前体上形成第一个芳基醚交联物。OxyBker的X-射线晶体结构确定为2.8？，表明可能对这些性质有贡献的结构特征。我们的结果为广泛使用OxyBker作为生物催化剂合成各种GPA类似物奠定了基础。
The emergence of multidrug-resistant pathogens poses a threat to public health and requires new antimicrobial agents. As the archetypal glycopeptide antibiotic (GPA) used against drug-resistant Gram-positive pathogens, vancomycin provides a promising starting point. Peripheral alterations to the vancomycin scaffold have enabled the development of new GPAs. However, modifying the core remains challenging due to the size and complexity of this compound family. The recent successful chemoenzymatic synthesis of vancomycin suggests that such an approach can be broadly applied. Herein, we describe the expansion of chemoenzymatic strategies to encompass type II GPAs bearing all aromatic amino acids through the production of the aglycone analogue of keratinimicin A, a GPA that is 5-fold more potent than vancomycin against Clostridioides difficile. In the course of these studies, we found that the cytochrome P450 enzyme OxyBker boasts both broad substrate tolerance and remarkable selectivity in the formation of the first aryl ether cross-link on the linear peptide precursors. The X-ray crystal structure of OxyBker, determined to 2.8 Å, points to structural features that may contribute to these properties. Our results set the stage for using OxyBker broadly as a biocatalyst toward the chemoenzymatic synthesis of diverse GPA analogues.
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影响因子：
15
作者：
Okano, Akinori;James, Robert C.;Pierce, Joshua G.;Xie, Jian;Boger, Dale L.
通讯作者：
Boger, Dale L.
影响因子：
5.2
作者：
Brieke, Clara;Cryle, Max J.
通讯作者：
Cryle, Max J.
影响因子：
3.2
作者：
Haslinger, Kristina;Maximowitsch, Egle;Cryle, Max J.
通讯作者：
Cryle, Max J.
影响因子：
5
作者：
Kim JM;Kim YS;Kim YR;Choi MJ;DasSarma P;DasSarma S
通讯作者：
DasSarma S
影响因子：
4.1
作者：
PERKINS, HR
通讯作者：
PERKINS, HR