酶的糖基化和酰胺化重塑多烯生物活性

酶的糖基化和酰胺化重塑多烯生物活性

作者： 小柯机器人 发布时间：2026/7/30 17:27:40

本期文章：《自然》：Online/在线发表

近日，英国曼彻斯特大学教授Jason Micklefield及其小组的论文发现了酶的糖基化和酰胺化重塑了多烯的生物活性。2026年7月29日，国际知名学术期刊《自然》发表了这一成果。

在这里，该课题组描述了先前未描述的多烯途径的发现和表征，包括将糖引入多烯支架的非糖基转移酶。研究组还展示了如何扩大氨基转移酶的反应范围，将有害的多烯羧酸取代基转化为替代功能。引入第二种糖与羧酸盐修饰相结合，导致更有效的多烯抗真菌药，毒性降低，可通过清洁和有效的发酵或酶促途径获得。

据介绍，由于抗菌素耐药性上升和缺乏新的抗真菌治疗方法，真菌疾病对人类健康的威胁不断升级。多烯是一类复杂的天然产物，由于其广谱活性而被广泛用作抗真菌药物。然而，它们的临床应用受到严重毒性和溶解度差的限制，迫切需要更安全、更有效的替代品。先前生产改良多烯的努力依赖于昂贵、步骤效率低和原子效率低的化学合成。

附：英文原文

Title: Enzymatic glycosylation and amidation reshapes polyene bioactivity

Author: Mirza, Saadia N., Carella, Alberto, Thompson, Joseph W., Panda, Deepanjan, McDonald, Anna R. I., Crossley, Matthew D., Thong, Wei Li, Robins, Katherine J., Shepherd, Sarah. A., Cliff, Matthew J., Valero, Clara, Thom, Andrew, Bromley, Michael, Micklefield, Jason

Issue&Volume: 2026-07-29

Abstract: Fungal diseases are an escalating threat to human health, driven by rising antimicrobial resistance and a lack of new antifungal treatments1,2. Polyenes, a class of complex natural products, have been widely used as antifungal agents due to their broad-spectrum activity3. However, their clinical use is limited by severe toxicity and poor solubility, making safer and more effective alternatives urgently needed4. Previous efforts to generate improved polyenes have relied on costly, step-inefficient and atom-inefficient chemical syntheses5,6. Here we describe the discovery and characterization of pathways to previously undescribed polyenes, including unusual glycosyltransferase enzymes that introduce sugars onto polyene scaffolds. We also show how the reaction scope of an amidotransferase enzyme can be expanded to transform the detrimental carboxylate substituent of polyenes to alternative functionality. Introduction of a second sugar combined with carboxylate modifications leads to more potent polyene antifungals, with reduced toxicity, that are accessible by clean and efficient fermentation or enzymatic routes.

DOI: 10.1038/s41586-026-10834-8

Source: https://www.nature.com/articles/s41586-026-10834-8

主题：多烯