Metabolic coupling of two small-molecule thiols programs the biosynthesis of lincomycin A
Metabolic coupling of two small-molecule thiols programs the biosynthesis of lincomycin A
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两种小分子硫醇的代谢偶联编程林可霉素 A 的生物合成
DOI：
10.1038/nature14137
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发表时间：
2015-02-05
期刊：
影响因子：
64.8
通讯作者：
Liu, Wen
中科院分区：
文献类型：
--
作者：
Zhao, Qunfei;Wang, Min;Liu, Wen
生物体中的低分子硫醇因其在抵御各种内源和外源压力方面的氧化还原相关作用而广为人知。在真核生物和革兰氏阴性细菌中，主要的硫醇是谷胱甘肽(GSH)，它是一种含有半胱氨酸基的三肽。相比之下，霉硫醇(MSH)是一种半胱氨酰伪二糖，在革兰氏阳性放线菌中占主导地位，包括产生抗生素的放线菌和致病分枝杆菌。MSH在许多生化过程中相当于GSH，无论是作为辅因子还是作为底物，其中大多数还没有被表征，主要是由于缺乏关于MSH依赖蛋白的信息。放线菌能够产生另一种硫醇，麦角硫醚(EGT)，一种组氨酸甜菜碱衍生物，被植物和动物广泛同化，用于各种生理活动。然而，EGT在酶反应中的参与尚无先例。在这里，我们报告了两种细菌硫醇的前所未有的偶联，MSH和EGT，在林可霉素A的生物合成中具有建设性的作用，林可霉素A是一种含硫的林可酰胺(C8糖)抗生素，半个世纪以来一直被广泛用于治疗革兰氏阳性细菌感染。EGT作为模板分子组装的载体，MSH是林可霉素硫醇交换后成熟的硫供体。这些硫醇通过两种不同寻常的糖基化作用来发挥作用-糖基化反应，它们编程林可酰胺的转移、激活和修饰，为EGT相关的生化过程和知之甚少的MSH依赖的生物转化提供了第一个范例，这是一种新描述的模型，可能在硫的结合中很常见，硫是生命所必需的，在生命系统中无处不在。
Low-molecular-mass thiols in organisms are well known for their redox-relevant role in protection against various endogenous and exogenous stresses,,. In eukaryotes and Gram-negative bacteria, the primary thiol is glutathione (GSH), a cysteinyl-containing tripeptide. In contrast, mycothiol (MSH), a cysteinyl pseudo-disaccharide, is dominant in Gram-positive actinobacteria, including antibiotic-producing actinomycetes and pathogenic mycobacteria. MSH is equivalent to GSH, either as a cofactor or as a substrate, in numerous biochemical processes, most of which have not been characterized, largely due to the dearth of information concerning MSH-dependent proteins. Actinomycetes are able to produce another thiol, ergothioneine (EGT), a histidine betaine derivative that is widely assimilated by plants and animals for variable physiological activities. The involvement of EGT in enzymatic reactions, however, lacks any precedent. Here we report that the unprecedented coupling of two bacterial thiols, MSH and EGT, has a constructive role in the biosynthesis of lincomycin A, a sulfur-containing lincosamide (C8 sugar) antibiotic that has been widely used for half a century to treat Gram-positive bacterial infections,,,. EGT acts as a carrier to template the molecular assembly, and MSH is the sulfur donor for lincomycin maturation after thiol exchange. These thiols function through two unusualS-glycosylations that program lincosamide transfer, activation and modification, providing the first paradigm for EGT-associated biochemical processes and for the poorly understood MSH-dependent biotransformations, a newly described model that is potentially common in the incorporation of sulfur, an element essential for life and ubiquitous in living systems.