Department of Molecular Biotechnology and Microbiology, Institute of Biotechnology, Faculty of Science and Technology, University of Debrecen, Debrecen, Hungary.
Teva Pharmaceutical Works Ltd., Debrecen, Hungary.
Appl Microbiol Biotechnol. 2019 Feb;103(4):1599-1616. doi: 10.1007/s00253-018-09594-x. Epub 2019 Jan 6.
Indole-diterpenes (IDTs) such as the aflatrems, janthitrems, lolitrems, paspalitrems, penitrems, shearinines, sulpinines, and terpendoles are biogenetically related but structurally varied tremorgenic and neurotoxic mycotoxins produced by fungi. All these metabolites derive from the biosynthetic intermediate paspaline, a frequently occurring IDT on its own right. In this comprehensive review, we highlight the similarities and differences of the IDT biosynthetic pathways that lead to the generation of the main paspaline-derived IDT subgroups. We survey the taxonomic distribution and the regulation of IDT production in various fungi and compare the organization of the known IDT biosynthetic gene clusters. A detailed assessment of the highly diverse biological activities of these mycotoxins leads us to emphasize the significant losses that paspaline-derived IDTs cause in agriculture, and compels us to warn about the various hazards they represent towards human and livestock health. Conversely, we also describe the potential utility of these versatile molecules as lead compounds for pharmaceutical drug discovery, and examine the prospects for their industrial scale manufacture in genetically manipulated IDT producers or domesticated host microorganisms in synthetic biological production systems.
吲哚二萜（IDTs）如 aflatrem、janthitrem、lolitrem、paspalitrems、penitrem、shearinines、sulpines 和 terpendoles 是生物相关的但结构不同的震颤原和神经毒素真菌毒素。所有这些代谢物都来源于生物合成中间体 paspaline，它本身就是一种常见的 IDT。在这篇综合综述中，我们强调了导致主要的 paspaline 衍生 IDT 亚组生成的 IDT 生物合成途径的相似性和差异。我们调查了各种真菌中 IDT 产生的分类分布和调控，并比较了已知 IDT 生物合成基因簇的组织。对这些真菌毒素高度多样化的生物活性的详细评估使我们认识到，paspaline 衍生的 IDTs 给农业造成了重大损失，并促使我们警告它们对人类和牲畜健康构成的各种危害。相反，我们还描述了这些多功能分子作为药物发现的先导化合物的潜在用途，并研究了在遗传修饰的 IDT 生产者或驯化的宿主微生物中进行工业规模生产的前景，这些生产是在合成生物学生产系统中进行的。
