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操控真菌发育作为生物技术新型次生代谢产物的来源。

Manipulation of fungal development as source of novel secondary metabolites for biotechnology.

作者信息

Gerke Jennifer, Braus Gerhard H

机构信息

Institut für Mikrobiologie & Genetik, Georg-August-Universität, Grisebachstr. 8, D-37077, Göttingen, Germany.

出版信息

Appl Microbiol Biotechnol. 2014 Oct;98(20):8443-55. doi: 10.1007/s00253-014-5997-8. Epub 2014 Aug 21.

Abstract

Fungal genomics revealed a large potential of yet-unexplored secondary metabolites, which are not produced during vegetative growth. The discovery of novel bioactive compounds is increasingly gaining importance. The high number of resistances against established antibiotics requires novel drugs to counteract increasing human and animal mortality rates. In addition, growth of plant pathogens has to be controlled to minimize harvest losses. An additional critical issue is the post-harvest production of deleterious mycotoxins. Fungal development and secondary metabolite production are linked processes. Therefore, molecular regulators of development might be suitable to discover new bioactive fungal molecules or to serve as targets to control fungal growth, development, or secondary metabolite production. The fungal impact is relevant as well for our healthcare systems as for agriculture. We propose here to use the knowledge about mutant strains discovered in fungal model systems for a broader application to detect and explore new fungal drugs or toxins. As examples, mutant strains impaired in two conserved eukaryotic regulatory complexes are discussed. The COP9 signalosome (CSN) and the velvet complex act at the interface between development and secondary metabolism. The CSN is a multi-protein complex of up to eight subunits and controls the activation of CULLIN-RING E3 ubiquitin ligases, which mark substrates with ubiquitin chains for protein degradation by the proteasome. The nuclear velvet complex consists of the velvet-domain proteins VeA and VelB and the putative methyltransferase LaeA acting as a global regulator for secondary metabolism. Defects in both complexes disturb fungal development, light perception, and the control of secondary metabolism. The potential biotechnological relevance of these developmental fungal mutant strains for drug discovery, agriculture, food safety, and human healthcare is discussed.

摘要

真菌基因组学揭示了大量尚未探索的次生代谢产物的潜力,这些次生代谢产物在营养生长过程中不产生。新型生物活性化合物的发现正变得越来越重要。对现有抗生素的大量耐药性需要新型药物来应对人类和动物死亡率的上升。此外,必须控制植物病原体的生长,以尽量减少收获损失。另一个关键问题是收获后有害霉菌毒素的产生。真菌发育和次生代谢产物的产生是相互关联的过程。因此,发育的分子调节因子可能适合于发现新的生物活性真菌分子,或作为控制真菌生长、发育或次生代谢产物产生的靶点。真菌的影响对我们的医疗保健系统和农业都很重要。我们在此提议利用在真菌模型系统中发现的突变菌株的知识,更广泛地应用于检测和探索新的真菌药物或毒素。作为例子,讨论了在两个保守的真核调节复合物中受损的突变菌株。COP9信号体(CSN)和天鹅绒复合物作用于发育和次生代谢之间的界面。CSN是一个由多达八个亚基组成的多蛋白复合物,控制CULLIN-RING E3泛素连接酶的激活,该酶用泛素链标记底物,以便蛋白酶体进行蛋白质降解。核天鹅绒复合物由天鹅绒结构域蛋白VeA和VelB以及假定的甲基转移酶LaeA组成,LaeA作为次生代谢的全局调节因子。这两种复合物的缺陷都会干扰真菌发育、光感知和次生代谢的控制。讨论了这些发育性真菌突变菌株在药物发现、农业、食品安全和人类医疗保健方面潜在的生物技术相关性。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/20f3/4192562/da1de20f3238/253_2014_5997_Fig1_HTML.jpg

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