Romsdahl Jillian, Wang Clay C C
Department of Pharmacology and Pharmaceutical Sciences , School of Pharmacy , University of Southern California , 1985 Zonal Avenue , Los Angeles , CA 90089 , USA . Email:
Department of Chemistry , Dornsife College of Letters, Arts, and Sciences , University of Southern California , 3551 Trousdale Pkwy , Los Angeles , CA 90089 , USA.
Medchemcomm. 2019 Apr 26;10(6):840-866. doi: 10.1039/c9md00054b. eCollection 2019 Jun 1.
Secondary metabolites (SMs) produced by filamentous fungi possess diverse bioactivities that make them excellent drug candidates. Whole genome sequencing has revealed that fungi have the capacity to produce a far greater number of SMs than have been isolated, since many of the genes involved in SM biosynthesis are either silent or expressed at very low levels in standard laboratory conditions. There has been significant effort to activate SM biosynthetic genes and link them to their downstream products, as the SMs produced by these "cryptic" pathways offer a promising source for new drug discovery. Further, an understanding of the genes involved in SM biosynthesis facilitates product yield optimization of first-generation molecules and genetic engineering of second-generation analogs. This review covers advances made in genome mining SMs produced by , , , and in the past six years (2012-2018). Genetic identification and molecular characterization of SM biosynthetic gene clusters, along with proposed biosynthetic pathways, will be discussed in depth.
丝状真菌产生的次生代谢产物(SMs)具有多种生物活性,使其成为优秀的药物候选物。全基因组测序表明,真菌产生的SMs数量远多于已分离出来的数量,因为许多参与SM生物合成的基因在标准实验室条件下要么沉默,要么表达水平很低。人们已做出巨大努力来激活SM生物合成基因并将它们与其下游产物联系起来,因为这些“隐秘”途径产生的SMs为新药发现提供了一个有前景的来源。此外,了解参与SM生物合成的基因有助于优化第一代分子的产物产量以及对第二代类似物进行基因工程改造。本综述涵盖了过去六年(2012 - 2018年)在对曲霉属、青霉属、链霉菌属和木霉属产生的SMs进行基因组挖掘方面取得的进展。将深入讨论SM生物合成基因簇的遗传鉴定和分子特征,以及提出的生物合成途径。