Abstract
Many fungi in the Stachybotrys genus can produce various isoindolinone derivatives. These compounds are formed by a spontaneous reaction between a phthalic aldehyde precursor and an ammonium ion or amino compounds. In this study, we suggested the isoindolinone biosynthetic gene cluster in Stachybotrys by genome mining based on three reported core genes. Remarkably, there is an additional nitrate reductase (NR) gene copy in the proposed cluster. NR is the rate-limiting enzyme of nitrate reduction. Accordingly, this cluster was speculated to play a role in the balance of ammonium ion concentration in Stachybotrys. Ammonium ions can be replaced by different amino compounds to create structural diversity in the biosynthetic process of isoindolinone. We tested a rational supply of amino compounds ((±)-3-amino-2-piperidinone, glycine, and l-threonine) in the culture of an isoindolinone high-producing marine fungus, Stachybotrys longispora FG216. As a result, we obtained four new kinds of isoindolinone derivatives (FGFC4–GFC7) by this method. Furthermore, high yields of FGFC4–FGFC7 confirmed the outstanding production capacity of FG216. Among the four new isoindolinone derivatives, FGFC6 and FGFC7 showed promising fibrinolytic activities. The knowledge of biosynthesis pathways may be an important attribute for the discovery of novel bioactive marine natural products.
Highlights
State Key Laboratory of Bioreactor Engineering, East China University of Science and Technology, College of Food Biotechnology, Shanghai Ocean University, 999 Huchenghuan Road, Shanghai 201306, Shanghai Collaborative Innovation Center for Biomanufacturing, 130 Meilong Road, Shanghai 200237, China
Drugs 2017, 15, 214 an increasing amount of information on fungi genomes is available, which facilitates the discovery of biosynthesis pathways by genome mining
According to the discovered in S.orbisbyi this study, we triedon tothe ascertain the complete biosynthetic gene cluster biosynthesis pathway, a rational supply strategy of amino compounds was developed for the for FGFCs or SMTPs by genome mining based on the three reported core genes
Summary
“Supply problem” is a major bottleneck in the discovery of marine drugs [1], and many research efforts on marine natural products (MNPs) are currently directed towards microorganisms. This study, we triedon tothe ascertain the complete biosynthetic gene cluster biosynthesis pathway, a rational supply strategy of amino compounds was developed for the for FGFCs or SMTPs by genome mining based on the three reported core genes. Strategy ofSince amino compounds developed for the abundant new derivatives could be obtained Their fibrinolytic activities production of other novel isoindolinone derivatives. Since FGFC1 is a high yield compound, abundant were tested to evaluate the potential of FG216 for manufacturing cardiovascular drugs more new derivatives could be obtained. To evaluate the potential of FG216 for manufacturing cardiovascular drugs more comprehensively
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