Producing Novel Fibrinolytic Isoindolinone Derivatives in Marine Fungus Stachybotrys longispora FG216 by the Rational Supply of Amino Compounds According to Its Biosynthesis Pathway

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.

Exploring Secondary Metabolite Profiles of Stachybotrys spp. by LC-MS/MS

“…Particularly in the last years, the number of publications dealing with isoindolinones from Stachybotrys species increased [53,54,55]. The specific supply of amino acids to the medium was more precisely investigated by Nishimura et al (2012) and Yin et al (2017) [56,57], and their findings are in good agreement with our results. When supplementing the medium with a specific primary amine, the production of the desired metabolite is selectively controlled and enhanced.…”

Artificial vs natural Stachybotrys infestation—Comparison of mycotoxin production on various building materials

“…But admittedly, since the natural sample was painted and certainly contained residues of paste, while the applied matrix‐matched calibration using pure wfWP can therefore only approximate the actual matrix. The minor but visibly higher formation of the isoindolinone compounds Stlac ac and Stlac in the naturally contaminated sample (Figure 3A, left bar chart) can be explained due to the presence of nitrogen‐containing components in the paint and/or paste, as it was previously reported 34,41 . Furthermore, a higher Stchr B production was also observed in the naturally contaminated sample.…”

Impact of SMTP Targeting Plasminogen and Soluble Epoxide Hydrolase on Thrombolysis, Inflammation, and Ischemic Stroke

“…Thus, various SMTP congeners can be nonenzymatically derived from pre-SMTP. Incorporating relevant information from other studies [63][64][65], we propose an overall pathway for SMTP biosynthesis, as presented in Figure 2. [63].…”