50 / 2021-10-09 23:23:58

Studies of sulfurated diketopiperazines from the deep-sea-derived fungus Penicillium janthinellum

Penicillium janthinellum, thiodiketopiperazines, biosynthesis

Due to the special environment of high salt, high pressure, low temperature, anoxia and lack of light in the ocean, marine organisms possess special metabolic pathways, which can produce many secondary metabolites with novel skeletons and special elements such as sulfur^[1]. Marine microorganisms have been proved their ability to produce disulfide- and multisulfide-containning metabolites, a unique and important class of marine natural products^[2]. It was found that many marine disulfides and multisulfides exhibit promising bioactivities including antitumor, antibiotic, anti-inflammatory and enzyme-inhibitory activities^[3].

Our laboratory has previously isolated and identified 25 thiodiketopiperazines (TDPKs) from the deep-sea derived fungus Penicillium janthinellum, among which compounds 1 and 8 showed prominent anti-tumor activity. On this basis, we continued to mine the secondary metabolites of P. janthinellum through the techniques of genomes and bioinformatics. Analysis of TDPKs biosynthesis gene clusters showed that the obtained TDPKs were produced by two known biosynthesis pathways. However, the TDPKs biosynthesis gene clusters expression level are very low, resulting in a low yield of TDPKs from wild-type strain, which is difficult to meet the needs of subsequent pharmacology, efficacy and animal experiments. In order to increase the yield of compound 8 and further to tap new TDPKs, the specific transcription factors that regulate biosynthesis pathways of TDPKs were overexpressed. Three positive transformants were obtained by techniques of genomic and metabolic engineering. The HPLC analysis showed that the yield of TDPKs from the positive transformant was greatly increased than that from the wild strain.