Biotechnology Bulletin ›› 2024, Vol. 40 ›› Issue (8): 275-287.doi: 10.13560/j.cnki.biotech.bull.1985.2024-0110

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Effects of Simulated Mutational Biosynthetic Regulation on the Secondary Metabolites of Aspergillus terreus C23-3

MA Xiao-xiang1(), MA Ze-yuan1, LIU Ya-yue1,2,3, ZHOU Long-jian1,2,3, HE Yi-fan4, ZHANG Yi1,2,3()   

  1. 1. College of Food Science and Technology, Guangdong Ocean University, Guangdong Provincial Key Laboratory of Aquatic Product Processing and Safety, Guangdong Province Engineering Laboratory for Marine Biological Products, Shenzhen Institute of Guangdong Ocean University, Zhanjiang Municipal Key Laboratory of Marine Drugs and Nutrition for Brain Health, Zhanjiang 524088
    2. Southern Marine Science and Engineering Guangdong Laboratory(Zhanjiang), Zhanjiang 524006
    3. Collaborative Innovation Center of Seafood Deep Processing, Dalian Polytechnic University, Dalian 116034
    4. Center for Marine Biotechnology and Biomedicine, Scripps Institution of Oceanography, University of California(San Diego), La Jolla 92093, USA
  • Received:2024-01-31 Online:2024-08-26 Published:2024-07-02
  • Contact: ZHANG Yi E-mail:ma.xiao.xiang@163.com;hubeizhangyi@163.com

Abstract:

【Objective】Butyrolactone I is a small molecular natural product of Aspergillus terreus with versatile bioactivities, thus the exploration of its structural diversity extension is significant. A marine-derived A. terreus strain C23-3 featuring producing butyrolactone I was used as the base strain to study the effects of butyrolactone I precursor analogs and precursor synthase inhibitors on its secondary metabolism.【Method】The strain was statically fermented under chemically regulative conditions established by seawater potato liquid medium supplied with three precursor small molecules and three 4-hydroxyphenylpyruvate synthase inhibitors. The high-performance liquid chromatography(HPLC), HPLC -ion trap mass spectrometry(MS), and MS based molecular networking together with database mining were used to further analyze the yields and diversity of secondary metabolites.【Result】The most of the precursor analogs and synthase inhibitors suppressed the synthesis of butyrolactone I to different extents. Moreover, the precursor analog 3,4-dihydroxyphenylpyruvate at a high dose, the combination of the two 4-hydroxyphenylpyruvate synthase inhibitors and the combination of these three demonstrated remarkable inhibitory effects. In addition, the global synthesis for sorts of secondary metabolites including butenoids, territrems, lovastatins, etc., was downregulated when butyrolactone I was inhibited for production. However, the yield of a cyclopeptide was upregulated by more than ten folds under this situation, which was supposed to be a stress response to the synthetic suppression of butyrolactone I as a quorum sensing molecule and inducer of global transcriptive factor lae A. The detailed mechanism deserves further investigation.【Conclusion】The present study manifests that 4-hydroxyphenylpyruvate is the precursor of butyrolactone I and reveals that 3,4-dihydroxyphenylpyruvate and 4-hydroxyphenylpyruvate synthase inhibitors can be used as small molecule tools to suppress the production of butyrolactone I, which may be applied in further study on simulated mutational biosynthesis to generate diverse butyrolactone derivatives and induce the production of cyclopeptide.

Key words: marine fungus, chemical regulation, simulated mutational biosynthesis, butyrolactone, precursor analog, synthase inhibitor, LC-MS/MS, molecular network