2. Academic Validation
  3. Discovery of a Potential Liver Fibrosis Inhibitor from a Mushroom Endophytic Fungus by Genome Mining of a Silent Biosynthetic Gene Cluster

Discovery of a Potential Liver Fibrosis Inhibitor from a Mushroom Endophytic Fungus by Genome Mining of a Silent Biosynthetic Gene Cluster

  • J Agric Food Chem. 2021 Sep 29;69(38):11303-11310. doi: 10.1021/acs.jafc.1c03639.
Jin-Tao Cheng 1 2,  Han-Min Wang 3 4,  Jia-Hui Yu 5,  Chen-Fan Sun 1 2,  Fei Cao 1 2,  Xin-Hang Jiang 6,  Xin-Ai Chen 1 2,  Qing-Wei Zhao 1,  Li-She Gan 5 7,  Rong-Rong Xie 3,  Shi-Lei Wang 8,  Jia Li 3 4,  Yi Zang 3 4,  Xu-Ming Mao 1 9 2
Affiliations

Affiliations

  • 1 Institute of Pharmaceutical Biotechnology & Research Center for Clinical Pharmacy, The First Affiliated Hospital, School of Medicine, Zhejiang University, Hangzhou 310058, China.
  • 2 Zhejiang Provincial Key Laboratory for Microbial Biochemistry and Metabolic Engineering, Hangzhou 310058, China.
  • 3 National Center for Drug Screening, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
  • 4 University of Chinese Academy of Sciences, Beijing 100049, China.
  • 5 College of Pharmaceutical Sciences, Zhejiang University, Hangzhou 310058, China.
  • 6 Equipment and Technology Service Platform, College of Life Sciences, Zhejiang University, Hangzhou 310058, China.
  • 7 School of Biotechnology and Health Sciences, Wuyi University, Jiangmen, Guangdong 529020, China.
  • 8 Zhejiang Shuren University, Hangzhou 310058, China.
  • 9 State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Materia Medica, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100050, China.
PMID: 34542281 DOI: 10.1021/acs.jafc.1c03639
Abstract

Liver fibrosis has accounted for liver diseases and overall mortality, but no relevant drug has been developed. Filamentous fungi are important resources of Natural Products for pharmaceutical development. Calcarisporium arbuscula is a mushroom endophytic fungus, which primarily produces aurovertins. Here, in an aurovertin null-production mutant, one silent gene cluster (mca17) was activated by overexpression of a pathway-specific zinc finger transcriptional regulator, and a tetramic acid-type compound (1, MCA17-1) was identified. Along with detailed structural characterization, its biosynthesis was proposed to be produced from the core PKS-NRPS hybrid Enzyme. Moreover, 1 suppressed the activation of LX-2 upon Transforming Growth Factor-β (TGF-β) challenge and had stronger bioactivity than the positive control obeticholic acid (OCA) against liver fibrosis. Our work suggested that this engineered fungus could be a producer of 1 for promising pharmaceutical development, and alternatively, it would be developed as a mushroom ingredient in dietary therapy to prevent liver fibrosis.

Keywords

Calcarisporium arbuscula; fungus; gene cluster activation; liver fibrosis; natural product.

Figures
Products