2. Academic Validation
  3. Harzianic Acid from Trichoderma afroharzianum Is a Natural Product Inhibitor of Acetohydroxyacid Synthase

Harzianic Acid from Trichoderma afroharzianum Is a Natural Product Inhibitor of Acetohydroxyacid Synthase

  • J Am Chem Soc. 2021 Jun 16;10.1021/jacs.1c03988. doi: 10.1021/jacs.1c03988.
Linan Xie 1,  Xin Zang 2,  Wei Cheng 3,  Zhuan Zhang 4,  Jiahai Zhou 2 5,  Mengbin Chen,  Yi Tang
Affiliations

Affiliations

  • 1 Biotechnology Research Institute, The Chinese Academy of Agricultural Sciences, 12 Zhongguancun South Street, Beijing 100081, P. R. China.
  • 2 State Key Laboratory of Bio-organic and Natural Products Chemistry, Center for Excellence in Molecular Synthesis, Shanghai Institute of Organic Chemistry, University of Chinese Academy of Sciences, Shanghai 200032, China.
  • 3 State Key Laboratory of Natural and Biomimetic Drugs, Peking University, Beijing 100191, China.
  • 4 Texas Therapeutics Institute, The Brown Foundation Institute of Molecular Medicine, The University of Texas Health Science Center at Houston, Houston, Texas 77054, United States.
  • 5 CAS Key Laboratory of Quantitative Engineering Biology, Shenzhen Institute of Synthetic Biology, Shenzhen Institute of Advanced Technology, Chinese Academy of Sciences, Shenzhen 518055, China.
PMID: 34132537 DOI: 10.1021/jacs.1c03988
Abstract

Acetohydroxyacid synthase (AHAS) is the first Enzyme in the branched-chain amino acid biosynthetic pathway and is a validated target for herbicide and fungicide development. Here we report harzianic acid (HA, 1) produced by the biocontrol fungus Trichoderma afroharzianum t-22 (Tht22) as a natural product inhibitor of AHAS. The biosynthetic pathway of HA was elucidated with heterologous reconstitution. Guided by a putative self-resistance Enzyme in the genome, HA was biochemically demonstrated to be a selective inhibitor of Fungal AHAS, including those from phytopathogenic fungi. In addition, HA can inhibit a common resistant variant of AHAS in which the active site proline is mutated. Structural analysis of AHAS complexed with HA revealed the molecular basis of competitive inhibition, which differs from all known commercial AHAS inhibitors. The alternative binding mode also rationalizes the selectivity of HA, as well as effectiveness toward resistant mutants. A proposed role of HA biosynthesis by Tht22 in the rhizosphere is discussed based on the data.

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