2. Academic Validation
  3. Discovery of P450-Modified Sesquiterpenoids Levinoids A-D through Global Genome Mining

Discovery of P450-Modified Sesquiterpenoids Levinoids A-D through Global Genome Mining

  • J Nat Prod. 2024 Feb 20. doi: 10.1021/acs.jnatprod.3c01136.
Wenchao Liu 1 2 3,  Xueying Tian 1 2,  Xin Huang 1 2,  Jessie James Limlingan Malit 4,  Chuanhai Wu 1 2,  Zhihong Guo 5,  Jian-Wei Tang 1 2,  Pei-Yuan Qian 1 2
Affiliations

Affiliations

  • 1 Department of Ocean Science and Hong Kong Branch of Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), The Hong Kong University of Science and Technology, Kowloon, Hong Kong, China.
  • 2 Southern Marine Science and Engineering Guangdong Laboratory (Guangzhou), Guangzhou 511458, China.
  • 3 Division of Emerging Interdisciplinary Areas, The Hong Kong University of Science and Technology, Kowloon, Hong Kong, China.
  • 4 Institute of Molecular Biology and Biophysics, ETH Zürich, 8093 Zürich, Switzerland.
  • 5 Department of Chemistry, Department of Physics, and Bioengineering Program, The Hong Kong University of Science and Technology, Kowloon, Hong Kong, China.
PMID: 38377956 DOI: 10.1021/acs.jnatprod.3c01136
Abstract

Cytochrome P450-modified bacterial Terpenoids remain in a vast chemical space to be explored. In the present study, we conducted global genome mining of 223,829 Bacterial genomes and identified 2892 Bacterial terpenoid biosynthetic gene clusters (BGCs) with Cytochrome P450 genes. Among these, we selected 562 with multiple P450 Enzymes, which were further clustered as 355 gene cluster families by sequence similarity analysis. We then chose lev, a BGC from Streptomyces levis MCCC1A01616, for heterologous expression and discovered four new α-amorphene-type sesquiterpenoids, levinoids A-D (1-4). The structures and absolute configurations of these four new compounds were determined by employing extensive NMR analysis, NMR chemical shift calculations with DP4+, and ECD calculations. Furthermore, levinoid C (3) exhibited a moderate level of neuroprotective activity (EC50 = 21 μM) in the glutamate-induced excitotoxicity cell model. Our findings highlight the untapped chemical diversity of P450-modified bacterial Terpenoids, opening new avenues for further exploration and discovery.

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