4.6 Article

1,10/1,11-Cyclization catalyzed by diverged plant sesquiterpene synthases is dependent on a single residue

期刊

ORGANIC & BIOMOLECULAR CHEMISTRY
卷 19, 期 30, 页码 6650-6656

出版社

ROYAL SOC CHEMISTRY
DOI: 10.1039/d1ob00827g

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资金

  1. National Key R&D Program of China [2018YFA0900600]
  2. National Natural Science Foundation of China [31788103, 31872666, 31700263]
  3. Chinese Academy of Sciences (CAS) [QYZDYSSWSMC026]
  4. Special Fund for Shanghai Landscaping Administration Bureau Program [G192416]
  5. Special Fund for Talent Introduction of Kunming Institute of Botany, CAS
  6. China Postdoctoral Science Foundation [2020M671252]
  7. Young Elite Scientists Sponsorship Program by CAST [2019QNRC001]
  8. Open Fund of Shanghai Key Laboratory of Plant Functional Genomics and Resources [PFGR201902]

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The research identified a crucial residue that determines product specificity of sesquiterpene synthases from different plant species, with a key role in 1,10-cyclization reactions. This residue can be engineered to improve the production of high-value terpenoids like patchoulol for potential medicinal use against SARS-CoV-2.
The exquisite chemodiversity of terpenoids is the product of the large diverse terpene synthase (TPS) superfamily. Here, by using structural and phylogenetic analyses and site-directed mutagenesis, we identified a residue (Cys440 in Nicotiana tabacum 5-epi-aristolochene synthase) proximal to an ion-binding motif common to all TPSs and named the (NSE)-N-pre/DTE residue, which determines the product specificity of sesquiterpene synthases from different plant species. In sesquiterpene synthases catalyzing 1,10-cyclization (1,10-cyclases) of farnesyl diphosphate, mutation of the residue in both specific and promiscuous 1,10-cyclases from different lineages leads to the accumulation of monocyclic germacrene A-11-ol, which is short-circuited from complex cyclization cascades, suggesting a key role of this residue in generating the first common intermediate of 1,10-cyclization. Altering this residue in a specific 1,11-cyclase results in alternative 1,10-cyclization products. Moreover, the (NSE)-N-pre/DTE residue can be harnessed to engineer highly specific sesquiterpene synthases for an improved proportion of high-value terpenoids, such as patchoulol, a main constituent of several traditional Chinese medicines that could treat SARS-CoV-2.

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