Novel Cyclohexyl Meroterpenes Produced by Combinatorial Biosynthesis

Area of Science:

• Natural Product Chemistry
• Synthetic Biology
• Mycology

Background:

• Fungal meroterpenoids represent a structurally diverse class of compounds with significant potential as drug leads.
• Developing novel meroterpene scaffolds is crucial for expanding the chemical space available for drug discovery.

Purpose of the Study:

• To generate unnatural, novel meroterpene scaffolds through combinatorial biosynthesis.
• To investigate the substrate scope of terpene cyclases (TPCs) using a defined precursor.

Main Methods:

• Co-expression of distinct terpene cyclase (TPC) genes (pyr4, ascF, andB, or cdmG) with genes for producing (10'R)-epoxyfarnesyl-dimethylorsellinic acid-3,5-methyl ester in Aspergillus oryzae.
• Utilizing a heterologous host system (Aspergillus oryzae NSAR1) for combinatorial biosynthesis.

Main Results:

• All tested TPCs, when co-expressed with the substrate biosynthetic genes, produced the same two novel mono-cyclization products.
• The study successfully demonstrated the creation of new meroterpene structures.

Conclusions:

• The findings provide valuable insights into the substrate specificity of the investigated TPCs.
• This work contributes to the potential production of novel unnatural molecules for future drug discovery efforts.