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Vinigrol Tricyclic Scaffold Biosynthesis Employs an Atypical Terpene Cyclase and a Multipotent Cyclization Cascade

Summary

Scientists have discovered how a fungus produces vinigrol, a complex molecule with potential health benefits including lowering blood pressure and reducing inflammation. Using advanced computational tools and genetic engineering, researchers identified the specific genes and enzymes the fungus uses to build this molecule’s intricate three-ring structure. By modifying a key enzyme, they were able to create an entirely new diterpene molecule that doesn’t exist in nature, demonstrating the potential to engineer biological systems to produce novel medicinal compounds.

Background

Vinigrol is a unique fungal diterpenoid with a distinctive decahydro-1,5-butanonaphthalene ring system that exhibits antihypertensive and anti-inflammatory activity. Despite numerous synthetic studies, the biosynthetic pathway and enzymes responsible for producing this complex molecule remained largely unknown.

Objective

To identify and characterize the biosynthetic gene cluster and enzymes responsible for vinigrol production in the fungus Virgaria nigra, and to elucidate the complete biosynthetic pathway including the unusual cyclization mechanism.

Results

Identified a three-gene cluster (vigA, vigB, vigC) essential for vinigrol biosynthesis. Characterized VigB as a noncanonical terpene cyclase with unique structural features and catalytic residues. Revealed the complete cyclization pathway via DFT-based retro-biosynthetic analysis. The G340A mutation redirected the cyclization cascade to produce virgarene, a novel tetracyclic diterpene.

Conclusion

This study elucidates the biosynthetic mechanism of a structurally unique diterpenoid through integrated theoretical and experimental approaches. The discovery of the multipotent cyclization cascade and ability to engineer the enzyme to produce novel scaffolds provides new tools for exploring previously unknown terpenoid chemistry and synthetic biology applications.
  • Published in:Journal of the American Chemical Society,
  • Study Type:Research Study,
  • Source: 10.1021/jacs.5c14400, PMID: 41309452
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