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Biosynthesis of mushroom-derived type II ganoderic acids by engineered yeast

Summary

Scientists successfully engineered baker’s yeast to produce ganoderic acids, potent anti-cancer compounds from medicinal mushrooms, at much higher levels than found in farmed mushrooms. By identifying key enzymes responsible for converting simpler compounds into active ganoderic acids, researchers created yeast strains that produce these valuable compounds 100-10,000 times more efficiently than traditional mushroom farming. This breakthrough could make these expensive medicinal compounds more accessible and affordable for medical research and potential drug development.

Background

Type II ganoderic acids (GAs) from Ganoderma mushrooms are potent triterpenoids with superior biological activities including anti-cancer properties. However, their low accumulation in farmed mushrooms, difficulty in genetic manipulation of native producers, and unknown biosynthetic pathways have hindered efficient production. Synthetic biology approaches using engineered yeast offer a promising alternative to traditional mushroom farming.

Objective

To identify key cytochrome P450 enzymes (CYPs) involved in type II GA biosynthesis from Ganoderma lucidum, elucidate their catalytic mechanisms, and develop engineered baker’s yeast strains capable of producing type II GAs at commercially viable levels.

Results

Two key CYPs (CYP512A2 and CYP512W2) capable of converting type I GAs to type II GAs were identified. Engineered yeast achieved production of GA-Y (51.30 mg/L) and GA-Jb (56.44 mg/L) at levels substantially higher than farmed mushrooms. Two previously unreported compounds (5 and 6) were also identified. CYP512W2 demonstrated promiscuous catalytic activity, producing multiple GA derivatives through complex, multi-step modifications.

Conclusion

The discovery of key CYPs converting type I to type II GAs represents a critical breakthrough in GA biosynthesis understanding. Engineered yeast strains achieved 1-4 orders of magnitude higher yields and 2-5 orders of magnitude higher production efficiency compared to farmed mushrooms, facilitating potential commercial-scale production of bioactive GAs.
  • Published in:Nature Communications,
  • Study Type:Experimental Research,
  • Source: 10.1038/s41467-022-35500-1, PMID: 36517496
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