Reconstituting the complete biosynthesis of D-lysergic acid in yeast

Garrett Wong,Yong Quan Tan,Wen Shan Yew,David J. Bell,Maybelle Kho Go,Paul S. Freemont,Li Rong Lim

doi:10.1038/s41467-022-28386-6

Abstract

The ergot alkaloids are a class of natural products known for their pharmacologically privileged molecular structure that are used in the treatment of neurological ailments, such as Parkinsonism and dementia. Their synthesis via chemical and biological routes are therefore of industrial relevance, but suffer from several challenges. Current chemical synthesis methods involve long, multi-step reactions with harsh conditions and are not enantioselective; biological methods utilizing ergot fungi, produce an assortment of products that complicate product recovery, and are susceptible to strain degradation. Reconstituting the ergot alkaloid pathway in a strain strongly amenable for liquid fermentation, could potentially resolve these issues. In this work, we report the production of the main ergoline therapeutic precursor, D-lysergic acid, to a titre of 1.7 mg L−1 in a 1 L bioreactor. Our work demonstrates the proof-of-concept for the biological production of ergoline-derived compounds from sugar in an engineered yeast chassis.

Highlights

The ergot alkaloids are a class of natural products known for their pharmacologically privileged molecular structure that are used in the treatment of neurological ailments, such as Parkinsonism and dementia
The key active pharmaceutical ingredient (API) of these ergoline-derivatives comes from D-lysergic acid (DLA)
We propose that the biosynthesis of DLA using an industrially tractable microorganism, such as baker’s yeast, would likely circumvent the aforementioned key issues with current methods of production

Summary

Introduction

The ergot alkaloids are a class of natural products known for their pharmacologically privileged molecular structure that are used in the treatment of neurological ailments, such as Parkinsonism and dementia. These orthologues were screened by co-expression with easD and easG in a strain with dmaW, easF, easC, and easE_Aj integrated in the yeast genome (YOCE; Supplementary Table 9).

Results

Conclusion