Reconstituting the complete biosynthesis of D-lysergic acid in yeast

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, b...

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Published inNature communications Vol. 13; no. 1; p. 712
Main Authors Wong, Garrett, Lim, Li Rong, Tan, Yong Quan, Go, Maybelle Kho, Bell, David J., Freemont, Paul S., Yew, Wen Shan
Format Journal Article
LanguageEnglish
Published London Nature Publishing Group UK 07.02.2022
Nature Publishing Group
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Summary: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. 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. Here the authors report on the production of the ergot (fungus)-derived therapeutic precursor, D-lysergic acid (DLA), in baker’s yeast.
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ISSN:2041-1723
2041-1723
DOI:10.1038/s41467-022-28386-6