To meet the global demand for DLA, 8 tons of ergopeptines and up to 10–15 tons of DLA are produced each year. The key active pharmaceutical ingredient (API) of these ergoline-derivatives comes from D-lysergic acid (DLA). As an illustration, D-lysergic acid diethylamide (LSD), a chemically-derived ergot alkaloid, is one of the most potent agonists for the 5-HT 2A serotonergic receptor ( K d = 0.33 nM) 8. The ergoline pharmacophore is an important scaffold for potential therapeutic discovery and development, particularly in the treatment of neurological and psychiatric disorders. The ergot alkaloids and their synthetic derivatives are used extensively in modern medicine for the treatment of several neurological ailments, such as Parkinsonism 5, dementia 6, and hypertension 7. The pharmacological effect of ergot alkaloids have been attributed to the molecular similarity between the ergoline skeleton and the monoamine neurotransmitters, such as adrenaline, dopamine, and serotonin) 3, 4. The ergot alkaloids have been used extensively as therapeutics throughout history 1, 2. Our work demonstrates the proof-of-concept for the biological production of ergoline-derived compounds from sugar in an engineered yeast chassis. 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. Reconstituting the ergot alkaloid pathway in a strain strongly amenable for liquid fermentation, could potentially resolve these issues. 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. Their synthesis via chemical and biological routes are therefore of industrial relevance, but suffer from several challenges.
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.
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