Delineating biosynthesis of Huperzine A, A plant-derived medicine for the treatment of Alzheimer's disease

Huperzine A (HupA) is a plant-derived lycopodium alkaloid used for the treatment of Alzheimer's disease due to its inhibition against acetylcholinesterase. Currently, industrial production of HupA relies primarily on direct extraction from Huperzia serrate, a perennial herbaceous plant. However, this strategy cannot satisfy the increasing demand for HupA due to scarcity of H. serrate whose growth is quite slow. Pathway engineering has emerged as a novel strategy for the production of HupA. Unfortunately, the biosynthesis mechanism of HupA has not been well documented. In this review, we summarize not only the methods for plant extraction and chemical synthesis but also state-of-the-art advances in biosynthesis of HupA, including synthetic pathways, key enzymes, and especially catalytic mechanisms. Overall, this review aims to provide valuable insights for complete biosynthesis of Hup A.