Nett, Ryan S. and Dho, Yaereen and Low, Yun-Yee and Sattely, Elizabeth S. (2021) A metabolic regulon reveals early and late acting enzymes in neuroactive lycopodium alkaloid biosynthesis. Proceedings of the National Academy of Sciences of the United States of America, 118 (24). ISSN 1091-6490, DOI https://doi.org/10.1073/pnas.2102949118.
Full text not available from this repository.Abstract
Plants synthesize many diverse small molecules that affect function of the mammalian central nervous system, making them crucial sources of therapeutics for neurological disorders. A notable portion of neuroactive phytochemicals are lysine-derived alkaloids, but the mechanisms by which plants produce these compounds have remained largely unexplored. To better understand how plants synthesize these metabolites, we focused on biosynthesis of the Lycopodium alkaloids that are produced by club mosses, a clade of plants used traditionally as herbal medicines. Hundreds of Lycopodium alkaloids have been described, including huperzine A (HupA), an acetylcholine esterase inhibitor that has generated interest as a treatment for the symptoms of Alzheimer's disease. Through combined metabolomic profiling and transcriptomics, we have identified a developmentally controlled set of biosynthetic genes, or potential regulon, for the Lycopodium alkaloids. The discovery of this putative regulon facilitated the biosynthetic reconstitution and functional characterization of six enzymes that act in the initiation and conclusion of HupA biosynthesis. This includes a type III polyketide synthase that catalyzes a crucial imine-polyketide condensation, as well as three Fe(II)/2-oxoglutarate-dependent dioxygenase (2OGD) enzymes that catalyze transformations (pyridone ring-forming desaturation, piperidine ring cleavage, and redox-neutral isomerization) within downstream HupA biosynthesis. Our results expand the diversity of known chemical transformations catalyzed by 2OGDs and provide mechanistic insight into the function of noncanonical type III PKS enzymes that generate plant alkaloid scaffolds. These data offer insight into the chemical logic of Lys-derived alkaloid biosynthesis and demonstrate the tightly coordinated coexpression of secondary metabolic genes for the biosynthesis of medicinal alkaloids.
| Item Type: | Article |
|---|---|
| Funders: | NIH S10 Instrumentation Grant[S10OD023452], United States Department of Health & Human Services National Institutes of Health (NIH) - USA[U01 GM110699], United States Department of Health & Human Services National Institutes of Health (NIH) - USA[R01 GM121527], HHMI Simons Faculty Scholar award |
| Uncontrolled Keywords: | Biosynthesis; Alkaloid; Dioxygenase; Huperzine A; Lycopodium |
| Subjects: | Q Science > QD Chemistry |
| Divisions: | Faculty of Science |
| Depositing User: | Ms. Juhaida Abd Rahim |
| Date Deposited: | 18 Apr 2022 01:17 |
| Last Modified: | 18 Apr 2022 01:17 |
| URI: | http://eprints.um.edu.my/id/eprint/26768 |
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