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A metabolic regulon reveals early and late acting enzymes in neuroactive lycopodium alkaloid biosynthesis

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 produc...

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Main Authors: Nett, Ryan S., Dho, Yaereen, Low, Yun-Yee, Sattely, Elizabeth S.
Format: Article
Published: National Academy of Sciences 2021
Subjects:
QD Chemistry
Online Access:http://eprints.um.edu.my/26768/
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spelling my.um.eprints.267682022-04-18T01:17:39Z http://eprints.um.edu.my/26768/ A metabolic regulon reveals early and late acting enzymes in neuroactive lycopodium alkaloid biosynthesis Nett, Ryan S. Dho, Yaereen Low, Yun-Yee Sattely, Elizabeth S. QD Chemistry 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. National Academy of Sciences 2021-06-15 Article PeerReviewed 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 <https://doi.org/10.1073/pnas.2102949118>. 10.1073/pnas.2102949118
institution Universiti Malaya
building UM Library
collection Institutional Repository
continent Asia
country Malaysia
content_provider Universiti Malaya
content_source UM Research Repository
url_provider http://eprints.um.edu.my/
topic QD Chemistry
spellingShingle QD Chemistry
Nett, Ryan S.
Dho, Yaereen
Low, Yun-Yee
Sattely, Elizabeth S.
A metabolic regulon reveals early and late acting enzymes in neuroactive lycopodium alkaloid biosynthesis
description 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.
format Article
author Nett, Ryan S.
Dho, Yaereen
Low, Yun-Yee
Sattely, Elizabeth S.
author_facet Nett, Ryan S.
Dho, Yaereen
Low, Yun-Yee
Sattely, Elizabeth S.
author_sort Nett, Ryan S.
title A metabolic regulon reveals early and late acting enzymes in neuroactive lycopodium alkaloid biosynthesis
title_short A metabolic regulon reveals early and late acting enzymes in neuroactive lycopodium alkaloid biosynthesis
title_full A metabolic regulon reveals early and late acting enzymes in neuroactive lycopodium alkaloid biosynthesis
title_fullStr A metabolic regulon reveals early and late acting enzymes in neuroactive lycopodium alkaloid biosynthesis
title_full_unstemmed A metabolic regulon reveals early and late acting enzymes in neuroactive lycopodium alkaloid biosynthesis
title_sort metabolic regulon reveals early and late acting enzymes in neuroactive lycopodium alkaloid biosynthesis
publisher National Academy of Sciences
publishDate 2021
url http://eprints.um.edu.my/26768/
_version_ 1735409455642705920
score 13.211869

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