Biology subjects

Nett, R. S.

Publications and source records attributed to Nett, R. S..

6 recordsLinked to original sources

bioRxiv2026

Independent evolution of harmala alkaloids in medicinal Syrian rue and ayahuasca plants

Plants from distantly related lineages can produce identical neuroactive molecules, many of which have been independently adopted across human societies for their medicinal and cognition-altering effects. This phenomenon is exemplified by the traditional use of Syrian rue (Peganum harmala) and the ayahuasca vine (Banisteriopsis caapi) for medicine and ritual. Despite diverging over 100 million years ago and inhabiting different continents and climates, both plants synthesize harmala alkaloids (HAs), which inhibit human monoamine oxidase and exhibit diverse neuroactive effects. Here, we combine gene expression analyses, genomics, and enzyme characterization to elucidate HA biosynthesis for both Syrian rue and ayahuasca vine. We reveal multiple layers of biochemical and genetic convergence in these pathways, including independent duplication and neofunctionalization of an ancestral enzyme from serotonin biosynthesis, and lineage-specific repurposing of primary metabolic genes to generate a reactive precursor for alkaloid scaffold formation. Our study resolves biosynthetic routes to HAs in two medicinal plants and demonstrates convergent evolution of specialized metabolism at the levels of enzymes, pathways, and genomes.

biochemistry↗

bioRxiv2026

Convergent biosynthesis of insect molting hormones in plants

Insect herbivores have driven plants to evolve complex chemical defenses, including mimics of the arthropod molting hormone 20-hydroxyecdysone (20E). Many distantly related plants produce 20E, suggesting multiple, independent evolutionary origins. However, despite the prevalence of 20E in arthropods and plants, complete biosynthetic pathways have remained elusive. Here, we combine genomics, gene co-expression, and enzyme characterization to discover convergent 20E biosynthetic pathways from spinach and quinoa (amaranth family) and Ajuga species (mint family). We reveal that these families use distinct biosynthetic gene clusters to produce 20E and related phytoecdysteroids, highlighting both biochemical and genetic convergence of 20E biosynthesis in plants. Our work establishes the first complete 20E pathways in any organism and provides foundational insight into the evolution of this animal hormone across kingdoms of life.

biochemistry↗

bioRxiv2026

Ancient origins of alkaloid biosynthesis in medicinal clubmosses

The plant kingdom is rich with medicinal natural products that are complex and difficult to access. Discovering how plants build these molecules can be challenging, especially for biosynthetic pathways that have unusual chemical transformations or require intricate coordination among cellular compartments. Here, we leveraged 300 million years of metabolic conservation to uncover how medicinal clubmosses organize extracellular and intracellular alkaloid biosynthesis to produce the Alzheimers disease therapeutic huperzine A (HupA). We reveal not only scaffold-forming enzymes that form key precursors to hundreds of clubmoss alkaloids, but also an essential transporter that connects metabolism across the plasma membrane to enable complete HupA biosynthesis. Our results demonstrate how ancient evolutionary conservation can be used to identify cryptic biosynthetic components and unexpected cellular organization in plant specialized metabolism.

biochemistry↗

bioRxiv2026

Harmala alkaloids regulate cell division planes in plants

Plants produce a vast diversity of specialized metabolites that function as chemical defenses against herbivores, pathogens, and competing plants. Many of these compounds also act as powerful tools for biological discovery, revealing fundamental cellular mechanisms through their effects on living systems. Among these metabolites, the harmala alkaloids from Peganum harmala (Syrian rue) possess cross-kingdom biological effects, including medicinal and neuroactive activity in humans, and allelopathic, growth-inhibiting effects on other plant species. However, the cellular processes in plants that are targeted by the harmala alkaloids are unknown. Here, we investigated the effects of the harmala alkaloids on plant growth and cell division using Arabidopsis thaliana as a model system. Of the harmala alkaloids, harmaline was identified as the most potent compound for root growth inhibition. Quantitative live cell imaging demonstrated that harmaline exposure causes progressive defects in cell division orientation and root cell morphology in a temporal manner. Furthermore, we identified harmaline-mediated phragmoplast orientation and morphology defects, pointing to a potential target related to phragmoplast guidance proteins. These findings position harmaline as a promising chemical probe for investigating the mechanisms that govern division plane positioning in plant cells and highlight a putative pathway by which harmala alkaloids exert allelopathic effects in competing plants. One sentence summaryHarmala alkaloids regulate cell division plane as an allelopathic mechanism

plant biology↗

bioRxiv2022

Neofunctionalized carbonic anhydrases in the biosynthesis of neuroactive plant alkaloids

Plants synthesize numerous alkaloids that mimic animal neurotransmitters. The diversity of alkaloid structures is achieved through the generation and tailoring of unique carbon scaffolds. However, many neuroactive alkaloids belong to a scaffold class for which no biosynthetic route or enzyme catalyst is known. By studying highly coordinated, tissue-specific gene expression in plants that produce neuroactive Lycopodium alkaloids, we identified a new enzyme class for alkaloid biosynthesis: neofunctionalized -carbonic anhydrases (CAHs). We show that three CAH-like (CAL) enzymes are involved in a cryptic biosynthetic route to a key bicyclic precursor of the Lycopodium alkaloids, and additionally, we describe a series of oxidative tailoring steps that generate the optimized acetylcholinesterase inhibition activity of huperzine A. Our findings suggest a broader involvement of CAL enzymes in specialized metabolism and provide an example for how successive scaffold tailoring steps can drive potency against a natural protein target of interest.

biochemistry↗

bioRxiv2019

Unraveling a tangled skein: Evolutionary analysis of the bacterial gibberellin biosynthetic operon

Gibberellin (GA) phytohormones are ubiquitous regulators of growth and developmental processes in vascular plants. The convergent evolution of GA production by plant-associated bacteria, including both symbiotic, nitrogen-fixing rhizobia and phytopathogens, suggests that manipulation of GA signaling is a powerful mechanism for microbes to gain an advantage in these interactions. Although homologous operons encode GA biosynthetic enzymes in both rhizobia and phytopathogens, notable genetic heterogeneity and scattered operon distribution in these lineages suggests distinct functions for GA in varied plant-microbe interactions. Therefore, deciphering GA operon evolutionary history could provide crucial evidence for understanding the distinct biological roles for bacterial GA production. To further establish the genetic composition of the GA operon, two operon-associated genes that exhibit limited distribution among rhizobia were biochemically characterized, verifying their roles in GA biosynthesis. Additionally, a maximum-parsimony ancestral gene block reconstruction algorithm was employed to characterize loss, gain, and horizontal gene transfer (HGT) of GA operon genes within alphaproteobacteria rhizobia, which exhibit the most heterogeneity among GA operon-containing bacteria. Collectively, this evolutionary analysis reveals a complex history for HGT of both individual genes and the entire GA operon, and ultimately provides a basis for linking genetic content to bacterial GA functions in diverse plant-microbe interactions.

microbiology↗