Uncovering the genetic, developmental and enzymatic logic of plant natural product biosynthesis
- In spite of the importance of plant chemistry, studying plant compounds and how they are made within plants remains challenging, limiting our ability to harness the power of these molecules. In my dissertation, I explore how plants utilize intricate genomic, enzymatic and developmental strategies to produce some of the world's most important bioactive compounds. First, I present a novel long-read genome sequencing approach that enhances our ability to predict plant natural product biosynthetic pathways. This approach uncovers new biosynthetic gene clusters in non-model medicinal plants with no genome sequences previously reported, and enables the genome-guided discovery of novel plant biosynthetic pathways. Second, I explore the developmental coordination of plant secondary metabolite biosynthesis in geophytes, a diverse group of plants with underground food-storage organs that comprise various species of important edible, ornamental and medicinal crops. I show that while clinically-relevant plant specialised metabolites like the Amaryllidaceae alkaloids produced by plants like daffodils accumulate to high levels in many tissues in their producer plants, their biosynthesis is localized to nascent, growing tissue at the base of leaves. A similar trend is found for the production of steroidal alkaloids (e.g. cyclopamine) in corn lily. Taken together, my work sheds light on the developmental logic of toxin biosynthesis in daffodil and corn lily and more broadly, it suggests a paradigm for biosynthesis regulation in monocot geophytes where plants are protected from herbivory through active charging of newly formed cells with potent eukaryotic toxins that persist as aboveground tissue develops. Third, with this understanding of the developmental logic of medicinal alkaloid biosynthesis in daffodils, I identify the genetic basis of medicinal alkaloid biosynthesis in daffodils and engineer their de novo production in heterologous hosts. My work led to the elucidation of a complete set of biosynthetic genes for the production of the FDA-approved Alzheimer's disease drug galantamine and the eukaryotic ribosome inhibitor haemanthamine, and revealed that a set of closely related cytochromes P450s differentially tailor a common intermediate to generate three scaffold types with distinct biological activities. This work enables the reconstitution of the de novo production of these toxins in a heterologous host, Nicotiana benthamiana (tobacco).
|Type of resource
|electronic resource; remote; computer; online resource
|1 online resource.
|Mehta, Niraj Sunil
|Degree committee member
|Degree committee member
|Stanford University, School of Humanities and Sciences
|Stanford University, Department of Chemistry
|Statement of responsibility
|Niraj Sunil Mehta.
|Submitted to the Department of Chemistry.
|Thesis Ph.D. Stanford University 2023.
- © 2023 by Niraj Sunil Mehta
- This work is licensed under a Creative Commons Attribution Non Commercial 3.0 Unported license (CC BY-NC).
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