UC San Diego

Nature is a gifted chemist, and marine organisms are capable producers of structurally and functionally diverse small molecules. Many of these genetically encoded small molecules, or natural products, are extremely bioactive and have inspired the development of new classes of therapeutic agents. However, the availability and scalability of marine systems has limited efforts to bring promising compounds to the clinic. Synthetic and biosynthetic research in natural products offers complementary strategies to preserve sensitive marine organisms while gaining access to their unique chemistry. Similarly, advancements in computing, and the emergence of technologies like long-read, third-generation sequencing, have made it cheaper, faster, and more efficient to connect genes to chemistry – a critical step in circumventing supply issues through the development of sustainable, biocatalytic routes to a target compound. The goal of this dissertation is to uncover the genetic basis for how marine red algae, or seaweeds produce anthropologically relevant chemicals, such as the neurotoxin, domoic acid, and the preclinical antitumor agent, halomon. Both molecular families discussed in this dissertation belong to the broader chemical classification of terpenoids. Chapter 1, which serves as an introduction to the dissertation, is a taxonomy guided review of terpenoid natural products. Chapter 2 of the dissertation describes the sequencing and assembly of the draft genome of the red macroalga Chondria armata. Here we identify and compare domoic acid biosynthetic gene clusters and describe the in vitro validation of key biosynthesis enzymes. This work fills a gap in understanding of kainoid biosynthesis in red macroalgae. Chapter 3 describes the sequencing of four haloterpenoid producing red algae, Plocamium pacificum, Laurencia subopposita, Laurencia pacifica, and Portieria hornemannii, the notable producer of the haloterpenoid antitumor agent, halomon. Through this work, I identify haloterpenoid biosynthesis pathways from each organism and report the in vitro reconstitution of algal class 1 microbial-type terpene synthases. Finally, Chapter 4 discusses genome sequencing and mining strategies in red algae. This work also addresses downstream tailoring steps of algal haloterpenoids. Overall, the work here describes genomic approaches to accessing and characterizing secondary metabolite biosynthetic pathways from marine red algae.