UC San Diego

Nature communicates using a vast array of chemical compounds known secondary metabolites or natural products. These diverse molecules mediate many critical ecological and developmental processes including predation, reproduction, and defense. For millennia, humans have harnessed the bioactivity of these natural products to improve human health. Many natural products have become or inspired ground-breaking drugs, such as the antiviral acyclovir or the antimalarial artemisinin. Through advancements in DNA sequencing technology, we have discovered that the instructions for making these natural products are encoded within an organism’s genome. Biosynthetic genes encode the production of powerful enzymes which act as nature’s chemists to synthesize the compounds we find in nature. Just as humans have harnessed natural products to address human needs, we have also harnessed these biosynthetic enzymes to produce a vast array of desirable molecules, including the antivirals islatravir and molnupiravir. This process is known as biocatalysis and it is a sustainable way to perform stereo- and regio-selective reactions in mild conditions with minimal byproducts.

Terpenoids are the largest class of natural products to date, with approximately 100,000 terpenoids characterized across all domains of life. Despite the massive structural diversity seen in terpenoids, all terpenoids derive from a small handful of linear polyprenyl diphosphate precursors, which are acted upon by terpene synthase enzymes. Marine sponges are well-known producers of terpenoids, with more than 4000 terpenoids reported from sponges. An unusual group of terpenoids only found in sponges and nudibranchs are the nitrogenous terpenes, which feature a suite of nitrogen-containing functional groups such as isonitriles, isothiocyanates, isocyanates, formamides, and amines. For decades, the biosynthesis of these nitrogenous terpenes remained a mystery, with natural product chemist John D Faulkner once remarking that there is “no more interesting biosynthetic study among the marine natural products.” Herein, I report my investigations into the biosynthesis of nitrogenous terpenes in marine sponges.Chapter 1 serves as an introduction to the dissertation, and includes background information on sponges, marine nitrogenous terpenes, and terpene biosynthesis across the tree of life. Chapter 2 covers the characterization of isonitrile terpenes from a San Diego sponge of the order Bubarida using a chemoselective chlorooxime probe. Thorough investigations into the biosynthesis of nitrogenous terpenes from sponges are detailed in Chapter 3. I report the discovery and characterization of the first terpene synthases from sponges and present evidence that the biosynthetic genes for terpene production are encoded within the sponge animal itself and not a microbial symbiont. Chapter 3 also includes investigations into the origin of the nitrogenous functional groups of nitrogenous terpenes.