CAREER: Understanding the Biosynthesis of Terpenoid Mycotoxins

Researchers from the University of California, Santa Barbara are uncovering how fungi evolve enzymes to construct structurally complex natural products with important implications for agriculture, food safety, and biotechnology. Fungal terpenoid mycotoxins contaminate crops, threaten human and animal health, and exhibit remarkable chemical diversity, yet many of the enzymes responsible for assembling these molecules remain unknown. Understanding how these enzymes catalyze challenging chemical transformations is essential for deciphering fungal metabolism and expanding the toolbox of nature-derived biocatalysts. The research team will integrate bioinformatics, biochemistry, synthetic biology, structural biology, and natural product chemistry to discover and characterize the enzymes responsible for the biosynthesis of two structurally distinct classes of terpenoid mycotoxins: macrocyclic trichothecenes and atranones. Their discoveries could reveal new enzymatic strategies for constructing complex molecular architectures, advance the understanding of fungal metabolism, and provide new opportunities for biotechnology, enzyme engineering, and synthetic biology. The project will also integrate research with education by developing research-based teaching modules, and providing undergraduate students with authentic research experiences in enzymology and natural product biosynthesis. The project will elucidate the biosynthetic mechanisms of macrocyclic trichothecenes and atranones through a multidisciplinary approach combining bioinformatics, fungal genetics, synthetic biology, enzymology, structural biochemistry, natural product chemistry, and genome-guided enzyme discovery. Previous studies established heterologous expression platforms for both biosynthetic systems and demonstrated that formation of the trichothecene core is mediated by an O-acetyltransferase and a novel ether-bridge-forming cyclase, overturning the long-standing hypothesis that this key cyclization occurs spontaneously. Building on these findings, the research team will determine the structural and mechanistic basis of this cyclization, identify and characterize the downstream enzymes responsible for macrocycle formation, and establish the complete enzymatic pathway leading to macrocyclic trichothecenes. The project will further apply complementary genome-guided discovery, heterologous pathway reconstruction, and biochemical characterization to identify the enzymes responsible for atranone biosynthesis and define the molecular logic underlying the assembly of this unusual diterpenoid scaffold. Comparative analysis of these biosynthetic systems will uncover previously unknown enzymatic transformations, and expand the catalytic repertoire of enzymes available for future applications in biotechnology. This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.