Event

Special Biological Chemistry Seminar at the University of Pennsylvania

Dr. Leah Bushin

Scripps Institution of Oceanography

Friday, January 10, 2025

10:30 AM

Carolyn Hoff Lynch Lecture Hall

Chemistry Complex

231 South 34th Street

Title:

Growth-coupled microbial biosynthesis of the animal pigment xanthommatin

Abstract:

Genome mining across all domains of life has unearthed a bounty of biosynthetic potential for diverse molecules, key to sustaining a biobased future. While the heterologous expression of metabolic pathways has achieved broad success, most approaches suffer a similar fate in low initial production levels that require extensive, resource-heavy, iterative strain engineering and refinement. First, I will present a story of uncovering nature’s biosynthetic potential. I will discuss the implementation of a bioinformatic search strategy that revealed novel peptide macrocyclization routes installed by radical S-adenosylmethionine enzymes in the biosynthesis of natural products from streptococci bacteria. Knowledge of the post-translation modifications enabled the discovery of the mature bioactive natural products, which were found to be potent growth regulation agents. Second, I will address the challenge of heterologous bioproduction. I will introduce a growth-coupled biosynthetic strategy that stoichiometrically connects microbial growth to specialized compound production and demonstrate its application towards production of the structurally complex animal pigment xanthommatin, a color-changing ommochrome with material and cosmetic potential. Xanthommatin biosynthesis directly fuels growth of a newly designed Pseudomonas putida 5,10-methylenetetrahydrofolate auxotroph (PUMA). Aided by genome-scale metabolic modeling, PUMA was designed and built to be controlled by endogenous formate co-produced as a coupled biosynthetic byproduct in the multistep conversion of tryptophan to xanthommatin. Adaptive laboratory evolution was utilized to streamline xanthommatin's gram-scale bioproduction via growth rate selection, establishing the platform as a promising biotechnological approach for optimizing the microbial production of value-added molecules.

Bio:

Dr. Leah Bushin is a NIH Ruth Kirschstein-NRSA postdoctoral fellow in the lab of Prof. Bradley Moore at the Scripps Institution of Oceanography at UCSD. At SIO, she worked on projects at the interface of marine natural product biosynthesis and synthetic biology - in particular applying new strategies in metabolic engineering to overcome limitations in microbial bioproduction of heterologous compounds. Prior to her position in the Moore lab, Dr. Bushin completed her graduate studies in the department of chemistry at Princeton University working in the lab of Prof. Mo Seyedsayamdost. Her graduate work focused on the discovery and structural elucidation of ribosomally synthesized post-translationally modified peptides (RiPPs) containing unusual chemical modifications installed by radical SAM tailoring enzymes. Her current research interests lie at the interface of primary and secondary metabolism and applying this knowledge toward the discovery and production of novel natural products.