Medicinal Chemistry Seminar: Katelyn Brown

Department: Medicinal Chemistry

Speaker: Katelyn Brown, PhD Candidate, Third-Year Student Seminar, College of Pharmacy, University of Michigan

Faculty Host: Marcy Balunas

Abstract:

Saxitoxin is a paralytic shellfish toxin (PST) produced by marine dinoflagellates and freshwater cyanobacteria. PSTs share a bisguandinium tricyclic core and have a high affinity for voltage-gated sodium channels (VGSCs). Isoform-specific inhibition of VGSCs is an attractive mechanism of action for the treatment of pain, epilepsy, and other neurological conditions. It has been shown that modifications of the PST core can affect the isoform specificity of analogs. Late-stage modification of PSTs using enzymes has proven to be a superior method compared to traditional chemical synthesis. Early-stage biosynthetic PST intermediates have yet to be explored for their VGSC isoform selectivity, and the full biosynthetic route toward the tricycle remains to be elucidated. I hypothesize that elucidating the activity and the scope of enzymes in the cyanobacterial saxitoxin biosynthetic gene cluster will unlock the potential to biocatalytically access natural and unnatural PST intermediates for testing against VGSCs. Using the insights gained from in vitro substrate-scope experiments, chemical characterization of enzymatic products, and the evaluation of substrates predicted by machine-learning models, we are making progress in elucidating the saxitoxin biosynthetic pathway while learning more about the biocatalytic potential of these biosynthetic enzymes.