Sunday, May 19, 2024
5/19/2024
PROJECT SUMMARY Polyamine biosynthesis in human cancer cells is a long-standing therapeutic target. Accumulating evidence suggests that polyamine production by gut microbes modulates the progression of colon and pancreatic cancer. Biosynthesis of the polyamine spermidine by gut bacteria follows a pathway distinct from the human pathway making this bacterial pathway a unique drug target. The two central enzymes in this pathway, carboxyspermidine dehydrogenase and carboxyspermidine decarboxylase, have received only limited characterization. We propose to solve the first structure of a carboxyspermidine dehydrogenase and to develop kinetic and structural models describing the function of both carboxyspermidine dehydrogenase and carboxyspermidine decarboxylase in major gut constituents from the Bacteroides and Clostridium genera. Both carboxyspermidine dehydrogenase and decarboxylase use coenzymes with unique spectroscopic “handles” that can be interrogated by stopped- flow spectrometry to discern the kinetic steps of their respective catalytic cycles. A thorough structural and functional understanding of enzyme mechanisms is a necessary precursor to mechanism-guided drug design. This work will expand our fundamental understanding of a key gut microbe metabolic pathway: polyamine biosynthesis.
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