Characterization of polyamine biosynthetic enzymes from human gut microbes associated with colon and pancreatic cancer

Abstract public domain (NIH RePORTER)

PROJECT SUMMARY Polyamine biosynthesis in human cancer cells is a long-standing therapeutic target. Accumulating evidence suggests that polyamine production by gut microbes contributes to 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 development kinetic and structural models describing the function of both carboxyspermidine dehydrogenase and carboxyspermidine decarboxylase in major gut constituents from the Bacteroides and Clostridium genera. These aims serve as a necessary precursor to a future program of mechanism-guided drug design. The long- term goal of this work is to open new avenues for the treatment of colorectal and pancreatic cancer. Interestingly, the genes of predicted polyamine biosynthetic enzymes from many gut genera appear to encode redundant paths toward the production of spermidine. We hypothesize that these paths are not redundant, but generate unique polyamine products. We propose the use of LC-TQ-MS assays to delineate the polyamine products from apparently redundant enzyme pairs found in Clostridium. Spermidine synthase is a key focus of this aim because the prokaryotic orthologs of this enzyme have been shown to produce a variety of polyamine products besides spermidine. This work will expand our fundamental understanding of the functional variations found within a key gut microbe metabolic pathway: polyamine biosynthesis.

Public health relevance public domain (NIH RePORTER)

PROJECT NARRATIVE The goal of this project is the mechanistic characterization of enzymes from the human gut microbiome that are involved in polyamine biosynthesis. This project is relevant to public health because polyamine production by gut microbes is associated with disease states such as colon and pancreatic cancer. Enhanced understanding of gut microbe polyamine biosynthesis will open new targets for drug design leading to new treatment options for patients with these cancers.