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

Award Number: R16GM146714
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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


Issue Date FY	Funding FY	Legal Entity Name	Legal Entity Address	Legal Entity City	Legal Entity State	Legal Entity Zip Code	Legal Entity COUNTY	Legal Entity COUNTRY	Assistance Listing	Award Code	Budget Year	Action Date	Action Type	Action Amount

Issue Date FY: 2024 ( Subtotal = $162,500 )
2024	2024	FORT LEWIS COLLEGE	1000 RIM DR	DURANGO	CO	81301	LA PLATA	USA	Biomedical Research and Research Training	000	3	6/5/2024	NON-COMPETING CONTINUATION	$162,500
														Subtotal = $162,500

Issue Date FY: 2023 ( Subtotal = $257,030 )
2023	2023	FORT LEWIS COLLEGE	1000 RIM DR	DURANGO	CO	81301	LA PLATA	USA	Biomedical Research and Research Training	000	2	7/25/2023	NON-COMPETING CONTINUATION	$162,500
2023	2023	FORT LEWIS COLLEGE	1000 RIM DR	DURANGO	CO	81301	LA PLATA	USA	Biomedical Research and Research Training	001	2	7/28/2023	SUPPLEMENT FOR EXPANSION	$94,530
														Subtotal = $257,030

Issue Date FY: 2022 ( Subtotal = $162,500 )
2022	2022	FORT LEWIS COLLEGE	1000 RIM DR	DURANGO	CO	81301	LA PLATA	USA	Biomedical Research and Research Training	000	1	7/12/2022	NEW	$162,500
														Subtotal = $162,500

Grand Total All Awards = $582,030

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

Award Number: R16GM146714

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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