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Investigating biosynthetic enzymes to enhance natural product discovery

Award Number: R35GM151137
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)
PERIOD OF PERFORMANCE START DATE: 08/05/2023
PERIOD OF PERFORMANCE END DATE: 05/31/2028

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Investigating biosynthetic enzymes to enhance natural product discovery - Project Summary Natural products (NPs) have diverse complex structures and play a vital role in drug discovery and development. Although the rate of discovery of natural products has increased significantly, traditional bioactivity-guided discovery methods frequently lead to the re-discovery of known compounds. Therefore, genetic information- driven isolation is becoming a powerful tool to uncover novel NPs. Genome mining efforts that target genes responsible for the biosynthesis of core structures of major NP classes, has identified tens of thousands of new biosynthetic gene cluster (BGC) families predicted to produce novel compounds. While this method has been very successful in predicting compounds from these major classes, it is limited to those scaffolds and cannot identify other specific features of NP structures. Furthermore, these methods will overlook “hidden” BGCs that do not contain traditional core biosynthetic machinery, leaving a major gap in NP discovery. The first direction of this proposal aims to use specialized genome mining strategies that target NP glycosyltransferases to identify uncharacterized BGCs that produce bioactive glycosylated NPs with distinct core structures. Consequently, identified compounds will be directly linked to their BGC and likely have biosynthetic pathways that consist of unique enzymes and biochemical reactions. The second direction of this proposal is to interrogate the activities and mechanisms of new biosynthetic enzymes. These will include enzymes discovered in direction one, along with enzymes responsible for the biosynthesis of the aminocyclitol found in hygromycin A, that contains a rare modification essential for bioavailability. Subsequent re-integration of newly characterized biosynthetic enzymes into standard or specialized genome mining methods will assist in annotating and identifying additional BGCs to improve NP discovery. In addition, these enzymes will add to the growing toolbox of biocatalytic reactions exploited for unnatural small molecule biosynthesis. Ultimately, this research program will significantly advance NP and enzymology research to boost drug discovery and development for the benefit of human health.


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: 2025 ( Subtotal = $360,271 )
2025	2025	UNIVERSITY OF ALABAMA	801 UNIVERSITY BLVD	TUSCALOOSA	AL	35401	TUSCALOOSA	USA	Biomedical Research and Research Training	000	3	5/8/2025	NON-COMPETING CONTINUATION	$360,271
														Subtotal = $360,271

Issue Date FY: 2024 ( Subtotal = $360,853 )
2024	2024	UNIVERSITY OF ALABAMA	801 UNIVERSITY BLVD	TUSCALOOSA	AL	35401	TUSCALOOSA	USA	Biomedical Research and Research Training	000	2	5/2/2024	NON-COMPETING CONTINUATION	$360,853
														Subtotal = $360,853

Issue Date FY: 2023 ( Subtotal = $361,407 )
2023	2023	UNIVERSITY OF ALABAMA	301 ROSE ADMIN BLDG	TUSCALOOSA	AL	35487	TUSCALOOSA	USA	Biomedical Research and Research Training	000	1	7/20/2023	NEW	$361,407
														Subtotal = $361,407

Grand Total All Awards = $1,082,531

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Investigating biosynthetic enzymes to enhance natural product discovery

Award Number: R35GM151137

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

PERIOD OF PERFORMANCE START DATE: 08/05/2023

PERIOD OF PERFORMANCE END DATE: 05/31/2028

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