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Posttranslational Modifications during Natural Product Biosynthesis

Award Number: R37GM058822
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: 02/01/1999
PERIOD OF PERFORMANCE END DATE: 05/31/2026

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Posttranslational Modifications during Natural Product Biosynthesis - Ribosomally synthesized and posttranslationally modified peptides (RiPPs) are a major group of natural products (NPs) produced in all domains of life. The number of RiPP families continues to expand rapidly based on genome sequencing. RiPPs a·re well suited for genome mining for new natural products by heterologous expression of biosynthetic gene clusters (BGCs) and for library generation of cyclic peptides to recognize diverse targets. Furthermore, RiPPs appear to be widely encoded in the human microbiome and have recently been implicated in causation and prevention of human disease. For the RiPP field to advance, a better understanding of the post-translational modification processes is important. Similarly, tools need to be developed to take advantage of the substrate tolerance of the biosynthetic enzymes. In the current application we describe our progress towards these goals and our proposed studies for continued advances. This application focuses mostly on the lanthipeptides, a group of polycyclic peptides with macrocyclic thioether crosslinks. Individual lanthipeptides have a variety of biological activities including antimicrobial, antiviral, antifungal and anti-allodynic. At least four different routes to lanthipeptides have evolved and lanthipeptide BGCs are ubiquitous amongst the RiPP family in sequenced genomes. For one of these four pathways, substrate recognition is reasonably understood but for the other three this information is lacking and will be a focus of continued research . Another poorly understood aspect is the factors that control the ring topology of the multiple thioether rings that are formed and this question will be a focus of investigation. Furthermore, previous work suggests that lanthipeptide biosynthesis takes place in enzyme complexes that may require its substrate. A method for catalytically competent covalent attachment of the substrate to the key enzyme will be used to try and structurally characterize such enzyme complexes. In addition, the mechanisms of a family of enzymes that make amino acid-derived NPs in a novel pathway will be investigated and the pathways in which they operate will be determined. Improved engineering technology to disrupt protein-protein interactions with cyclic peptides will be developed. RELEVANCE (See instructions): Based on historical precedent, the most likely group of compounds to deliver new antibiotics to fight antibiotic resistance are natural products. Genome sequences offer unprecedented access to new natural products that could be future antibiotics but for this information to be used, biosynthetic enzymes that make the natural products need to be better understood. This application aims to obtain this information.


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 = $300,120 )
2025	2025	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	26	6/16/2025	NON-COMPETING CONTINUATION	$300,120
														Subtotal = $300,120

Issue Date FY: 2024 ( Subtotal = $300,120 )
2024	2024	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	25	5/3/2024	NON-COMPETING CONTINUATION	$300,120
														Subtotal = $300,120

Issue Date FY: 2023 ( Subtotal = $300,120 )
2023	2023	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	24	5/9/2023	NON-COMPETING CONTINUATION	$300,120
														Subtotal = $300,120

Issue Date FY: 2022 ( Subtotal = $300,120 )
2022	2022	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	002	23	5/5/2022	NON-COMPETING CONTINUATION	$300,120
2022	2021	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	001	22	11/11/2021	EXTENSION WITH OR WITHOUT FUNDS	$20,453
2022	2020	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	21	11/11/2021	NON-COMPETING CONTINUATION	-$20,453
														Subtotal = $300,120

Issue Date FY: 2021 ( Subtotal = $300,136 )
2021	2021	UNIVERSITY OF ILLINOIS	364 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	22	4/27/2021	EXTENSION WITH OR WITHOUT FUNDS	$300,136
														Subtotal = $300,136

Issue Date FY: 2020 ( Subtotal = $275,370 )
2020	2020	UNIVERSITY OF ILLINOIS	364 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	21	4/24/2020	NON-COMPETING CONTINUATION	$275,370
														Subtotal = $275,370

Issue Date FY: 2019 ( Subtotal = $275,729 )
2019	2019	UNIVERSITY OF ILLINOIS	364 HENRY ADMINISTRATION BLDG	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	20	8/23/2019	NON-COMPETING CONTINUATION	$275,729
														Subtotal = $275,729

Issue Date FY: 2018 ( Subtotal = $273,850 )
2018	2018	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST STE 364	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	19	5/17/2018	NON-COMPETING CONTINUATION	$273,850
														Subtotal = $273,850

Issue Date FY: 2017 ( Subtotal = $277,708 )
2017	2017	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST STE 364	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	002	18	8/14/2017	NON-COMPETING CONTINUATION	$27,419
2017	2017	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST STE 364	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	001	18	5/16/2017	NON-COMPETING CONTINUATION	$246,769
2017	2016	UNIVERSITY OF ILLINOIS	506 S WRIGHT ST STE 364	URBANA	IL	61801	CHAMPAIGN	USA	Biomedical Research and Research Training	000	17	1/14/2017	COMPETING CONTINUATION	$3,520
														Subtotal = $277,708

Issue Date FY: 2016 ( Subtotal = $274,516 )
2016	2016	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Biomedical Research and Research Training	001	17	7/12/2016	COMPETING CONTINUATION	$0
2016	2016	UNIVERSITY OF ILLINOIS BOARD OF TRUSTEES	109 COBLE HALL, 801 S WRIGHT S	CHAMPAIGN	IL	61820	CHAMPAIGN	USA	Biomedical Research and Research Training	000	17	5/17/2016	COMPETING CONTINUATION	$274,516
														Subtotal = $274,516

Grand Total All Awards = $2,877,789

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Posttranslational Modifications during Natural Product Biosynthesis

Award Number: R37GM058822

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: 02/01/1999

PERIOD OF PERFORMANCE END DATE: 05/31/2026

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