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High throughput biosynthesis of ribosomally synthesized and post-translationally modified peptide natural products

Award Number: R35GM142530
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Chemicals produced by living systems, or natural products, have had a tremendous impact on human health. For example, nearly one third of all small molecule drugs approved by a regulatory agency over the past nearly four decades have been natural products or derivatives of natural products, including over 70% of antibiotics and 40% of anticancer drugs [1]. While very useful molecules have been identified among the hundreds of thousands of natural products that have been characterized to date, genome sequencing efforts over the past decade and a half have revealed that we have only characterized the products of a small fraction of the biosynthetic pathways that exist in nature. The products of these pathways have the potential to greatly impact the diagnosis and treatment of disease, and it is critical that we develop new approaches to accelerate the identification and characterization of new natural products and natural product-like compounds. Towards this critical need, my group focuses on the ribosomally synthesized and post-translationally modified peptide (RiPP) class of natural products [2], and the enzymes involved in their biosynthesis. Unique among natural product biosynthetic pathways, the substrate of the RiPP biosynthetic enzymes is a genetically encoded precursor peptide. This feature of the substrates allows for deep mutational analysis, not just of the enzymes, but of their substrates as well. We will develop a platform for high throughput examination of the substrate selectivity and activity of RiPP biosynthetic enzymes based on yeast or bacterial surface display, fluorescence activated cell sorting, and next generation sequencing. Using this platform and gene libraries encoding substrate variants we will study the substrate scope of these enzymes, and how that scope relates to the sequence of the native substrate of the enzymes. Additionally, we will perform deep mutational analysis of the enzymes to identify contributions to substrate recognition and selectivity. These studies will provide us with a deeper understanding of how these enzymes function. With this deeper understanding, we will be able to use these enzymes as tools to generate large libraries of natural product-like compounds that can be screened to identify those with useful biological activities more efficiently than current natural product discovery approaches.


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 = $342,605 )
2024	2024	UNIVERSITY OF NEW MEXICO	1700 LOMAS BLVD NE STE 2200	ALBUQUERQUE	NM	87131	BERNALILLO	USA	Biomedical Research and Research Training	000	4	6/27/2024	NON-COMPETING CONTINUATION	$342,605
														Subtotal = $342,605

Issue Date FY: 2023 ( Subtotal = $342,964 )
2023	2023	UNIVERSITY OF NEW MEXICO, THE	1700 LOMAS BLVD NE STE 2200	ALBUQUERQUE	NM	87106	BERNALILLO	USA	Biomedical Research and Research Training	000	3	4/28/2023	NON-COMPETING CONTINUATION	$342,964
														Subtotal = $342,964

Issue Date FY: 2022 ( Subtotal = $343,303 )
2022	2022	UNIVERSITY OF NEW MEXICO, THE	1700 LOMAS BLVD NE STE 2200	ALBUQUERQUE	NM	87106	BERNALILLO	USA	Biomedical Research and Research Training	000	2	5/6/2022	NON-COMPETING CONTINUATION	$343,303
														Subtotal = $343,303

Issue Date FY: 2021 ( Subtotal = $343,623 )
2021	2021	UNIVERSITY OF NEW MEXICO, THE	1700 LOMAS BLVD NE STE 2200	ALBUQUERQUE	NM	87106	BERNALILLO	USA	Biomedical Research and Research Training	000	1	6/3/2021	NEW	$343,623
														Subtotal = $343,623

Grand Total All Awards = $1,372,495

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High throughput biosynthesis of ribosomally synthesized and post-translationally modified peptide natural products

Award Number: R35GM142530

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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