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Characterization of the Thioacid Biosynthetic Machinery and Isolation of a Novel Thioacid Enediyne Natural Product

Award Number: F32GM134688
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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PROJECT SUMMARY Natural products have always been at the forefront of new drug discovery, and with the advent of the post- genomic era, they will remain so well into the future. During this process, thousands of natural products have been characterized, but of these, very few have been characterized to contain the thioacid functional group. Currently, there is a critical need to discover natural products that have novel and useful scaffolds or bioactivities. Due to its extraordinary rarity, the thioacid-containing natural products therefore are mostly unexplored to date. Recently, our lab has demonstrated that the thioacid functional group is introduced by a pair of enzymes, encoded by a two-gene cassette, that catalyze the transfer of sulfur from a sulfur carrier protein to a carboxylic acid-containing natural product. This gene cassette has now been identified in over 250 gene clusters, with more than 98% uncharacterized and encoding the biosynthesis of diverse families of natural products. In order to better characterize these new thioacid natural products, and to better understand the chemistry involved, the relevant biosynthetic machinery needs further study. Due to the novelty and bioactivities of the known thioacid- containing natural products, it is expected that further exploration of this chemical space will yield new scaffolds and enzymatic activities. The long-term goal of this project is to fully characterize the thioacid moiety and its biosynthesis for a significantly improved fundamental understanding of rare sulfur-containing natural products and sulfur-incorporating enzymes. This proposal contains two aims: (i) detailed mechanistic enzymology (including kinetics, structural characterization, residue mapping, and expansion of substrate scope) of the thioacid biosynthetic machinery from the thioplatensimycin (tPTM) and thioplatencin (tPTN) pathway and (ii) the heterologous production and structural elucidation of a novel and medicinally relevant enediyne thioacid in combination with biochemical analysis of the cognate thioacid machinery. The central hypotheses of this proposal are that (i) structural characterization of the tPTM/tPTN thioacid machinery will enable improved study of other thioacid pathways and (ii) discovery and characterization of an additional thioacid-containing natural product with a novel scaffold will provide crucial information about the inclusion of the thioacid functional group in natural products. This hypothesis is supported by a bioinformatic analysis unveiling the rich diversity of thioacid-containing natural product biosynthetic gene clusters in Nature—all containing the same well-conserved thioacid biosynthesis gene cassette. The outcomes of the proposed research will be access to structures and engineered variants of sulfur-incorporating enzymes and discovery of a novel thioacid-containing enediyne natural product.


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: 2023 ( Subtotal = -$1,359 )
2023	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	3	5/15/2023	NON-COMPETING CONTINUATION	$0
2023	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	4	5/15/2023	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	-$1,359
														Subtotal = -$1,359

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2021	UNIVERSITY OF FLORIDA	1523 UNION RD RM 207	GAINESVILLE	FL	32611	ALACHUA	USA	Biomedical Research and Research Training	001	4	6/6/2022	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$19,070
2022	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	3	6/2/2022	NON-COMPETING CONTINUATION	-$19,070
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $66,390 )
2021	2021	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	3	6/24/2021	NON-COMPETING CONTINUATION	$66,390
														Subtotal = $66,390

Issue Date FY: 2020 ( Subtotal = $64,926 )
2020	2020	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	2	6/11/2020	NON-COMPETING CONTINUATION	$64,926
														Subtotal = $64,926

Issue Date FY: 2019 ( Subtotal = $60,854 )
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	000	1	7/4/2019	NEW	$60,854
2019	2019	SCRIPPS RESEARCH INSTITUTE, THE	130 SCRIPPS WAY	JUPITER	FL	33458	PALM BEACH	USA	Biomedical Research and Research Training	001	1	7/4/2019	NEW	$0
														Subtotal = $60,854

Grand Total All Awards = $190,811

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Characterization of the Thioacid Biosynthetic Machinery and Isolation of a Novel Thioacid Enediyne Natural Product

Award Number: F32GM134688

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: FELLOWSHIP/SCHOLARSHIP/STUDENT LOANS

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