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Functional Hybrid Natural Product Synthases by Tracking Acyl Carrier Protein Binding and Conformational Dynamics

Award Number: R15GM120704
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: 09/01/2016
PERIOD OF PERFORMANCE END DATE: 08/31/2027

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Functional Hybrid Natural Product Synthases by Tracking Acyl Carrier Protein Binding and Conformational Dynamics - PROJECT SUMMARY Microorganisms produce molecules of vast structural and functional diversity. In particular, the polyketide class of natural products holds a profound track record for being repurposed as medicinally relevant molecules. Polyketides are natively produced by multi-enzyme assemblies called synthases. Within each polyketide synthase (PKS) an acyl carrier protein (ACP) plays the central role of transferring and presenting molecular building blocks and intermediates to its team of enzymatic partners. The strategic redesign of PKSs presents an exciting and sustainable route to access new antibiotics and anticancer agents; However, the success of any redesign approach hinges on a thorough understanding of how ACPs interact with different substrates and enzymes during the biosynthetic process. In particular, how ACPs select their molecular building blocks is a foundational question that if answered could enable the strategic engineering of PKSs to incorporate desired structures at targeted locations on the polyketide product. The goal of this study is to uncover the molecular ground rules for why some ACPs strictly accept a single substrate through an acyl transferase (AT) facilitated exchange whereas others can bypass the gate-keeping AT and ‘self-acylate’ with a broader range of substrates. This will be accomplished by 1) connecting ACP self-acylation ability to ACP sequence and secondary structure, 2) characterizing ACP conformational dynamics and substrate scope, and 3) engineering ACPs to display modified acylation properties. Innovative methods, such as site-specific vibrational spectroscopy, will be used to connect fast ACP conformational dynamics to acylation properties, providing unprecedented temporal insights. The approach to PKS engineering is novel in that critical ACP-protein interactions, which when disrupted often lead to system failure, will be maintained. Thus, these studies directly address the limited substrate scope of native polyketide biosynthetic pathways as an alternative route to unlocking access to novel polyketides. Over 30 undergraduate students will engage in this work at the chemistry-biology interface through independent research projects and course-based undergraduate research experiences, thereby expanding the impact of the proposed research into training the next generation of critical thinkers and innovators.


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 = $0 )
2025	2024	THE CORPORATION OF HAVERFORD COLLEGE	370 W LANCASTER AVE	HAVERFORD	PA	19041	MONTGOMERY	USA	Biomedical Research and Research Training	001	3	3/28/2025	COMPETING CONTINUATION	$8
2025	2022	THE CORPORATION OF HAVERFORD COLLEGE	370 W LANCASTER AVE	HAVERFORD	PA	19041	MONTGOMERY	USA	Biomedical Research and Research Training	000	2	3/28/2025	SUPPLEMENT FOR EXPANSION	-$8
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $462,351 )
2024	2024	THE CORPORATION OF HAVERFORD COLLEGE	370 W LANCASTER AVE	HAVERFORD	PA	19041	MONTGOMERY	USA	Biomedical Research and Research Training	000	3	8/9/2024	COMPETING CONTINUATION	$462,351
														Subtotal = $462,351

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2020	CORPORATION OF HAVERFORD COLLEGE, THE	370 LANCASTER AVE	HAVERFORD	PA	19041	MONTGOMERY	USA	Biomedical Research and Research Training	000	2	8/11/2023	COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $33,122 )
2022	2022	CORPORATION OF HAVERFORD COLLEGE, THE	370 LANCASTER AVE	HAVERFORD	PA	19041	MONTGOMERY	USA	Biomedical Research and Research Training	000	2	5/24/2022	SUPPLEMENT FOR EXPANSION	$33,122
														Subtotal = $33,122

Issue Date FY: 2021 ( Subtotal = $0 )
2021	2020	CORPORATION OF HAVERFORD COLLEGE, THE	370 LANCASTER AVE	HAVERFORD	PA	19041	MONTGOMERY	USA	Biomedical Research and Research Training	001	2	5/7/2021	COMPETING CONTINUATION	$8,335
2021	2016	CORPORATION OF HAVERFORD COLLEGE, THE	370 LANCASTER AVE	HAVERFORD	PA	19041	MONTGOMERY	USA	Biomedical Research and Research Training	000	1	5/7/2021	NEW	-$8,335
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $297,992 )
2020	2020	CORPORATION OF HAVERFORD COLLEGE, THE	370 LANCASTER AVE	HAVERFORD	PA	19041	MONTGOMERY	USA	Biomedical Research and Research Training	000	2	8/13/2020	COMPETING CONTINUATION	$297,992
														Subtotal = $297,992

Issue Date FY: 2016 ( Subtotal = $390,344 )
2016	2016	HAVERFORD COLLEGE	370 Lancaster Ave	HAVERFORD	PA	19041	MONTGOMERY	USA	Biomedical Research and Research Training	000	1	8/29/2016	NEW	$390,344
														Subtotal = $390,344

Grand Total All Awards = $1,183,809

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Functional Hybrid Natural Product Synthases by Tracking Acyl Carrier Protein Binding and Conformational Dynamics

Award Number: R15GM120704

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: 09/01/2016

PERIOD OF PERFORMANCE END DATE: 08/31/2027

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