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A Chemoenzymatic Approach to Accessing Novel Isoprenoid Scaffolds

Award Number: R01GM138800
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: 01/01/2022
PERIOD OF PERFORMANCE END DATE: 12/31/2026

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A Chemoenzymatic Approach to Accessing Novel Isoprenoid Scaffolds - Project Summary Isoprenoids represent a diverse class of compounds with a broad range of applications in medicine and industry. Their extraction from natural sources is both challenging and potentially harmful to the environment, while the enormous structural complexity of many isoprenoids makes traditional chemical synthesis nontrivial. Modern metabolic engineering and synthetic biology approaches have overcome some of these difficulties, but issues related to metabolic flux and the limited availability of the universal isoprenoid precursors complicate their widespread implementation. The artificial pathways developed thus far have been solely focused on synthesizing dimethylallyl and isopentenyl diphosphates and require additional enzymes for the generation of polyprenyl- diphosphates (polyprenyl-PPs). Thus, the primary objective of this proposal is to develop an efficient strategy for the synthesis of both natural and unnatural (poly)prenyl-PPs for downstream applications. This will be achieved using two complementary methods: i) employing undecaprenol kinases and isopentenyl phosphate kinases; and ii) employing hydroxyethylthiazole kinase, isopentenyl phosphate kinases, and farnesyl diphosphate synthase. Additionally, the two methods will work in conjunction with isoprenoid methylatransferases to incorporate additional diversity into the polyprenyl-PPs. The proposed studies include: i) structural and functional assessment of selected enzymes, ii) catalyst engineering, and iii) optimization of coupled in vitro and in vivo platforms for the generation of diversified libraries of select natural products. We expect these studies to generate: i) rules and concepts to advance knowledge on structure-activity relationships in selected classes of enzymes; ii) an optimized, enzyme-coupled platform to generate diversified substrates and isoprenoids; and iii) novel isoprenoid analogs with potential therapeutic applications. Thus, the proposed work will offer unprecedented access to uniquely bioactive isoprenoid libraries not readily accessible via traditional methods, and it stands to deepen our fundamental understanding of four enzyme classes while also developing them into useful biocatalysts.


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 = $279,261 )
2025	2025	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	000	4	12/12/2024	NON-COMPETING CONTINUATION	$279,261
														Subtotal = $279,261

Issue Date FY: 2024 ( Subtotal = $395,714 )
2024	2024	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	000	3	12/1/2023	NON-COMPETING CONTINUATION	$261,643
2024	2024	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	002	3	9/4/2024	SUPPLEMENT FOR EXPANSION	$105,000
2024	2024	UNIVERSITY OF OKLAHOMA	660 PARRINGTON OVAL RM 301	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	001	3	6/11/2024	NON-COMPETING CONTINUATION	$29,071
														Subtotal = $395,714

Issue Date FY: 2023 ( Subtotal = $291,061 )
2023	2023	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	000	2	12/2/2022	NON-COMPETING CONTINUATION	$261,955
2023	2023	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	001	2	2/16/2023	NON-COMPETING CONTINUATION	$29,106
														Subtotal = $291,061

Issue Date FY: 2022 ( Subtotal = $445,761 )
2022	2022	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	001	1	9/7/2022	SUPPLEMENT FOR EXPANSION	$140,635
2022	2022	UNIVERSITY OF OKLAHOMA	1000 ASP AVE RM 105	NORMAN	OK	73019	CLEVELAND	USA	Biomedical Research and Research Training	000	1	12/23/2021	NEW	$305,126
														Subtotal = $445,761

Grand Total All Awards = $1,411,797

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A Chemoenzymatic Approach to Accessing Novel Isoprenoid Scaffolds

Award Number: R01GM138800

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: 01/01/2022

PERIOD OF PERFORMANCE END DATE: 12/31/2026

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