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Understanding How Nonheme Iron-Dependent Enzymes Assemble Pharmacophores: Studies of Cyclopropane, Aziridine, and Isonitrile Formation

Award Number: R01GM127588
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: 06/01/2018
PERIOD OF PERFORMANCE END DATE: 06/30/2028

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Understanding How Nonheme Iron-Dependent Enzymes Assemble Pharmacophores: Studies of Cyclopropane, Aziridine, and Isonitrile Formation - Project Summary/Abstract Late-stage functionalization is a powerful strategy used in nature and in synthetic chemistry to expand structural complexity and diversity. In natural product biosynthesis, this strategy is exemplified by diverse reactions catalyzed by metalloenzymes. Among them, non-heme-iron- and 2-oxoglutarate-dependent (Fe/2OG) enzymes have been shown to perform a staggering array of transformations including carbo- and hetero-cyclization, halogenation, hydroxylation, olefination, and rearrangement. The catalytic diversity makes Fe/2OG enzymes an attractive target for biocatalyst development, organic synthesis, and other applications. However, despite the prevalence of Fe/2OG enzymes in all kingdoms of life (>160,000 encoded Fe/2OG enzyme genes in genomic data), efficient and precise strategies to annotate Fe/2OG enzyme functions are still lacking. Cyclopropane and aza-cyclopropane (aziridine) are unique three-membered carbo-/hetero-cycles, and are important pharmacophores widely used in drugs. In addition, the isocyano (isonitrile) group is found in hundreds of secondary metabolites with roles in metal trafficking. As demonstrated in the preliminary results, our combined bioinformatics and retro-biosynthetic analysis has identified Fe/2OG cyclopropanases, aziridinases and isonitrilases from thousands of functionally unannotated Fe/2OG enzymes. In this project, we will continue to apply this strategy to identify enzymes with these targeted activities. In cyclopropanation and aziridination, these newly discovered Fe/2OG enzymes and the related Fe/2OG hydroxylases will be subjected to mechanistic studies using a multifaceted approach consisting of molecular probe design/synthesis, product analysis, spectroscopic (EPR and Mössbauer) characterization, transient enzyme kinetics, and protein structure prediction and computational modeling. The acquired mechanistic insights, together with bioinformatics and retro-synthetic analysis, will be used to guide Fe/2OG enzyme functional (re)assignment in genomic data, to formulate effective strategies for conversion of hydroxylases to cyclopropanases or aziridinases, and to enable alternative carbo- and hetero-cycle formations. In the isonitrilase project, we will define factors that govern substrate selectivity of these enzymes, elucidate product structures, innovate a versatile method to prepare isonitrile-containing molecules, and assess their metal-binding properties.


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 = $405,445 )
2025	2025	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Biomedical Research and Research Training	001	7	6/20/2025	NON-COMPETING CONTINUATION	$405,445
2025	2022	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Biomedical Research and Research Training	000	5	2/11/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $405,445

Issue Date FY: 2024 ( Subtotal = $418,445 )
2024	2024	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27695	WAKE	USA	Biomedical Research and Research Training	000	6	9/3/2024	COMPETING CONTINUATION	$418,445
														Subtotal = $418,445

Issue Date FY: 2022 ( Subtotal = $390,373 )
2022	2022	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Biomedical Research and Research Training	000	5	5/23/2022	NON-COMPETING CONTINUATION	$390,373
														Subtotal = $390,373

Issue Date FY: 2021 ( Subtotal = $390,673 )
2021	2021	NORTH CAROLINA STATE UNIVERSITY	2601 WOLF VILLAGE WAY	RALEIGH	NC	27607	WAKE	USA	Biomedical Research and Research Training	000	4	5/6/2021	NON-COMPETING CONTINUATION	$390,673
														Subtotal = $390,673

Issue Date FY: 2020 ( Subtotal = $390,973 )
2020	2020	NORTH CAROLINA STATE UNIVERSITY	2701 SULLIVAN DR STE 240	RALEIGH	NC	27695	WAKE	USA	Biomedical Research and Research Training	000	3	5/29/2020	NON-COMPETING CONTINUATION	$390,973
														Subtotal = $390,973

Issue Date FY: 2019 ( Subtotal = $391,273 )
2019	2019	NORTH CAROLINA STATE UNIVERSITY	2701 SULLIVAN DR STE 240	RALEIGH	NC	27695	WAKE	USA	Biomedical Research and Research Training	000	2	5/13/2019	NON-COMPETING CONTINUATION	$391,273
														Subtotal = $391,273

Issue Date FY: 2018 ( Subtotal = $404,594 )
2018	2018	NORTH CAROLINA STATE UNIVERSITY	2701 SULLIVAN DR STE 240 CAMPUS BX 7514	RALEIGH	NC	27695	WAKE	USA	Biomedical Research and Research Training	000	1	5/21/2018	NEW	$404,594
														Subtotal = $404,594

Grand Total All Awards = $2,791,776

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Understanding How Nonheme Iron-Dependent Enzymes Assemble Pharmacophores: Studies of Cyclopropane, Aziridine, and Isonitrile Formation

Award Number: R01GM127588

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: 06/01/2018

PERIOD OF PERFORMANCE END DATE: 06/30/2028

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