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Diverse Transition-Metal and Free-Radical Chemistry Enabling 2'-Deoxyribonucleotide Production by Bacteria in Restrictive Environments

Award Number: R01GM132653
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: 06/01/2019
PERIOD OF PERFORMANCE END DATE: 05/31/2025

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Diverse Transition-Metal and Free-Radical Chemistry Enabling 2'-Deoxyribonucleotide Production by Bacteria in Restrictive Environments - Project Summary/Abstract All organisms obtain the deoxynucleotide substrates for DNA synthesis and repair by the action of an enzyme known as ribonucleotide reductase (RNR). The several known types of RNRs, which have been divided into classes I, II, and III, differ in the transition-metal and free-radical chemistry that they use to initiate their common, challenging reduction/dehydroxylation reaction. Recent studies have shown that many bacteria that infect and cause disease in humans use class I RNRs that differ markedly from the human class I, subclass a enzyme. Some of these microbial RNRs (subclasses b and d) use manganese instead of iron in what is thought to be an adaptation to iron deprivation caused by the human immune response, and others use both metals (subclass c). We just discovered that a new type of RNR from the causative agent of strep throat and scarlet fever may have fully escaped the usual dependence on transition metals by using a previously unknown type of stable amino acid radical, thus founding subclass e. This project will reveal precisely how the members of three new subclasses of class I RNRs (including d and e) that were recently identified in pathogenic bacteria acquire their catalytic activity and initiate nucleotide reduction. The very different initiation chemistry used by the pathogens' enzymes offers opportunities for their selective inhibition by antibiotics. This project will provide the conceptual underpinnings for such drug discovery efforts and will shed light on the ways in which pathogenic microbes have adapted to cope with their hosts' hostile immune response.


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	2022	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	4	9/25/2025	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $0 )
2024	2022	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	4	4/19/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $375,871 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	4	5/18/2022	NON-COMPETING CONTINUATION	$375,871
														Subtotal = $375,871

Issue Date FY: 2021 ( Subtotal = $377,432 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	3	6/3/2021	NON-COMPETING CONTINUATION	$377,432
														Subtotal = $377,432

Issue Date FY: 2020 ( Subtotal = $377,427 )
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	2	5/15/2020	NON-COMPETING CONTINUATION	$377,427
														Subtotal = $377,427

Issue Date FY: 2019 ( Subtotal = $468,509 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	1	5/16/2019	NEW	$404,247
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	1	5/24/2019	NEW	$2,887
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	002	1	8/5/2019	SUPPLEMENT FOR EXPANSION	$61,375
														Subtotal = $468,509

Grand Total All Awards = $1,599,239

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Diverse Transition-Metal and Free-Radical Chemistry Enabling 2'-Deoxyribonucleotide Production by Bacteria in Restrictive Environments

Award Number: R01GM132653

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: 06/01/2019

PERIOD OF PERFORMANCE END DATE: 05/31/2025

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