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Mechanisms of Iron-Sulfur Dependent Reactions

Award Number: R35GM122595
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: 04/01/2017
PERIOD OF PERFORMANCE END DATE: 03/31/2027

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Mechanisms of Iron-Sulfur Dependent Reactions - PROJECT SUMMARY/ABSTRACT The prevalence and significance of methylation reactions in biology is well established. Methyl groups are appended to a wide array of biological molecules, including numerous small-molecule metabolites and natural products, and various macromolecules, such as proteins, DNA, RNA, carbohydrates, and lipids. In the vast majority of methylation reactions, S-adenosylmethionine (SAM) is the source of the appended methyl group. In classical methyltransferase reactions, strong nucleophiles such as oxygen, nitrogen, and sulfur attack the sp3- hybridized methyl group of SAM in a polar SN2 reaction, affording S-adenosylhomocysteine as a co-product. Carbon atoms can also be methylated by this mechanism, but only if a suitably nucleophilic carbanion can be generated. Relatively recently, it has come to light that SAM can be used to methylate inert carbon or phosphinate phosphorous atoms via pathways involving radical intermediates. These noncanonical SAM- dependent methylations are found in numerous biosynthetic pathways for antibiotic, antifungal, anticancer, and herbicidal natural products, and are catalyzed exclusively by enzymes within the radical S- adenosylmethionine superfamily. Radical SAM methylases currently consist of three classes (Class A, Class B, and Class C) based on structural architecture, cofactor requirement, and mechanism of action. Class A enzymes use a Cys dyad to catalyze methylation of sp2-hybridized carbon centers. Class B enzymes use cobalamin cofactors to catalyze methylation of both sp2- and sp3-hybridized carbon centers. Class C enzymes use two simultaneously bound molecules of SAM to methylate sp2-hybridized carbon centers. In all cases, the appended methyl group derives from a second molecule of SAM. This work will continue our efforts to understand how these radical SAM methylases work, with a particular focus on efforts to determine structures of these enzymes with bound substrates, cofactors, and intermediates. Important systems include RNA methylases that are involved in antibiotic resistance, as well as methylases that are involved in the biosynthesis of important antibiotics, such as thiostrepton A, nosiheptide, and carbapenems, the antibiotics currently of last resort.


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: 2026 ( Subtotal = $385,901 )
2026	2026	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT ST	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	003	11	4/2/2026	NON-COMPETING CONTINUATION	$378,000
2026	2025	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	002	9	3/31/2026	NON-COMPETING CONTINUATION	$0
2026	2025	TRUSTEES OF THE UNIVERSITY OF PENNSYLVANIA, THE	3451 WALNUT STREET	PHILADELPHIA	PA	19104	PHILADELPHIA	USA	Biomedical Research and Research Training	001	10	1/19/2026	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$377,999
2026	2025	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	9	1/16/2026	NON-COMPETING CONTINUATION	-$370,098
														Subtotal = $385,901

Issue Date FY: 2025 ( Subtotal = $370,099 )
2025	2025	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	9	3/25/2025	NON-COMPETING CONTINUATION	$333,089
2025	2025	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	002	9	8/28/2025	NON-COMPETING CONTINUATION	$37,010
2025	2024	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	8	12/13/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $370,099

Issue Date FY: 2024 ( Subtotal = $370,099 )
2024	2024	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	8	8/5/2024	NON-COMPETING CONTINUATION	$37,011
2024	2024	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	8	3/14/2024	NON-COMPETING CONTINUATION	$333,088
														Subtotal = $370,099

Issue Date FY: 2023 ( Subtotal = $370,099 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	7	3/10/2023	NON-COMPETING CONTINUATION	$370,099
2023	2022	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	002	6	5/11/2023	COMPETING CONTINUATION	$59,539
2023	2021	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	5	5/11/2023	NON-COMPETING CONTINUATION	-$59,539
														Subtotal = $370,099

Issue Date FY: 2022 ( Subtotal = $370,099 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	6	3/17/2022	COMPETING CONTINUATION	$370,099
														Subtotal = $370,099

Issue Date FY: 2021 ( Subtotal = $298,215 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	5	3/15/2021	NON-COMPETING CONTINUATION	$298,215
														Subtotal = $298,215

Issue Date FY: 2020 ( Subtotal = $298,357 )
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	4	3/20/2020	NON-COMPETING CONTINUATION	$298,357
														Subtotal = $298,357

Issue Date FY: 2019 ( Subtotal = $298,493 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	3	6/19/2019	NON-COMPETING CONTINUATION	$298,493
														Subtotal = $298,493

Issue Date FY: 2018 ( Subtotal = $298,625 )
2018	2018	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	2	5/16/2018	NON-COMPETING CONTINUATION	$298,625
														Subtotal = $298,625

Issue Date FY: 2017 ( Subtotal = $298,753 )
2017	2017	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	1	3/28/2017	NEW	$298,753
														Subtotal = $298,753

Grand Total All Awards = $3,358,740

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Mechanisms of Iron-Sulfur Dependent Reactions

Award Number: R35GM122595

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: 04/01/2017

PERIOD OF PERFORMANCE END DATE: 03/31/2027

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