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Peptide Processing by Copper Enzymes

Award Number: R35GM136239
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: 05/01/2020
PERIOD OF PERFORMANCE END DATE: 02/28/2031

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Peptide Processing by Copper Enzymes - ABSTRACT Peptide processing is a post-translational function that converts pro-peptides into their mature forms. Amidated peptides interact with GPCRs at the cell membrane leading to production of essential hormones, while NRPS or RiPPs are a major source of lead compounds for antibacterial, antiviral and anticancer therapeutics. Our R35 program aims to explore the reaction chemistry of copper-mediated peptide processing via studies that compare the reaction chemistry of peptide amidation with RiPP. Peptidylglycine monooxygenase (PHM) is the only enzyme able to catalyze peptide amidation, while the newly discovered BURP peptide cyclase is the first example of a Cu-dependent RiPP enzyme. Although genetically unrelated, the BURP cyclase resembles PHM in metal site coordination and Cu-Cu separation, and an important question is why its chemistry leads to peptide cross-linking rather than substrate hydroxylation. In the previous funding cycle we obtained data challenging the canonical PHM mechanism, leading to the suggestion that an “open-to-closed” conformational transition brings the copper centers closer to facilitate reaction at a binuclear center. Evidence supporting this paradigm shift was the discovery of binuclear complexes of PHM with the peptidyl substrate analogue AAF- homocysteine via the isolation of thiolate-bridged binuclear complexes in both mixed-valence (MV) and fully reduced forms. In the next cycle we will develop this reaction chemistry via (i) electronic structural studies on the MV AAF-hCys peptide complex and its Se analogue using advanced X-ray and EPR spectroscopies coupled to DFT (ii) exploration of the reaction chemistry of PHM with new Cα- and Cβ- substituted bifunctional substrate analogues designed to capture the binuclear state in catalytically active forms (iii) parallel studies on the newly characterized AhyBURP domain with emphasis on whether the chemistry proceeds via mono- or binuclear copper intermediates, and (iv) cryo-EM studies of dopamine β-monooxygenase (catalytic core similar to PHM) in open and closed conformations.


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 = $619,006 )
2026	2026	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	6	3/19/2026	COMPETING CONTINUATION	$619,006
														Subtotal = $619,006

Issue Date FY: 2025 ( Subtotal = $0 )
2025	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	5	11/7/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2024 ( Subtotal = $611,364 )
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	5	3/27/2024	NON-COMPETING CONTINUATION	$550,227
2024	2024	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	001	5	8/6/2024	NON-COMPETING CONTINUATION	$61,137
														Subtotal = $611,364

Issue Date FY: 2023 ( Subtotal = $611,364 )
2023	2023	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	4	4/14/2023	NON-COMPETING CONTINUATION	$611,364
														Subtotal = $611,364

Issue Date FY: 2022 ( Subtotal = $611,364 )
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	3	4/15/2022	NON-COMPETING CONTINUATION	$550,224
2022	2022	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	001	3	6/23/2022	NON-COMPETING CONTINUATION	$61,140
														Subtotal = $611,364

Issue Date FY: 2021 ( Subtotal = $611,364 )
2021	2021	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	2	4/27/2021	NON-COMPETING CONTINUATION	$611,364
														Subtotal = $611,364

Issue Date FY: 2020 ( Subtotal = $299,673 )
2020	2020	OREGON HEALTH & SCIENCE UNIVERSITY	3181 SW SAM JACKSON PARK RD	PORTLAND	OR	97239	MULTNOMAH	USA	Biomedical Research and Research Training	000	1	4/8/2020	NEW	$299,673
														Subtotal = $299,673

Grand Total All Awards = $3,364,135

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Peptide Processing by Copper Enzymes

Award Number: R35GM136239

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: 05/01/2020

PERIOD OF PERFORMANCE END DATE: 02/28/2031

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