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Heme Oxygenases: chemically complex enzymes found in diverse biological pathways

Award Number: R35GM139516
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: 03/01/2021
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Heme Oxygenases: chemically complex enzymes found in diverse biological pathways - Project Summary This research program will develop accurate, detailed models of enzymatic heme degradation. In biological systems, heme oxygenases degrade heme to non-heme iron and oxygenated organic products, such as: biliverdin, staphylobilin, and mycobilin. In eukaryotes, the liberated non-heme iron is ultimately recycled into iron-dependent proteins. In prokaryotes, heme oxygenases are often part of iron acquisition pathways whereby pathogenic organisms acquire iron from host-derived heme. Despite a general understanding of the overall reactions catalyzed by heme oxygenases, the mechanistic details of how these enzymes catalyze the insertion of two to three oxygen atoms into a heme substrate remain poorly understood. This mechanistic knowledge is needed to selectively target heme oxygenase without disrupting other heme-dependent proteins. Recently, we developed new optical assays to accurately measure heme binding constants and elucidate the partitioning of heme between heme oxygenases and other heme-dependent proteins. We have also discovered an unprecedented, dynamic out-of-plane distortion of heme within some heme oxygenase active sites, which is correlated with enzymatic activity. Finally, we have revealed that an active site hydrogen bond promotes heme degradation in staphylobilin-producing heme oxygenases by stabilizing a resonance structure with a cationic radical at the carbon site of oxygenation. In the next five years, we will employ a combined spectroscopic and computational approach to elucidate the mechanism of heme monooxygenation to meso-hydroxyheme by mycobilin-producing heme oxygenases, and the mechanisms of meso-hydroxyheme oxygenation by biliverdin- and staphylobilin-producing heme oxygenases. In general, we will employ a variety of spectroscopic techniques to characterize analogues of key enzymatic intermediates. These experimental data will be used to develop accurate computational models of the enzymatic reactions. Ultimately, this program will provide detailed insight into a fascinating chapter of heme biochemistry, namely, self-oxygenation.


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 = $269,177 )
2025	2025	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Biomedical Research and Research Training	001	5	2/25/2025	NON-COMPETING CONTINUATION	$269,177
2025	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Biomedical Research and Research Training	000	4	11/15/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $269,177

Issue Date FY: 2024 ( Subtotal = $299,462 )
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Biomedical Research and Research Training	000	4	1/29/2024	NON-COMPETING CONTINUATION	$269,515
2024	2024	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT STREET	BURLINGTON	VT	05405	CHITTENDEN	USA	Biomedical Research and Research Training	001	4	5/20/2024	NON-COMPETING CONTINUATION	$29,947
														Subtotal = $299,462

Issue Date FY: 2023 ( Subtotal = $299,827 )
2023	2023	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Biomedical Research and Research Training	000	3	3/14/2023	NON-COMPETING CONTINUATION	$299,827
														Subtotal = $299,827

Issue Date FY: 2022 ( Subtotal = $300,182 )
2022	2022	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Biomedical Research and Research Training	001	2	6/30/2022	NON-COMPETING CONTINUATION	$30,020
2022	2022	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Biomedical Research and Research Training	000	2	2/22/2022	NON-COMPETING CONTINUATION	$270,162
														Subtotal = $300,182

Issue Date FY: 2021 ( Subtotal = $190,906 )
2021	2021	UNIVERSITY OF VERMONT & STATE AGRICULTURAL COLLEGE	85 S PROSPECT ST	BURLINGTON	VT	05405	CHITTENDEN	USA	Biomedical Research and Research Training	000	1	2/19/2021	NEW	$190,906
														Subtotal = $190,906

Grand Total All Awards = $1,359,554

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Heme Oxygenases: chemically complex enzymes found in diverse biological pathways

Award Number: R35GM139516

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: 03/01/2021

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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