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A radical new paradigm for heme degradation in enteric pathogens

Award Number: R01GM124203
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: 07/15/2017
PERIOD OF PERFORMANCE END DATE: 04/30/2023

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A radical new paradigm for heme degradation in enteric pathogens - PROJECT SUMMARY For pathogens, the ability to acquire iron is critical and one of the best-understood indicators of virulence. Numerous pathogenic organisms take advantage of the abundance of heme in the host cell and the human diet as a source of essential iron. Until recently however, all of the known heme degrading enzymes required molecular oxygen for function. In this project, we will investigate the mechanism of anaerobic heme degradation in enterohemorrhagic E. coli (EHEC), a facultative anaerobic pathogen (e.g. O157:H7, which causes bloody diarrhea, hemolytic uremic syndrome, kidney failure and death). We recently found that the ChuW enzyme from EHEC catabolyzes heme and liberates iron under strictly anaerobic conditions. This newly identified anaerobic heme degradation enzyme is part of an important module of heme utilization proteins (ChuW, X, Y in E. coli) that is also found in other aggressive pathogens such as Vibrio cholerae. Identification and characterization of this new pathway in enteric pathogens provides an unexplored opportunity for developing novel antimicrobial compounds. In addition, the enzyme at the heart of this investigation (ChuW) is a radical SAM methyltransferase (RSMT); it utilizes a [4Fe-4S] cluster to generate a powerful radical species that facilitates the liberation of iron from heme through a methyl transfer reaction and chemical rearrangement of the porphyrin. ChuW is capable of methylating an otherwise unreactive sp2- hybridized carbon atom. Furthermore, ChuW is a member of the class C RSMTs, which are poorly understood but have already been shown to catalyze key reactions in the biosynthesis of novel compounds with antitumor and antibiotic properties. This work will provide new insight into this important class of RSMTs and how they control highly reactive radicals to facilitate specific chemical conversions in the biosynthesis of compounds including anti-microbial and anti-tumor agents. Using a multifaceted approach that combines traditional enzyme kinetics, rigorous spectroscopic techniques, and modern structural biology tools, we will characterize the mechanism of anaerobic heme degradation by ChuW, the properties of the anaerobic catabolites, and the interplay of two additional proteins with ChuW in the anaerobic degradation of heme as well as the transport and further reduction of the catabolites. The latter is important given recent work showing that heme degradation products play a vital role in regulation of heme flux and iron homeostasis in other aggressive pathogens. Our specific aims are to determine whether: ChuW catalyzes the liberation of iron from heme via a radical SAM methyltransferase mechanism (using 5'-dAdo• and resulting in formation of “anaerobilin”) (Aim 1); ChuX facilitates the chelation of the iron atom and delivery of “anaerobilin” to ChuY (Aim 3); and ChuY catalyzes the NADPH-dependent reduction of anaerobilin to “anaerorubin” (Aim 2). Our long term goal is to provide the necessary mechanistic insight to selectivity target the anaerobic heme degradation pathway, which appears to be specifically associated with a select set of aggressive, opportunistic, and pathogenic bacteria.


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: 2023 ( Subtotal = $0 )
2023	2020	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 E CAMPUS RD RM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	000	4	9/14/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	000	4	2/16/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $306,832 )
2020	2020	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	000	4	5/21/2020	NON-COMPETING CONTINUATION	$306,832
														Subtotal = $306,832

Issue Date FY: 2019 ( Subtotal = $341,308 )
2019	2019	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	000	3	4/4/2019	NON-COMPETING CONTINUATION	$306,808
2019	2019	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	001	3	6/19/2019	SUPPLEMENT FOR EXPANSION	$34,500
														Subtotal = $341,308

Issue Date FY: 2018 ( Subtotal = $306,786 )
2018	2018	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	000	2	4/19/2018	NON-COMPETING CONTINUATION	$306,786
														Subtotal = $306,786

Issue Date FY: 2017 ( Subtotal = $327,109 )
2017	2017	UNIVERSITY OF GEORGIA RESEARCH FOUNDATION, INC.	310 EAST CAMPUS RD TUCKER HALL ROOM 409	ATHENS	GA	30602	CLARKE	USA	Biomedical Research and Research Training	000	1	6/30/2017	NEW	$327,109
														Subtotal = $327,109

Grand Total All Awards = $1,282,035

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A radical new paradigm for heme degradation in enteric pathogens

Award Number: R01GM124203

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: 07/15/2017

PERIOD OF PERFORMANCE END DATE: 04/30/2023

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