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MECHANISMS INVOLVED IN FLAVIN-LINKED OXYGEN METABOLISM

Award Number: R01GM035394
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: 07/01/1985
PERIOD OF PERFORMANCE END DATE: 06/30/2006

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MECHANISMS INVOLVED IN FLAVIN-LINKED OXYGEN METABOLISM - DESCRIPTION: (provided by applicant) Lactic acid bacteria are known to represent strong paradigms for the biochemical diversity in oxygen metabolism, due to their lack of respiratory cytochromes and other hemeproteins. Instead these organisms rely on networks of unusual flavin-linked respiratory enzymes, and this application is focused on detailed structural and mechanistic studies of three particularly interesting representatives of this group: (1) NADH oxidase (Nox; 2NADH + O2 to 2NAD+ + 2H2O) from the severe human pathogen Streptococcus pyogenes, (2) NADH peroxidase (Npx; NADH + H2O2 - to NAD+ + 2H2O) from Enterococcus faecalis, and (3) alpha-glycerophosphate oxidase (GlpO; alpha-glycerophosphate + O2 - to dihydroxyacetone phosphate + H2O2) from Streptococcus sp. The GlpO sequence is closely related to those of the membrane-associated a-glycerophosphate dehydrogenases (GlpDs); the enzymes are distinguished primarily by the presence of a 50-residue insert unique to GlpO, which has furthermore been shown in limited proteolysis experiments to represent a flexible surface region that plays a crucial role in flavin reduction. Elucidation of the GlpO structure should provide insight into the structures of the related GIpDs as well and should better define the role of the GlpO surface loop during aglycerophosphate oxidation. While the structural homology between Nox and Npx has been reinforced dramatically with new crystal structures during the current project period, only recently has a third member of this small class of NAD(P)H-linked peroxide/disulfide reductases been identified - the FAD-dependent coenzyme A-disulfide reductase (CoADR; NADPH + CoASSCoA to NADP+ + 2CoASH) from the serious human pathogen Staphylococcus aureus. CoADR nicely complements this emerging group of flavoproteins which utilize a single active-site Cys as the basis for an essential redox center - the Cys-sulfenic acid (Cys-SOH) documented with Nox and Npx, and the Cys-SSCoA disulfide present in CoADR. An additional long-term objective of this application is the ongoing definition of the structural, redox, and mechanistic parameters for Cys-SOH function in Nox and Npx, as these enzymes provide the benchmarks by which protein-SOH centers now known to participate in diverse aspects of redox signaling and catalysis are analyzed. The new structures available for Nox and Npx also provide the basis for continuing analyses of the functional distinction between the relatively rare reduction of O2 to 2H2O catalyzed by Nox and the peroxidatic reaction of Npx. The interpretable electron density map recently calculated for CoADR now makes it possible to model and refine the atomic structure of this enzyme as well, thus allowing detailed comparisons with Nox and Npx and providing structural insights into the basis for the functional asymmetry exhibited by this unusual disulfide reductase.


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: 2005 ( Subtotal = $365,174 )
2005	2005	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Biomedical Research and Research Training	000	20	6/20/2005	NON-COMPETING CONTINUATION	$365,174
														Subtotal = $365,174

Issue Date FY: 2004 ( Subtotal = $354,931 )
2004	2004	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Biomedical Research and Research Training	000	19	6/7/2004	NON-COMPETING CONTINUATION	$354,931
														Subtotal = $354,931

Issue Date FY: 2003 ( Subtotal = $345,576 )
2003	2003	WAKE FOREST UNIVERSITY HEALTH SCIENCES	MEDICAL CENTER BOULEVARD	WINSTON SALEM	NC	27157	FORSYTH	USA	Biomedical Research and Research Training	000	18	5/30/2003	NON-COMPETING CONTINUATION	$345,576
														Subtotal = $345,576

Issue Date FY: 2002 ( Subtotal = $370,713 )
2002	2002	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Biomedical Research and Research Training	000	17	6/3/2002	COMPETING CONTINUATION	$370,713
														Subtotal = $370,713

Issue Date FY: 2001 ( Subtotal = $105,085 )
2001	2001	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Biomedical Research and Research Training	001	16	7/12/2001	SUPPLEMENT FOR EXPANSION	$105,085
														Subtotal = $105,085

Issue Date FY: 2000 ( Subtotal = $298,531 )
2000	2000	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Biomedical Research and Research Training	000	16	8/7/2000	NON-COMPETING CONTINUATION	$298,531
														Subtotal = $298,531

Issue Date FY: 1999 ( Subtotal = $290,803 )
1999	1999	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Biomedical Research and Research Training	000	15	6/11/1999	NON-COMPETING CONTINUATION	$290,803
														Subtotal = $290,803

Issue Date FY: 1998 ( Subtotal = $281,869 )
1998	1998	WAKE FOREST UNIVERSITY SCHOOL OF MEDICINE	MEDICAL CENTER BOULEVARD	WINSTON-SALEM	NC	27157		USA	Biomedical Research and Research Training	000	14	6/22/1998	NON-COMPETING CONTINUATION	$281,869
														Subtotal = $281,869

Grand Total All Awards = $2,412,682

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MECHANISMS INVOLVED IN FLAVIN-LINKED OXYGEN METABOLISM

Award Number: R01GM035394

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: 07/01/1985

PERIOD OF PERFORMANCE END DATE: 06/30/2006

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