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Structure Function & Biosynthesis of Respiratory Enzymes

Award Number: R37GM041574
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: 08/01/1988
PERIOD OF PERFORMANCE END DATE: 07/31/2020

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Structure Function & Biosynthesis of Respiratory Enzymes - This proposal describes how specific enzymes control the transfer of electrons and activation of molecular oxygen, while minimizing oxidative damage. This is central to cell development, health and survival. This project includes studies of enzyme reaction mechanisms, protein structure-function relationships, protein-protein interactions, protein post-translational modification, and mechanisms of long range biological electron transfer. Kinetic, biochemical, spectroscopic and structural studies together with site-directed mutagenesis will be used in these studies. This proposal focuses on the mechanism of biosynthesis ofthe protein-derived cofactor, tryptophan tryptophylquinone (TTQ), and the structure and function of a novel di-heme enzyme MauG which catalyzes the oxygenation and cross-linking of specific tryptophan residues during TTQ biogenesis in methylamine dehydrogenase (MADH). The substrate for MauG is a 119-kDa precursor protein of MADH with mono-hydroxylated Trp57 and no cross-link. MauG catalyzes the 6-electron oxidation of the substrate that results in the second oxygenation of Trp57, cross-linking of Trp57 and Trp108, and oxidation of the quinol product of the first two reactions to form oxidized TTQ. These studies will describe a new biological mechanism for oxygen activation and factors that make specific amino acid residues in proteins susceptible to oxidative modification.The results will provide insight for development of strategies to introduce novel catalytic sites into proteins and manipulate the functions of enzyme-bound hemes, as well as provide clues as to how one might mitigate naturally occurring oxidative damage to proteins. Ongoing mechanistic studies of biological electron transfer (ET) in the MADH-amicyanin-cytochrome c-551 i protein complex will be extended and ET studies will be initiated with MauG. Defining mechanisms of long range ET reactions will enhance our understanding of the fundamental processes of respiration and intermediary metabolism at the molecular level. A fundamental understanding of the mechanisms of control of biological ET reactions will provide insight into how defective protein ET leads to production of reactive oxygen species and free radicals both of which are associated with many disease states, oxidative stress and aging. RELEVANCE (See instructions): Reactive oxygen species and free radicals produced as by-products of biological electron transfer and oxygen metabolism damage cell components that cause many disease states, oxidative stress and aging. However, free radicals and reactive oxygen species are also used productively in biosynthetic processes. These studies describe how specific enzymes control the transfer of electrons and activate oxygen, while minimizing oxidative damage.


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: 2021 ( Subtotal = -$1 )
2021	2018	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CENTRAL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Biomedical Research and Research Training	000	31	1/30/2021	NON-COMPETING CONTINUATION	-$1
														Subtotal = -$1

Issue Date FY: 2018 ( Subtotal = $365,000 )
2018	2018	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CNTRL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Biomedical Research and Research Training	000	31	7/24/2018	NON-COMPETING CONTINUATION	$365,000
														Subtotal = $365,000

Issue Date FY: 2017 ( Subtotal = $365,000 )
2017	2017	UNIVERSITY OF CENTRAL FLORIDA BOARD OF TRUSTEES, THE	4000 CNTRL FLORIDA BLVD	ORLANDO	FL	32816	ORANGE	USA	Biomedical Research and Research Training	000	30	7/19/2017	NON-COMPETING CONTINUATION	$365,000
														Subtotal = $365,000

Issue Date FY: 2016 ( Subtotal = $365,000 )
2016	2016	UNIVERSITY OF CENTRAL FLORIDA	12201 RESEARCH PARKWAY	ORLANDO	FL	32826	ORANGE	USA	Biomedical Research and Research Training	000	29	7/19/2016	NON-COMPETING CONTINUATION	$365,000
														Subtotal = $365,000

Issue Date FY: 2015 ( Subtotal = $365,000 )
2015	2015	UNIVERSITY OF CENTRAL FLORIDA	12201 RESEARCH PARKWAY	ORLANDO	FL	32826	ORANGE	USA	Biomedical Research and Research Training	000	28	7/16/2015	NON-COMPETING CONTINUATION	$365,000
														Subtotal = $365,000

Issue Date FY: 2014 ( Subtotal = $365,000 )
2014	2014	UNIVERSITY OF CENTRAL FLORIDA	12201 RESEARCH PARKWAY	ORLANDO	FL	32826	ORANGE	USA	Biomedical Research and Research Training	000	27	7/23/2014	EXTENSION WITH OR WITHOUT FUNDS	$365,000
														Subtotal = $365,000

Issue Date FY: 2013 ( Subtotal = $308,568 )
2013	2013	UNIVERSITY OF CENTRAL FLORIDA	12201 RESEARCH PARKWAY	ORLANDO	FL	32826	ORANGE	USA	Biomedical Research and Research Training	000	26	7/11/2013	NON-COMPETING CONTINUATION	$308,568
														Subtotal = $308,568

Issue Date FY: 2012 ( Subtotal = $319,759 )
2012	2012	UNIVERSITY OF CENTRAL FLORIDA	12201 RESEARCH PARKWAY	ORLANDO	FL	32826	ORANGE	USA	Biomedical Research and Research Training	000	25	7/24/2012	NON-COMPETING CONTINUATION	$319,759
														Subtotal = $319,759

Issue Date FY: 2011 ( Subtotal = $319,759 )
2011	2011	UNIVERSITY OF CENTRAL FLORIDA	12201 RESEARCH PARKWAY	ORLANDO	FL	32826	ORANGE	USA	Biomedical Research and Research Training	000	24	7/29/2011	CHANGE OF GRANTEE / TRAINING INSTITUTION / AWARDING INSTITUTION	$319,759
														Subtotal = $319,759

Issue Date FY: 2010 ( Subtotal = $329,670 )
2010	2010	UNIVERSITY OF MISSISSIPPI MEDICAL CENTER	2500 NORTH STATE STREET	JACKSON	MS	39216	HINDS	USA	Biomedical Research and Research Training	000	23	7/30/2010	NON-COMPETING CONTINUATION	$329,670
														Subtotal = $329,670

Issue Date FY: 2009 ( Subtotal = $333,000 )
2009	2009	UNIVERSITY OF MISSISSIPPI MEDICAL CENTER	2500 NORTH STATE STREET	JACKSON	MS	39216	HINDS	USA	Biomedical Research and Research Training	000	22	7/27/2009	COMPETING CONTINUATION	$333,000
														Subtotal = $333,000

Grand Total All Awards = $3,435,755

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Structure Function & Biosynthesis of Respiratory Enzymes

Award Number: R37GM041574

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: 08/01/1988

PERIOD OF PERFORMANCE END DATE: 07/31/2020

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