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Deciphering the Principles of Membrane-Associated Glycan Assembly for Glycoconjugate Biosynthesis

Award Number: R01GM039334
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: 02/01/1988
PERIOD OF PERFORMANCE END DATE: 02/28/2026

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Deciphering the Principles of Membrane-Associated Glycan Assembly for Glycoconjugate Biosynthesis - Metabolons are non-covalent complexes of enzymes that play crucial roles in primary and secondary metabolism. Such supramolecular complexes carry out a series of reactions in a pathway while protecting intermediates from diffusion into the bulk phase and promoting product channeling. This mechanism increases reaction efficiency and fidelity and protects labile intermediates. Although there has been tremendous progress in understanding the structures and functions of soluble metabolons, the study of membrane-associated metabolons is complicated by the extra dimensions added by membrane and lipidic substrates. A membrane- associated metabolon of significance is the eukaryotic dolichol pathway in which the dolichol diphosphate-linked glycan for asparagine (N)-linked of glycosylation is assembled. Bacterial glycoproteins in the epsilon proteobacteria including Campylobacter, are also generated through stepwise, membrane-associated pathways and culminate in the biosynthesis of important virulence-associated glycoproteins. Study of the bacterial pathway and extensive genomic information from Campylobacter, providing data on the enzymes and substrates in vivo across >50 discrete genera, adds a important dimension to our studies as operon order is highly conserved but, glycan output varies and there is considerable sequence divergence. Development of systematic approaches for investigating the pgl pathways will provide a valuable template for future studies on important multistep biological processes occurring at the membrane. Despite the importance of such pathways, our understanding of how the enzymes function, and whether as a metabolon or in a distributed fashion with diffusion of substrates/products between enzymes is limited. It is also unknown how the GT-B fold, common to most pgl glycosyltransferases (GTs) leads to function and substrate selectivity, as the similarity of active-site residues does not lead to a clear structure/function view, or account for the impact of the interaction of enzymes or substrates with the membrane. The research has three aims. In Aim 1, PglA, J, H1 and H2 from the C. concisus glycan assembly metabolon will be investigated via X-ray structure determination of complexes with UDP-sugar and PrenPP-sugar substrates, ligand binding and kinetic analysis, MD simulations and membrane association determination in model membrane (styrene maleic acid lipoparticles). In Aim 2, we will predict and validate protein-protein and protein-membrane interactions, determine the effect of protein-protein interactions on pathway flux and test for product channeling. Aim 3 will generate sequence similarity networks and genome neighborhood diagrams to identify orthologs in divergent species to identify structural elements governing membrane and membrane-bound substrate interactions. We will also investigate why a GT-A fold (GT) is recruited to perform the ultimate biosynthetic step. If successful, the research will provide a newly proposed paradigm for specificity established by membrane interactions and the approaches to enable study of other membrane-resident biosynthesis pathways.


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 = $413,929 )
2025	2025	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	001	36	8/12/2025	NON-COMPETING CONTINUATION	$41,393
2025	2025	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	36	2/17/2025	NON-COMPETING CONTINUATION	$372,536
														Subtotal = $413,929

Issue Date FY: 2024 ( Subtotal = $413,929 )
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	35	2/6/2024	NON-COMPETING CONTINUATION	$372,536
2024	2024	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	001	35	7/16/2024	NON-COMPETING CONTINUATION	$41,393
														Subtotal = $413,929

Issue Date FY: 2023 ( Subtotal = $413,929 )
2023	2023	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	34	2/17/2023	NON-COMPETING CONTINUATION	$413,929
														Subtotal = $413,929

Issue Date FY: 2022 ( Subtotal = $427,704 )
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	004	33	8/28/2022	COMPETING CONTINUATION	$82,129
2022	2022	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	002	33	3/11/2022	COMPETING CONTINUATION	$427,704
2022	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	003	32	8/28/2022	NON-COMPETING CONTINUATION	-$82,129
2022	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	32	2/3/2022	NON-COMPETING CONTINUATION	$0
2022	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	001	32	3/11/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $427,704

Issue Date FY: 2020 ( Subtotal = $349,740 )
2020	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	001	32	3/3/2020	NON-COMPETING CONTINUATION	$34,974
2020	2020	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	32	1/28/2020	NON-COMPETING CONTINUATION	$314,766
														Subtotal = $349,740

Issue Date FY: 2019 ( Subtotal = $349,064 )
2019	2019	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	31	1/24/2019	NON-COMPETING CONTINUATION	$349,064
														Subtotal = $349,064

Issue Date FY: 2018 ( Subtotal = $348,408 )
2018	2018	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	30	1/18/2018	NON-COMPETING CONTINUATION	$313,567
2018	2018	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	001	30	5/23/2018	NON-COMPETING CONTINUATION	$34,841
														Subtotal = $348,408

Issue Date FY: 2017 ( Subtotal = $347,770 )
2017	2017	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	002	29	8/31/2017	COMPETING CONTINUATION	$18,572
2017	2017	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	29	3/28/2017	COMPETING CONTINUATION	$347,770
2017	2015	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASSACHUSETTS AVE	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	001	28	8/31/2017	NON-COMPETING CONTINUATION	-$18,572
														Subtotal = $347,770

Issue Date FY: 2015 ( Subtotal = $421,045 )
2015	2015	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	28	3/20/2015	NON-COMPETING CONTINUATION	$421,045
														Subtotal = $421,045

Issue Date FY: 2014 ( Subtotal = $411,770 )
2014	2014	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	001	27	4/18/2014	SUPPLEMENT FOR EXPANSION	$85,340
2014	2014	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	27	4/16/2014	NON-COMPETING CONTINUATION	$326,430
														Subtotal = $411,770

Issue Date FY: 2013 ( Subtotal = $313,700 )
2013	2013	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	001	26	6/21/2013	NON-COMPETING CONTINUATION	$21,130
2013	2013	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	26	3/14/2013	NON-COMPETING CONTINUATION	$292,570
														Subtotal = $313,700

Issue Date FY: 2012 ( Subtotal = $313,182 )
2012	2012	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	25	3/30/2012	COMPETING CONTINUATION	$313,182
														Subtotal = $313,182

Issue Date FY: 2010 ( Subtotal = $334,366 )
2010	2010	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	000	24	8/23/2010	NON-COMPETING CONTINUATION	$334,366
														Subtotal = $334,366

Issue Date FY: 2009 ( Subtotal = $326,954 )
2009	2009	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Trans-NIH Recovery Act Research Support	000	23	9/8/2009	COMPETING CONTINUATION	$326,954
														Subtotal = $326,954

Issue Date FY: 2008 ( Subtotal = $317,909 )
2008	2008	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	22	2/29/2008	NON-COMPETING CONTINUATION	$317,909
														Subtotal = $317,909

Issue Date FY: 2007 ( Subtotal = $318,679 )
2007	2007	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	21	2/28/2007	NON-COMPETING CONTINUATION	$318,679
														Subtotal = $318,679

Issue Date FY: 2006 ( Subtotal = $328,959 )
2006	2006	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	20	2/17/2006	NON-COMPETING CONTINUATION	$328,959
														Subtotal = $328,959

Issue Date FY: 2005 ( Subtotal = $322,869 )
2005	2005	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	000	19	3/11/2005	COMPETING CONTINUATION	$322,869
														Subtotal = $322,869

Issue Date FY: 2004 ( Subtotal = $121,091 )
2004	2004	MASSACHUSETTS INSTITUTE OF TECHNOLOGY	77 MASS AVE, BLDG E19-583	CAMBRIDGE	MA	02139	MIDDLESEX	USA	Biomedical Research and Research Training	001	18	8/23/2004	SUPPLEMENT FOR EXPANSION	$121,091
														Subtotal = $121,091

Grand Total All Awards = $8,546,287

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Deciphering the Principles of Membrane-Associated Glycan Assembly for Glycoconjugate Biosynthesis

Award Number: R01GM039334

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: 02/01/1988

PERIOD OF PERFORMANCE END DATE: 02/28/2026

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