Sunday, September 15, 2024 9/15/2024

Transformylase Enzymes Dihydrofolate Reductase

Award Number: R01GM024129
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Project Summary/Abstract Combining isotopic labeling and gas cluster ion beam surface ionization mass spectrometry (GCIB-SIMS), we found the purinosome metabolon consists of nine enzymes that channel phosphoribosyl pyrophosphate to AMP and GMP. The metabolon greatly increases the pathway flux and unexpectedly favors partitioning of IMP to AMP. Chemical imaging of the cell revealed “hot spots” of these metabolites. We presume that these are located at the microtubule/mitochondrion interface based on temporal fluorescent imaging that found a directional movement of the purinosome along the microtubules to the mitochondria. We uncovered two mechanisms that govern purinosome assembly. One involves the participation of the chaperones HSP90/70 that act to fold two nascent enzymes prior to their incorporation into the purinosome. A second involves the multiple phosphorylation that occurs on the majority of the pathway enzymes upon purinosome assembly. We plan to exploit the unique isotopic labeling pattern that signals the presence of a functional purinosome to survey human cell lines to ascertain the generality of this metabolon at endogenous levels. By extending our chemical imaging capabilities, we will show that the cellular “hot spots” are loci of the pathway enzymes and their respective metabolites. The determination of the actual number of enzyme copies within a purinosome will be undertaken with a novel application of STORM. The actual organization of the metabolon will be probed by a combination of intracellular photo- and enzyme- specific crosslinking. We will resort to APEX to validate the identity of nearest neighbors within the purinosome and to discover other adjacent proteins that emanate from nearby structures such as the mitochondrial membrane. Through a collaborative effort, cell lines that use a functioning purinosome for purine synthesis will be examined in cells and in xenografts to ascertain the metabolic requirements and the advantage of the metabolon for cellular proliferation. The proposed studies have important ramifications for characterizing the importance of the purinosome to human cell viability.


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: 2024 ( Subtotal = $329,025 )
2024	2024	THE PENNSYLVANIA STATE UNIVERSITY	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	43	4/26/2024	NON-COMPETING CONTINUATION	$329,025
														Subtotal = $329,025

Issue Date FY: 2023 ( Subtotal = $329,025 )
2023	2023	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	42	3/21/2023	NON-COMPETING CONTINUATION	$329,025
														Subtotal = $329,025

Issue Date FY: 2022 ( Subtotal = $329,025 )
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	41	5/17/2022	NON-COMPETING CONTINUATION	$32,906
2022	2022	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	41	3/14/2022	NON-COMPETING CONTINUATION	$296,119
2022	2021	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	003	40	5/27/2022	COMPETING CONTINUATION	$37,517
2022	2020	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	002	39	5/27/2022	NON-COMPETING CONTINUATION	-$37,517
														Subtotal = $329,025

Issue Date FY: 2021 ( Subtotal = $329,025 )
2021	2021	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	40	2/16/2021	COMPETING CONTINUATION	$329,025
														Subtotal = $329,025

Issue Date FY: 2020 ( Subtotal = $258,885 )
2020	2020	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	39	3/13/2020	NON-COMPETING CONTINUATION	$258,885
														Subtotal = $258,885

Issue Date FY: 2019 ( Subtotal = $258,885 )
2019	2019	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	38	3/26/2019	NON-COMPETING CONTINUATION	$258,885
														Subtotal = $258,885

Issue Date FY: 2018 ( Subtotal = $258,885 )
2018	2018	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	002	37	7/16/2018	NON-COMPETING CONTINUATION	$25,890
2018	2018	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	37	3/8/2018	NON-COMPETING CONTINUATION	$232,995
2018	2015	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	35	11/11/2017	NON-COMPETING CONTINUATION	$0
														Subtotal = $258,885

Issue Date FY: 2017 ( Subtotal = $258,885 )
2017	2017	PENNSYLVANIA STATE UNIVERSITY, THE	201 OLD MAIN	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	36	6/30/2017	COMPETING CONTINUATION	$258,885
														Subtotal = $258,885

Issue Date FY: 2015 ( Subtotal = $223,500 )
2015	2015	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	35	5/6/2015	NON-COMPETING CONTINUATION	$223,500
														Subtotal = $223,500

Issue Date FY: 2014 ( Subtotal = $223,500 )
2014	2014	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	34	5/20/2014	NON-COMPETING CONTINUATION	$223,500
														Subtotal = $223,500

Issue Date FY: 2013 ( Subtotal = $215,678 )
2013	2013	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	33	5/24/2013	NON-COMPETING CONTINUATION	$215,678
														Subtotal = $215,678

Issue Date FY: 2012 ( Subtotal = $223,500 )
2012	2012	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	31	5/14/2012	SUPPLEMENT FOR EXPANSION	$60,849
2012	2012	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	004	31	8/31/2012	SUPPLEMENT FOR EXPANSION	$0
2012	2012	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	003	32	8/31/2012	COMPETING CONTINUATION	$162,651
2012	2011	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	31	5/14/2012	NON-COMPETING CONTINUATION	$0
2012	2011	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	002	31	8/29/2012	NON-COMPETING CONTINUATION	$0
														Subtotal = $223,500

Issue Date FY: 2011 ( Subtotal = $181,319 )
2011	2011	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	31	3/2/2011	NON-COMPETING CONTINUATION	$164,835
2011	2011	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	001	31	6/7/2011	NON-COMPETING CONTINUATION	$16,484
														Subtotal = $181,319

Issue Date FY: 2010 ( Subtotal = $183,150 )
2010	2010	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	30	3/18/2010	NON-COMPETING CONTINUATION	$183,150
														Subtotal = $183,150

Issue Date FY: 2009 ( Subtotal = $184,844 )
2009	2009	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	29	4/13/2009	COMPETING CONTINUATION	$184,844
														Subtotal = $184,844

Issue Date FY: 2004 ( Subtotal = $281,197 )
2004	2004	PENNSYLVANIA STATE UNIVERSITY	313 RIDER BUILDING	UNIVERSITY PARK	PA	16801		USA	Biomedical Research and Research Training	000	28	6/21/2004	NON-COMPETING CONTINUATION	$281,197
														Subtotal = $281,197

Issue Date FY: 2003 ( Subtotal = $281,243 )
2003	2003	PENNSYLVANIA STATE UNIVERSITY	313 RIDER BUILDING	UNIVERSITY PARK	PA	16801		USA	Biomedical Research and Research Training	000	27	6/23/2003	NON-COMPETING CONTINUATION	$281,243
														Subtotal = $281,243

Issue Date FY: 2002 ( Subtotal = $281,289 )
2002	2002	PENNSYLVANIA STATE UNIVERSITY	313 RIDER BUILDING	UNIVERSITY PARK	PA	16801		USA	Biomedical Research and Research Training	000	26	6/26/2002	NON-COMPETING CONTINUATION	$281,289
														Subtotal = $281,289

Issue Date FY: 2001 ( Subtotal = $281,333 )
2001	2001	PENNSYLVANIA STATE UNIVERSITY	313 RIDER BUILDING	UNIVERSITY PARK	PA	16801		USA	Biomedical Research and Research Training	000	25	6/4/2001	COMPETING CONTINUATION	$281,333
														Subtotal = $281,333

Issue Date FY: 2000 ( Subtotal = $260,359 )
2000	2000	PENNSYLVANIA STATE UNIVERSITY	110 TECHNOLOGY CENTER BUILDING	UNIVERSITY PARK	PA	16802	CENTRE	USA	Biomedical Research and Research Training	000	24	8/7/2000	NON-COMPETING CONTINUATION	$260,359
														Subtotal = $260,359

Grand Total All Awards = $5,672,684

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Transformylase Enzymes Dihydrofolate Reductase

Award Number: R01GM024129

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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