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MOLECULAR STUDY OF PHA BIOSYNTHESIS: PRODUCTION OF BIODEGRADABLE POLYMERS FOR MEDICAL APPLICATIONS

Award Number: R01GM117259
ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES
OPDIV: NIH
AWARD CLASS: DISCRETIONARY
AWARD ACTIVITY TYPE: SCIENTIFIC/HEALTH RESEARCH (INCLUDES SURVEYS)

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Polyhydroxyalkanoates (PHAs) are polyoxoesters produced by a wide range of bacteria under nutrient-limited growth conditions except for carbon. Due to their excellent biocompatibility, biodegradability, and versatility, PHAs have been developed for various biomedical applications in medical devices, drug delivery, and tissue engineering. The FDA approved the first medical use of PHAs in 2009 as an absorbable suture under the trade name TephaFLEX. However, the high cost of PHA production has been an impediment to their further development and downstream commercialization. Our goal is to identify and understand the complete PHA biosynthetic machinery so that PHAs with defined properties can be produced economically. To facilitate this, the present proposal will focus on the PHA synthase (PhaC) and phasin protein (PhaP), which are key to both PHA production and the properties of the material produced. The specific aims are: (1) to characterize the mechanism of PhaC in PHA production and control of molecular weight (MW). We will investigate chain elongation of class I synthases that are much more challenging than the class III enzymes using multiple approaches involving enzymology, molecular biology, and synthetic chemistry. Efforts will also be made to look for the “additional factors” that are proposed to participate in the control of PHA MWs using genetically modified organisms. Protein-protein interactions will be identified through pull-down assays for strong interactions and by incorporating photoactive unnatural amino acids for weak interactions. The MW control by PhaC itself will also be studied in vitro through a synthetic analog or in vivo through identifying the residues involved in the chain termination/re-initiation processes; (2) to obtain structural information on PHA synthases through X-ray crystallography. In collaboration with Dr. Geisbrecht who is an accomplished crystallographer on the same campus, synthases from different bacterial sources will be purified and screened for crystallization in the absence and presence of ligands. Our preliminary results of co-crystallization with a nonhydrolyzable CoA analog have provided a clear path toward an initial PhaC structure. The availability of this X-ray structure will provide us with valuable insight on substrate recognition and enzyme mechanism as well as enabling our long- term goal of protein engineering; (3) to characterize roles of PhaP in PHA production and granule formation. The relationship of PhaC and PhaP will be characterized in vitro and in vivo using various binding assays and with Escherichia coli supplemented with a PHA biosynthetic pathway. Granule formation will be monitored in vivo for the first time through a combination of fluorescence microscopy and click-chemistry. Elucidating the roles and relationships of PhaC, PhaP, “additional factors” and granule (PHA) formation at the molecular level is of great importance to complete our understanding of PHA production. Ultimately, this will allow PHAs with defined properties to be economically produced for medical applications. Our results will also shed light on the widespread reactions of template-independent polymerizations where the mechanism remains enigmatic.


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 = $0 )
2024	2020	KANSAS STATE UNIVERSITY	1601 VATTIER STREET	MANHATTAN	KS	66506	RILEY	USA	Biomedical Research and Research Training	000	5	2/14/2024	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2022 ( Subtotal = $0 )
2022	2020	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Biomedical Research and Research Training	001	5	3/21/2022	SUPPLEMENT FOR EXPANSION	$0
2022	2020	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Biomedical Research and Research Training	000	5	3/21/2022	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2020 ( Subtotal = $375,561 )
2020	2020	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Biomedical Research and Research Training	001	5	9/3/2020	SUPPLEMENT FOR EXPANSION	$90,000
2020	2020	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Biomedical Research and Research Training	000	5	4/8/2020	NON-COMPETING CONTINUATION	$285,561
														Subtotal = $375,561

Issue Date FY: 2019 ( Subtotal = $406,711 )
2019	2019	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Biomedical Research and Research Training	001	4	6/17/2019	SUPPLEMENT FOR EXPANSION	$121,150
2019	2019	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Biomedical Research and Research Training	000	4	4/15/2019	NON-COMPETING CONTINUATION	$285,561
														Subtotal = $406,711

Issue Date FY: 2018 ( Subtotal = $385,561 )
2018	2018	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Biomedical Research and Research Training	001	3	8/29/2018	SUPPLEMENT FOR EXPANSION	$100,000
2018	2018	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Biomedical Research and Research Training	000	3	4/23/2018	NON-COMPETING CONTINUATION	$285,561
														Subtotal = $385,561

Issue Date FY: 2017 ( Subtotal = $285,561 )
2017	2017	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Biomedical Research and Research Training	001	2	6/15/2017	NON-COMPETING CONTINUATION	$28,555
2017	2017	KANSAS STATE UNIVERSITY	2 FAIRCHILD HALL	MANHATTAN	KS	66506	RILEY	USA	Biomedical Research and Research Training	000	2	4/24/2017	NON-COMPETING CONTINUATION	$257,006
														Subtotal = $285,561

Issue Date FY: 2016 ( Subtotal = $512,547 )
2016	2016	KANSAS STATE UNIVERSITY, AGRICULTURE & APPLIED SCIENCE	ANDERSON HALL ROOM 206	MANHATTAN	KS	66506	RILEY	USA	Biomedical Research and Research Training	000	1	5/5/2016	NEW	$337,547
2016	2016	KANSAS STATE UNIVERSITY, AGRICULTURE & APPLIED SCIENCE	ANDERSON HALL ROOM 206	MANHATTAN	KS	66506	RILEY	USA	Biomedical Research and Research Training	001	1	8/1/2016	SUPPLEMENT FOR EXPANSION	$175,000
														Subtotal = $512,547

Grand Total All Awards = $1,965,941

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MOLECULAR STUDY OF PHA BIOSYNTHESIS: PRODUCTION OF BIODEGRADABLE POLYMERS FOR MEDICAL APPLICATIONS

Award Number: R01GM117259

ORGANIZATION: NATIONAL INSTITUTE OF GENERAL MEDICAL SCIENCES

OPDIV: NIH

AWARD CLASS: DISCRETIONARY

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

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