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Mechanistic Studies of a Bacterial Capsule Polymerase

Award Number: SC2GM125517
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: 07/26/2018
PERIOD OF PERFORMANCE END DATE: 05/31/2022

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Mechanistic Studies of a Bacterial Capsule Polymerase - PROJECT SUMMARY This proposal seeks to investigate catalysis of a capsule polymerase enzyme from Neisseria meningitidis, one of the leading bacterial causes of meningitis. This capsule around the bacteria is rich in polysaccharides. Serogroup-specific enzymes are responsible for synthesis of these carbohydrates. The capsule enzymes that synthesize polymers of a single sugar have been well studied compared to those that synthesize polymers containing two different sugars. As a result, much less is known about catalysis by these heteropolymeric capsule polymerase enzymes. This class of enzymes provides one target for vaccine research and drug development. The overall goal of this work is to develop an understanding of the Neisseria meningitidis serogroup W capsule polymerase enzyme which makes a polysaccharide containing alternate repeats of two different sugars. Our goal in this work is to perform series of fundamental experiments that will provide insight into this enzyme's mechanism. This goal will be accomplished by the following specific aims: Aim 1: Determine the kinetics of catalysis by the N. meningitidis serogroup W capsule polymerase. We will perform kinetics measurements using an HPLC-based fluorescent assay. To carry out this assay, we will first define optimal fluorescent acceptors. The knowledge gained from completion of this aim (kinetic parameters [Km, Vmax, kcat] of the enzyme that are currently unknown), will provide important insight into catalytic rates and mechanism. Aim 2: Determine key amino acids critical to N. meningitidis serogroup W capsule polymerase catalysis. We will chemoenzymatically synthesize a photoactivatable substrate analog, CMP-SiaDAz, which will be used to achieve photoactivated labeling of binding site residues. We will determine the location of modified amino acids by mass spectrometry analysis and perform activity assay of mutant forms of the protein. The knowledge gained will provide new insight into substrate recognition and binding during enzyme catalysis. Aim 3: Use chain-terminating nucleotide sugar donors to rationally control polysaccharide synthesis. We will react modified nucleotide donor sugars with the enzyme under various conditions and assess polysaccharide composition/chain length. Completion of this aim will reveal how this enzyme can react with alternate substrates leading to new potential enzyme inhibitors.


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: 2023 ( Subtotal = -$38,850 )
2023	2020	MORGAN STATE UNIVERSITY	1700 E COLD SPRING LN	BALTIMORE	MD	21251	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	3	11/15/2022	NON-COMPETING CONTINUATION	-$38,850
														Subtotal = -$38,850

Issue Date FY: 2020 ( Subtotal = $151,000 )
2020	2020	MORGAN STATE UNIVERSITY	1700 E COLD SPRING LN	BALTIMORE	MD	21251	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	3	5/19/2020	NON-COMPETING CONTINUATION	$151,000
														Subtotal = $151,000

Issue Date FY: 2019 ( Subtotal = $151,000 )
2019	2019	MORGAN STATE UNIVERSITY	1700 E COLD SPRING LN	BALTIMORE	MD	21251	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	2	6/4/2019	NON-COMPETING CONTINUATION	$151,000
														Subtotal = $151,000

Issue Date FY: 2018 ( Subtotal = $138,855 )
2018	2018	MORGAN STATE UNIVERSITY	1700 E COLD SPRING LN	BALTIMORE	MD	21251	BALTIMORE CITY	USA	Biomedical Research and Research Training	000	1	7/26/2018	NEW	$138,855
														Subtotal = $138,855

Grand Total All Awards = $402,005

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Mechanistic Studies of a Bacterial Capsule Polymerase

Award Number: SC2GM125517

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: 07/26/2018

PERIOD OF PERFORMANCE END DATE: 05/31/2022

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