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Mechanistic studies to enable rational design Class D monooxygenases

Award Number: SC3GM122652
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: 09/15/2018
PERIOD OF PERFORMANCE END DATE: 07/31/2024

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Mechanistic studies to enable rational design Class D monooxygenases - PROJECT SUMMARY / ABSTRACT With the emergence of bacterial resistance, identification of new diseases, and the need for new therapeutics with different efficacies, our ability to design new drugs is becoming a more urgent priority. Natural products are often useful as therapeutics for humans, though problems such as side effects and production difficulties can preclude their successful development. This proposal seeks to enable development of therapeutics through synthetic biology methods, in which the molecule's biosynthetic pathway is engineered in order to alter the product. The Class D flavin monooxygenases are found in numerous natural product biosynthetic pathways, including those of valanimycin and daunorubicin, two medicinally useful natural products. With this research we hope to make the Class D flavin monooxygenases of these representative biosynthetic pathways amenable to engineering for synthetic biology purposes. The enzyme-catalyzed step of interest here is a biosynthetic step common to multiple natural products – flavin-dependent hydroxylation of a primary amine. The enzymes responsible for this step in the two biosynthetic pathways – vlmH and DnmZ, respectively – will be biochemically characterized using transient- state kinetics. Site-directed mutagenesis of active site residues will be combined with enzymatic activity and binding studies to validate mechanistic steps and substrate binding interactions. The effect of changes in the substrate binding site on the kinetics of intermediate formation will be investigated for use in validating modifications to the enzyme's substrate specificity. The data yielded will enable rational design of vlmH and DnmZ to alter their substrate binding preferences. Similar studies can be applied to other enzymes of the pathways to introduce diversity into the molecules' final structures.


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 = -$11,201 )
2025	2021	THE UNIVERSITY CORPORATION	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	3/12/2025	NON-COMPETING CONTINUATION	-$11,201
														Subtotal = -$11,201

Issue Date FY: 2023 ( Subtotal = $0 )
2023	2021	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	8/3/2023	NON-COMPETING CONTINUATION	$0
														Subtotal = $0

Issue Date FY: 2021 ( Subtotal = $108,750 )
2021	2021	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	4	7/29/2021	NON-COMPETING CONTINUATION	$108,750
														Subtotal = $108,750

Issue Date FY: 2020 ( Subtotal = $105,150 )
2020	2020	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	3	7/28/2020	NON-COMPETING CONTINUATION	$105,150
														Subtotal = $105,150

Issue Date FY: 2019 ( Subtotal = $105,150 )
2019	2019	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	2	7/11/2019	NON-COMPETING CONTINUATION	$105,150
														Subtotal = $105,150

Issue Date FY: 2018 ( Subtotal = $102,900 )
2018	2018	UNIVERSITY CORPORATION, THE	18111 NORDHOFF ST	NORTHRIDGE	CA	91330	LOS ANGELES	USA	Biomedical Research and Research Training	000	1	9/12/2018	NEW	$102,900
														Subtotal = $102,900

Grand Total All Awards = $410,749

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Mechanistic studies to enable rational design Class D monooxygenases

Award Number: SC3GM122652

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: 09/15/2018

PERIOD OF PERFORMANCE END DATE: 07/31/2024

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