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Investigating neofunctionalized alpha-carbonic anhydrases as an emerging class of biosynthetic enzyme in plant and animal metabolism

Award Number: R35GM150908
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: 07/01/2023
PERIOD OF PERFORMANCE END DATE: 04/30/2028

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Investigating neofunctionalized alpha-carbonic anhydrases as an emerging class of biosynthetic enzyme in plant and animal metabolism - ABSTRACT Natural metabolic diversity is generated through the evolution of novel function in enzymes (neofunctionalization). Society uses this metabolic diversity to obtain many high-value chemicals, such as microbial and plant-derived pharmaceuticals, but harnessing this chemistry relies on discovery of the underlying biosynthetic machinery. While some biosynthetic enzymes are readily identifiable, there are many metabolic reactions with no defined enzyme family, and this acts as a roadblock to elucidating new metabolic pathways. My lab studies enzymes and chemical reactions from the natural world, with a focus on identifying biosynthetic genes and pathways in medicinal plants. We are particularly interested in finding new enzymes that expand the ‘catalog’ of known metabolic protein families. Recently, we identified several α-carbonic anhydrase (CAH)-like proteins that have neofunctionalized to catalyze novel scaffold-forming reactions in the biosynthesis of neuroactive plant compounds. While these are the first CAH family proteins shown to act as biosynthetic enzymes, we predict that neofunctionalized CAHs (neo-CAHs) have critical, undefined functions in metabolism more broadly. Over the next five years, my lab will advance a fundamental understanding of neo-CAHs by providing a mechanistic basis on their enzymatic function and by investigating the breadth and diversity of neo-CAH enzymes throughout nature. While canonical CAHs are very well-studied, the biochemical properties of neo-CAHs are yet to be defined. We will study the foundational biochemistry and catalytic mechanisms of the neo-CAHs through enzymatic characterization, structural biology, and analysis of native post-translational modifications and sub-cellular localization. This work will provide a mechanistic understanding of neo-CAH enzyme catalysis and will yield basic insight into novel chemistry used to produce bioactive plant molecules. Simultaneously, we will investigate the widespread occurrence of neo-CAHs throughout nature. Each neo-CAH identified thus far has mutations in conserved active site residues that are essential for canonical CAH function. Similar mutations are found in other uncharacterized CAH family proteins within plants, bacteria, and animals, suggesting that CAHs have unappreciated biosynthetic functions in multiple kingdoms of life. We will leverage these distinguishing mutations to identify and functionally characterize other neo-CAH enzymes - including homologs from medicinal plants, microbes, and humans - to better define the metabolic capacity of this protein family. Through this work, we will a) provide insight on a previously unknown class of metabolic enzyme that likely has broader biosynthetic roles in nature, and b) further determine how conserved enzymes can gain new function to yield the striking structural and functional diversity of natural metabolites.


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 = $415,824 )
2025	2025	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	3	7/10/2025	NON-COMPETING CONTINUATION	$415,824
														Subtotal = $415,824

Issue Date FY: 2024 ( Subtotal = $408,575 )
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	2	3/22/2024	NON-COMPETING CONTINUATION	$367,718
2024	2024	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE STE 3	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	001	2	7/29/2024	NON-COMPETING CONTINUATION	$40,857
														Subtotal = $408,575

Issue Date FY: 2023 ( Subtotal = $408,981 )
2023	2023	PRESIDENT AND FELLOWS OF HARVARD COLLEGE	1033 MASSACHUSETTS AVE 5TH FL	CAMBRIDGE	MA	02138	MIDDLESEX	USA	Biomedical Research and Research Training	000	1	6/23/2023	NEW	$408,981
														Subtotal = $408,981

Grand Total All Awards = $1,233,380

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Investigating neofunctionalized alpha-carbonic anhydrases as an emerging class of biosynthetic enzyme in plant and animal metabolism

Award Number: R35GM150908

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: 07/01/2023

PERIOD OF PERFORMANCE END DATE: 04/30/2028

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