Exploring the ascorbate requirement of the 2-oxoglutarate-dependent dioxygenases

Smith-Díaz, Carlos C., Das, Andrew B., Jurkowski, Tomasz P. ORCID: https://orcid.org/0000-0002-2012-0240, Hore, Timothy A. and Vissers, Margreet C. M. 2025. Exploring the ascorbate requirement of the 2-oxoglutarate-dependent dioxygenases. Journal of Medicinal Chemistry 68 (3) , pp. 2219-2237. 10.1021/acs.jmedchem.4c02342

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Abstract

In humans, the 2-oxoglutarate-dependent dioxygenases (2-OGDDs) catalyze hydroxylation reactions involved in cell metabolism, the biosynthesis of small molecules, DNA and RNA demethylation, the hypoxic response and the formation of collagen. The reaction is catalyzed by a highly oxidizing ferryl-oxo species produced when the active site non-heme iron engages molecular oxygen. Enzyme activity is specifically stimulated by l-ascorbic acid (ascorbate, vitamin C), an effect not well mimicked by other reducing agents. In this perspective article we discuss the reliance of the 2-OGDDs on ascorbate availability. We draw upon findings from studies with different 2-OGDDs to piece together a comprehensive theory for the specific role of ascorbate in supporting enzyme activity. Our discussion centers on the capacity for ascorbate to act as an efficient radical scavenger and its propensity to reduce and chelate transition metals. In addition, we consider the evidence supporting stereospecific binding of ascorbate in the enzyme active site.

Item Type:	Article
Status:	Published
Schools:	Biosciences
Additional Information:	License information from Publisher: LICENSE 1: URL: https://creativecommons.org/licenses/by-nc-nd/4.0/, Start Date: 2025-01-30
Publisher:	American Chemical Society
ISSN:	0022-2623
Date of First Compliant Deposit:	13 February 2025
Date of Acceptance:	16 January 2025
Last Modified:	13 Feb 2025 16:45
URI:	https://orca.cardiff.ac.uk/id/eprint/176174

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