Arginine kinase activates Arginine for phosphorylation by pyramidalization and polarization

Falcioni, Fabio, Molt, Robert W., Jin, Yi, Waltho, Jonathan P., Hay, Sam, Richards, Nigel G. J. ORCID: https://orcid.org/0000-0002-0375-0881 and Blackburn, G. Michael 2024. Arginine kinase activates Arginine for phosphorylation by pyramidalization and polarization. ACS Catalysis 14 (9) , 6650–6658. 10.1021/acscatal.4c00380

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Abstract

Arginine phosphorylation plays numerous roles throughout biology. Arginine kinase (AK) catalyzes the delivery of an anionic phosphoryl group (PO3–) from ATP to a planar, trigonal nitrogen in a guanidinium cation. Density functional theory (DFT) calculations have yielded a model of the transition state (TS) for the AK-catalyzed reaction. They reveal a network of over 50 hydrogen bonds that delivers unprecedented pyramidalization and out-of-plane polarization of the arginine guanidinium nitrogen (Nη2) and aligns the electron density on Nη2 with the scissile P–O bond, leading to in-line phosphoryl transfer via an associative mechanism. In the reverse reaction, the hydrogen-bonding network enforces the conformational distortion of a bound phosphoarginine substrate to increase the basicity of Nη2. This enables Nη2 protonation, which triggers PO3– migration to generate ATP. This polarization–pyramidalization of nitrogen in the arginine side chain is likely a general phenomenon that is exploited by many classes of enzymes mediating the post-translational modification of arginine.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Advanced Research Computing @ Cardiff (ARCCA) Chemistry
Publisher:	American Chemical Society
ISSN:	2155-5435
Funders:	BBSRC, Wellcome Trust, EPSRC
Date of First Compliant Deposit:	3 May 2024
Date of Acceptance:	2 April 2024
Last Modified:	01 Jul 2024 12:25
URI:	https://orca.cardiff.ac.uk/id/eprint/168704

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