Transition State Analysis of SAMHD1 from Primary ¹⁸O, ³³P, and Solvent Kinetic Isotope Effects

Journal of the American Chemical Society, Journal Year: 2025, Volume and Issue: unknown

Published: Feb. 27, 2025

Human sterile alpha motif and HD-domain-containing protein 1 (SAMHD1) is an allosterically regulated dNTP triphosphohydrolase (dNTP + H2O → dNuc PPPi) involved in deoxynucleotide regulation DNA repair. We characterized the chemical features of SAMHD1 transition state for 2′-deoxyadenosine 5′-triphosphate (dATP) hydrolysis by analysis 18O 33P primary kinetic isotope effects (KIEs) at α-phosphoryl leaving triphosphate group. The intrinsic KIE values [5′-18O]dATP 1.028 ± 0.003 [α-33P]dATP 1.015 0.004 provide insights into mechanistic details state. Solvent 2H2O dATP indicate that a single proton being transferred to give solvent 3.2 0.1. Quantum matching supports concerted, loose, highly asymmetric DNAN with Pauling bond order 0.17 attacking hydroxide oxygen nucleophile 0.53 departing deoxyadenosine. reaction coordinate distance 4.7 Å from hydroxyl 5′-deoxyadenosine oxygen. consistent near-midpoint transfer His215 catalytic site donor deoxyadenosine 5′-oxygen This first be use effect characterize phosphotransferase

Language: Английский

New strategies to hit hematological cancers

European Journal of Medicinal Chemistry, Journal Year: 2024, Volume and Issue: 270, P. 116350 - 116350

Published: March 20, 2024

Language: Английский