Calcium ions as catalysts: Quantum chemical and experimental study of creatine cyclization to creatinine.

Creatine acts as a crucial energy carrier in the cardiac muscle, facilitating the transport of phosphate from mitochondria to myofibrils for ATP regeneration. However, creatine spontaneously undergoes non-enzymatic cyclization to creatinine. The molecular mechanisms of this reaction remain poorly understood, particularly in the presence of calcium ions, which accumulate during myocardial ischemia. We employed quantum chemical calculations using DFT/MN15/Def2-TZVP methodology with PCM solvent modeling to investigate creatine cyclization paths under various conditions: intramolecular, with water molecules, in the presence of Ca2+, K+ and Mg2+ ions. Experimental validation was performed using in situ UV-Vis microfluidimetry. Quantum chemical analysis revealed that Ca2+ ions act as catalytic agents, dramatically reducing the energy barrier for creatine cyclization. The most favorable path involves Ca2+ coordination of water molecules near the reaction center, facilitating both cyclization and water elimination steps. The Mg2+ ion act as cyclization protector, competing with Ca2+ for binding site and preventing the kinetic barriers diminishing. Experimental studies confirmed a 13% increase in conversion rate in the presence of Ca2+ ions, supporting the theoretical predictions. Our findings demonstrate that elevated intracellular Ca2+ concentrations, common during myocardial ischemia and tachycardia, significantly accelerate creatine cyclization, potentially contributing to cardiac energy depletion. This mechanistic insight suggests a necessary of the monitoring the Mg2+ level in patients with pre-ischemia or heart chronic diseases.