Metal-Pyridoxal Cooperativity in Nonenzymatic Transamination

Coenzymes are involved in ≥30% of enzymatic reactions and likely predate enzymes, going back to prebiotic chemistry. However, they are considered poor organocatalysts, and thus their pre-enzymatic function remains unclear. Since metal ions are known to catalyze metabolic reactions in the absence of enzymes, here we explore the influence of metal ions on coenzyme catalysis under conditions relevant to the origin of life (20-75 °C, pH 5-7.5). Specifically, Fe or Al, the two most abundant metals in the Earth's crust, were found to exhibit substantial cooperative effects in transamination reactions catalyzed by pyridoxal (PL), a coenzyme scaffold used by roughly 4% of all enzymes. At 75 °C and 7.5 mol % loading of PL/metal ion, Fe3+-PL was found to be 90-fold faster at catalyzing transamination than PL alone and 174-fold faster than Fe3+ alone, whereas Al3+-PL was 85-fold faster than PL alone and 38-fold faster than Al3+ alone. Under milder conditions, reactions catalyzed by Al3+-PL were >1000 times faster than those catalyzed by PL alone. Pyridoxal phosphate (PLP) exhibited similar behavior to PL. Experimental and theoretical mechanistic studies indicate that the rate-determining step in the PL-metal-catalyzed transamination is different from metal-free and biological PL-based catalysis. Metal coordination to PL lowers the pKa of the PL-metal complex by several units and slows the hydrolysis of imine intermediates by up to 259-fold. Coenzymes, specifically pyridoxal derivatives, could have exhibited useful catalytic function even before enzymes.