Metal-Pyridoxal Cooperativity in Nonenzymatic Transamination

Coenzymes are involved in >= 30% of enzymatic reactionsandlikely predate enzymes, going back to prebiotic chemistry. However,they are considered poor organocatalysts, and thus their pre-enzymaticfunction remains unclear. Since metal ions are known to catalyze metabolicreactions in the absence of enzymes, here we explore the influenceof metal ions on coenzyme catalysis under conditions relevant to theorigin of life (20-75 degrees 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 transaminationreactions catalyzed by pyridoxal (PL), a coenzyme scaffold used byroughly 4% of all enzymes. At 75 degrees C and 7.5 mol % loading ofPL/metal ion, Fe3+-PL was found to be 90-fold faster atcatalyzing transamination than PL alone and 174-fold faster than Fe3+ alone, whereas Al3+-PL was 85-fold faster thanPL alone and 38-fold faster than Al3+ alone. Under milderconditions, reactions catalyzed by Al3+-PL were >1000timesfaster than those catalyzed by PL alone. Pyridoxal phosphate (PLP)exhibited similar behavior to PL. Experimental and theoretical mechanisticstudies indicate that the rate-determining step in the PL-metal-catalyzedtransamination is different from metal-free and biological PL-basedcatalysis. Metal coordination to PL lowers the pK (a) of the PL-metal complex by several units and slows thehydrolysis of imine intermediates by up to 259-fold. Coenzymes, specificallypyridoxal derivatives, could have exhibited useful catalytic functioneven before enzymes.