Abstract
Half-of-sites reactivity in many homodimeric and homotetrameric metalloenzymes has been known for half a century, yet its benefit remains poorly understood. A recently reported cryo-electron microscopy structure has given some clues on the less optimized reactivity of Escherichia coli ribonucleotide reductase with an asymmetric association of α2β2 subunits during catalysis. Moreover, nonequivalence of enzyme active sites has been reported in many other enzymes, possibly as a means of regulation. They are often induced by substrate binding or caused by a critical component introduced from a neighboring subunit in response to substrate loadings, such as in prostaglandin endoperoxide H synthase, cytidine triphosphate synthase, glyoxalase, tryptophan dioxygenase, and several decarboxylases or dehydrogenases. Overall, half-of-sites reactivity is likely not an act of wasting resources but rather a method devised in nature to accommodate catalytic or regulatory needs.