Acetyl-coenzyme A synthase:: the case for a Nip0-based mechanism of catalysis

Acetyl-CoA synthase (also known as carbon monoxide dehydrogenase) is a bifunctional Ni-Fe-S-containing enzyme that catalyzes the reversible reduction of CO2 to CO and the synthesis of acetyl-coenzyme A from CO, CoA, and a methyl group donated by a corrinoid iron-sulfur protein. The active site for the latter reaction, called the A-cluster, consists of an Fe4S4 cubane bridged to the proximal Ni site (Ni-p), which is bridged in turn to the so-called distal Ni site. In this review, evidence is presented that Ni-p achieves a zero-valent state at low potentials and during catalysis. Ni-p appears to be the metal to which CO and methyl groups bind and then react to form an acetyl-Ni-p intermediate. Methyl group binding requires reductive activation, where two electrons reduce some site on the A-cluster. The coordination environment of the distal Ni suggests that it could not be stabilized in redox states lower than 2+. The rate at which the [Fe4S4](2+) cubane is reduced is far slower than that at which reductive activation occurs, suggesting that the cubane is not the site of reduction. An intriguing possibility is that Ni-p(2+) might be reduced to the zero-valent state. Reinforcing this idea are Ni-organometallic complexes in which the Ni exhibits analogous reactivity properties when reduced to the zero-valent state. A zero-valent Ni stabilized exclusively with biological ligands would be remarkable and unprecedented in biology.