Two-metal-ion catalysis in adenylyl cyclase

Adenylyl cyclase (AC) converts adenosine triphosphate (ATP) to cyclic adeno sine monophosphate, a ubiquitous second messenger that regulates many cellu lar functions. Recent structural studies have revealed much about the struc ture and function of mammalian AC but have not fully defined its active sit e or catalytic mechanism. Four crystal structures were determined of the ca talytic domains of AC in complex with two different ATP analogs and various divalent metal ions. These structures provide a model for the enzyme-subst rate complex and conclusively demonstrate that two metal ions bind in the a ctive site. The similarity of the active site of AC to those of DNA polymer ases suggests that the enzymes catalyze phosphoryl transfer by the same two -metal-ion mechanism and likely have evolved from a common ancestor.