The reaction path for the catalytic conversion of adenosine triphosphate (ATP) to. cyclic adenosine monophosphate (cAMP) by the enzyme mammalian adenylyl cyclase has been calculated theoretically using the Hartree-Fock method. The crystal structure of a thiophosphate reactant analogue, ATPalphaS, provides the basic structure of the active site binding that is then leveraged into the native reaction path by energy gradient optimization of protein binding residues and the ATP. A two-metal cluster bound to two aspartate residues and the ATP is important both structurally and catalytically. Autocatalytic activation of the reacting ribose 3'OH group is calculated in the reactant conformation but the catalytic MgA divalent cation binds to the developing 3'O anion and stabilizes the formation of a five-coordinate intermediate with the cyclic phosphate already formed. Changes in the coordination of the metals in the complex and the H-bonding of arginines that bridge the phosphate groups stabilize the reaction path complex from reactive intermediate to the product. Final transfer of the 3'H proton to the oxygen bridging the alpha and beta phosphate groups yields the cAMP and pyrophosphate product still bound by many H-bonds in the active site.