Structure and Reaction in the Active Site of Mammalian Adenylyl Cyclase

Published

April 8, 2004

Author(s)

Y. S. Lee, Morris Krauss

Abstract

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, ATPaS, provides the basic structure of the active site binding that is then leveraged into the 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. Auto-catalytic activation of the reacting ribose 3'-OH group is calculated in the reactant conformation but the catalytic MgA divalent cation binds to the developing O3' anion and stabilizes the formation of a five-coordinate intermediate that already forms the cAMP molecule. Final transfer of the H3' proton to the oxygen bridging the a and b phosphate groups yields the product still bound by many hydrogen bonds in the active site.

Citation

Journal of Physical Chemistry B

Volume

108

Issue

14

Pub Type

Journals

Keywords

adenylyl cyclase, auto-catalysis, electrophilic metal assistance, reaction mechanism, substrate recognition, two-metal catalytic site

Citation

Lee, Y. and Krauss, M. (2004), Structure and Reaction in the Active Site of Mammalian Adenylyl Cyclase, Journal of Physical Chemistry B (Accessed February 8, 2026)