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J Biol Chem, Vol. 273, Issue 31, 19650-19655, July 31, 1998
From the Department of Biological Chemistry, University of Michigan
Medical School, Ann Arbor, Michigan 48109-0636
The recent determination of the crystal structure
of adenylyl cyclase has elucidated many structural features that
determine the regulatory properties of the enzyme. In addition, the
characterization of adenylyl cyclase by mutagenic techniques and the
identification of the binding site for P-site inhibitors have led to
modeling studies that describe the ATP-binding site. Despite these
advances, the catalytic mechanism of adenylyl cyclase remains
uncertain, especially with respect to the role that magnesium ions may
play in this process. We have identified four mutant mammalian adenylyl cyclases defective in their metal dependence, allowing us to further characterize the function of metal ions in the catalytic mechanism of
this enzyme. The wild-type adenylyl cyclase shows a biphasic Mg2+ dose-response curve in which the high-affinity
component displays cooperativity (Hill coefficient of 1.4). Two
mutations (C441R and Y442H) reduce the affinity of the adenylyl cyclase
for Mg2+ dramatically without affecting the binding of
MgATP, suggesting that there is a metal requirement in addition to the
ATP-bound Mg2+. The results of this study thus demonstrate
multiple metal requirements of adenylyl cyclase and support the
existence of a Mg2+ ion essential for catalysis and
distinct from the ATP-bound ion. We propose that adenylyl cyclase
employs a catalytic mechanism analogous to that of DNA polymerase, in
which two key magnesium ions facilitate the nucleophilic attack of the
3'-hydroxyl group and the subsequent elimination of
pyrophosphate.
Mutations Uncover a Role for Two Magnesium Ions in the Catalytic
Mechanism of Adenylyl Cyclase
Copyright © 1998 by The American Society for Biochemistry and Molecular Biology, Inc.
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