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Two-metal-Ion catalysis in adenylyl cyclase
J J Tesmer1, R K Sunahara, R A Johnson
1Howard Hughes Medical Institute, Department of Biochemistry, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75235-9050, USA.
Science (New York, N.Y.)
|July 31, 1999
Summary
Adenylyl cyclase (AC) uses a two-metal-ion mechanism for ATP conversion, similar to DNA polymerases. Structural studies reveal AC's active site, offering insights into its catalytic function and evolutionary origins.
Area of Science:
- Biochemistry
- Molecular Biology
- Enzymology
Background:
- Adenylyl cyclase (AC) synthesizes cyclic adenosine monophosphate (cAMP), a crucial second messenger regulating diverse cellular processes.
- While mammalian AC structure is partly known, its active site and catalytic mechanism remain incompletely defined.
Purpose of the Study:
- To elucidate the active site structure and catalytic mechanism of adenylyl cyclase.
- To investigate the role of metal ions in AC enzymatic activity.
Main Methods:
- Determined four crystal structures of AC catalytic domains.
- Complexed AC with ATP analogs and various divalent metal ions.
Main Results:
- Provided a detailed model of the enzyme-substrate complex for AC.
- Conclusively demonstrated the binding of two metal ions within the AC active site.
- Identified structural similarities between the AC active site and those of DNA polymerases.
Conclusions:
- The two-metal-ion mechanism is central to AC's catalytic activity.
- AC and DNA polymerases likely share a common evolutionary ancestor due to conserved active site structures and catalytic mechanisms.
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