Abstract
The discovery of 39,59-cyclic adenosine monophosphate (cAMP) in the late 1950s by Sutherland and co-workers was the pivotal event that led to our current paradigm of hormone signaling through second messengers. Despite the subsequent discovery of many other second messengers, cAMP has never left center stage. The adenylyl cyclases are the family of enzymes that synthesize cAMP (1–5). Breakthroughs in determining the first structures of the mammalian adenylyl cyclase catalytic core (6, 7) provide a new context for understanding the action of many regulators, both physiological and pharmacological: free metal ions, P-site inhibitors, forskolin, G-proteins, Ca/calmodulin, and protein phosphorylation. Understanding the catalytic mechanism of an enzyme is a prerequisite to understanding its regulation. Here I will describe the essentials of catalysis and then consider how these elements are controlled by each of the major regulators.
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