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Volume 271, Number 24, Issue of June 14, 1996 pp. 14028-14034
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Inhibition of Adenylyl Cyclase by a Family of Newly Synthesized Adenine Nucleoside 3-Polyphosphates

(Received for publication, January 22, 1996, and in revised form, March 26, 1996)

From the Department of Physiology and Biophysics, State University of New York, Health Sciences Center, Stony Brook, New York 11794-8661

The synthesis of a number of adenine nucleoside 3-polyphosphates has been devised via a phosphotriester approach that combines the method of alkoxide activation with the use of 2,2,2-tribromoethyl phosphoromorpholinochloridate as a phosphorylating agent. The family of compounds included 3ADP, 3ATP, 2-deoxy-3ADP, 2-deoxy-3ATP, 2,5-dideoxy-3ADP, and 2,5-dideoxy-3ATP. Potency as inhibitors of adenylyl cyclases followed the order: 3-mono- < 3-di- < 3-triphosphate and adenosine (Ado) < 2-d-Ado < 2,5-dd-Ado derivatives, with 2,5-dideoxy-3ATP exhibiting an IC₅₀ of ~40 nM. This order was maintained with purified and recombinant forms of the type I enzyme. The nucleoside 3-phosphates caused noncompetitive inhibition of the type I adenylyl cyclase from bovine brain, consistent with inhibition via the P-site. Inhibition was not due to hydrolytic products because this was minimal and inhibition kinetics by inorganic polyphosphates were inconsistent with those caused by the nucleoside 3-polyphosphates. Only 3ATP underwent cation-catalyzed, nonenzymatic hydrolysis, with the primary product being 2:3-cAMP. Because 3-ADP and 3-ATP are naturally occurring, this class of compounds may physiologically regulate adenylyl cyclases and possibly other enzymes, mediating responses that include a reduction in 3:5-cAMP levels and consequent reductions in protein kinase A-activated pathways.

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