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Volume 271, Number 39, Issue of September 27, 1996 pp. 23967-23972
©1996 by The American Society for Biochemistry and Molecular Biology, Inc.

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Mechanism of Cyclization of Pyridine Nucleotides by Bovine Spleen NAD⁺ Glycohydrolase

(Received for publication, April 17, 1996, and in revised form, July 17, 1996)

From the Laboratoire de Chimie Bioorganique, Laboratoire Associé au Centre National de la Recherche Scientifique 1386, Faculté de Pharmacie, Université Louis Pasteur Strasbourg, 74 route du Rhin, 67400 Illkirch, France

We have shown that bovine spleen NAD⁺ glycohydrolase (EC), purified to homogeneity, is a multifunctional enzyme. A time-dependent formation of cADPR from NAD⁺ that did not exceed 1.5-2% of the reaction products was measurable. The cyclase activity of this enzyme was, however, best evidenced by its transformation of NGD⁺ into cyclic GDP-ribose (cGDPR). The formation of the cyclic compound could be monitored spectroscopically (UV and fluorescence) and by high-performance liquid chromatography; the product ratio of cGDPR/GDP-ribose was 2:1. Bovine spleen NAD⁺ glycohydrolase is also able to hydrolyze cADPR (Muller-Steffner et al. (1994) Biochem. Biophys. Res. Commun. 204, 1279-1285); the kinetic parameters (V/K_m) measured exclude, however, the possibility that cADPR is a kinetically competent reaction intermediate in the transformation of NAD⁺ into ADP-ribose. Experimental data indicating that NAD⁺ glycohydrolase-catalyzed hydrolysis and methanolysis of NA(G)D⁺ occurred at the expense of the formation of the cyclic compounds are in favor of a reaction mechanism involving the partitioning of a common oxocarbenium reaction intermediate between the different acceptors. Thus E·A(G)DP-ribosyl oxocarbenium intermediate can react according to i) intramolecular processes with the positions N-1 of adenine and N-7 of guanine to give cA(G)DPR as reaction products, and ii) intermolecular reactions with water (formation of A(G)DP-ribose) and methanol (formation of methyl A(G)DP-ribose). We attribute the marked difference in yield of cADPR and cGDPR to the intrinsic reactivity (nucleophilicity and positioning) of the purine N-positions that are involved in the cyclization reactions within the E·A(G)DP-ribosyl oxocarbenium complexes.

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