ADP-ribosyl cyclases generate two unusual adenine homodinucleotides with cytotoxic activity on mammalian cells
- Giovanna Basile†,‡,
- Orazio Taglialatela-Scafati§,
- Gianluca Damonte†,¶,
- Andrea Armirotti¶,
- Santina Bruzzone†,¶,
- Lucrezia Guida†,¶,
- Luisa Franco†,¶,
- Cesare Usai∥,
- Ernesto Fattorusso§,
- Antonio De Flora†,¶, and
- Elena Zocchi†,¶,††
- †Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy; ‡Advanced Biotechnology Center, Largo Giovanna Benzi 1, 16132 Genoa, Italy; §Department of Chemistry of Natural Products, University of Napoli “Federico II”, Via D. Montesano 49, 80131 Naples, Italy; ¶Center of Excellence for Biomedical Research, University of Genoa, Viale Benedetto XV 3, 16132 Genoa, Italy; and ∥Institute of Biophysics, Consiglio Nazionale delle Ricerche, Via De Marini 6, 16149 Genoa, Italy
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Edited by Joseph A. Beavo, University of Washington School of Medicine, Seattle, WA (received for review May 5, 2005)
Abstract
ADP-ribosyl cyclases are ubiquitous enzymes responsible for synthesis from NAD+ of the intracellular calcium-releasing signal molecules cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP+). Here, we show that cyclases from lower and higher Metazoa also synthesize three adenylic dinucleotides from cADPR and adenine: diadenosine diphosphate and two isomers thereof. These dinucleotides are present and metabolized in mammalian cells and affect intracellular calcium and cell proliferation. The diadenosine diphosphate isomers are naturally occurring nucleotides containing an N-glycosidic bond different from the usual C1′-N9. The identification of these members of the family of NAD+-derived, calcium-active nucleotides opens new areas of investigation into their functional cooperation with cADPR and NAADP+ and into their involvement in the physiology and pathology of calcium-controlled cell functions.
Footnotes
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↵ †† To whom correspondence should be addressed at: Department of Experimental Medicine, Section Biochemistry, Viale Benedetto XV 1, 16132 Genoa, Italy. E-mail: ezocchi{at}unige.it.
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This paper was submitted directly (Track II) to the PNAS office.
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Abbreviations: ADPRC, ADP-ribosyl cyclase; Ap2A, diadenosine diphosphate; [Ca2+]i, cytosolic free calcium concentration; cADPR, cyclic ADP-ribose; CB MNC, cord blood-derived mononuclear cells; CFC, colony-forming cell; CIP, calf intestinal phosphatase; CM, conditioned medium; ER, endoplasmic reticulum; HP, hemopoietic progenitors; NPP, nucleotide pyrophosphatase.
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Freely available online through the PNAS open access option.
- Copyright © 2005, The National Academy of Sciences
