title: ADP-ribosyl cyclases generate two unusual adenine homodinucleotides with cytotoxic activity on mammalian cells.
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.
authors.affiliation: Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy.
authors.forename: Giovanna
authors.initials: G
authors.lastname: Basile
authors.forename: Orazio
authors.initials: O
authors.lastname: Taglialatela-Scafati
authors.forename: Gianluca
authors.initials: G
authors.lastname: Damonte
authors.forename: Andrea
authors.initials: A
authors.lastname: Armirotti
authors.forename: Santina
authors.initials: S
authors.lastname: Bruzzone
authors.forename: Lucrezia
authors.initials: L
authors.lastname: Guida
authors.forename: Luisa
authors.initials: L
authors.lastname: Franco
authors.forename: Cesare
authors.initials: C
authors.lastname: Usai
authors.forename: Ernesto
authors.initials: E
authors.lastname: Fattorusso
authors.forename: Antonio
authors.initials: A
authors.lastname: De Flora
authors.forename: Elena
authors.initials: E
authors.lastname: Zocchi
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000378:metabolism*; D000227:Adenine Nucleotides / Q000096:biosynthesis*; D000818:Animals; D002118:Calcium / Q000378:metabolism; D049109:Cell Proliferation / Q000187:drug effects; D036563:Cyclic ADP-Ribose / Q000378:metabolism*; D015226:Dinucleoside Phosphates / Q000096:biosynthesis* / Q000737:chemistry / Q000633:toxicity; D006367:HeLa Cells; D006801:Humans; D011161:Porifera / Q000737:chemistry*; D020033:Protein Isoforms / Q000633:toxicity
chemical_list: D000227:Adenine Nucleotides; D015226:Dinucleoside Phosphates; D020033:Protein Isoforms; D036563:Cyclic ADP-Ribose; D036541:ADP-ribosyl Cyclase; D002118:Calcium