ADP-ribosyl cyclases generate two unusual adenine homodinucleotides with cytotoxic activity on mammalian cells.
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.
Basile
Giovanna
G
Department of Experimental Medicine, Section of Biochemistry, University of Genoa, Viale Benedetto XV 1, 16132 Genoa, Italy.
Taglialatela-Scafati
Orazio
O
Damonte
Gianluca
G
Armirotti
Andrea
A
Bruzzone
Santina
S
Guida
Lucrezia
L
Franco
Luisa
L
Usai
Cesare
C
Fattorusso
Ernesto
E
De Flora
Antonio
A
Zocchi
Elena
E
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
D000227:Adenine Nucleotides; D015226:Dinucleoside Phosphates; D020033:Protein Isoforms; D036563:Cyclic ADP-Ribose; D036541:ADP-ribosyl Cyclase; D002118:Calcium