title: Production of calcium-mobilizing metabolites by a novel member of the ADP-ribosyl cyclase family expressed in Schistosoma mansoni.
abstract: ADP-ribosyl cyclases are structurally conserved enzymes that are best known for catalyzing the production of the calcium-mobilizing metabolite, cyclic adenosine diphosphate ribose (cADPR), from nicotinamide adenine dinucleotide (NAD(+)). However, these enzymes also produce adenosine diphosphate ribose (ADPR) and nicotinic acid adenine dinucleotide phosphate (NAADP(+)), both of which have been shown to modulate calcium mobilization in vitro. We have now characterized a new member of the cyclase family from Schistosoma mansoni, a member of the Platyhelminthes phylum. We show that the novel NAD(P)(+) catabolizing enzyme (NACE) expressed by schistosomes is structurally most closely related to the cyclases cloned from Aplysia but also shows significant homology with the mammalian cyclases, CD38 and CD157. NACE expression is developmentally regulated in schistosomes, and the GPI-anchored protein is localized to the outer tegument of the adult schistosome. Importantly, NACE, like all members of the cyclase family, is a multifunctional enzyme and catalyzes NAD(+) glycohydrolase and base-exchange reactions to produce ADPR and NAADP(+). However, despite being competent to generate a cyclic product from NGD(+), a nonphysiologic surrogate substrate, NACE is so far the only enzyme in the cyclase family that is unable to produce significant amounts of cADPR (<0.02% of reaction products) using NAD(+) as the substrate. This suggests that the other calcium-mobilizing metabolites produced by NACE may be more important for calcium signaling in schistosomes. Alternatively, the function of NACE may be to catabolize extracellular NAD(+) to prevent its use by host enzymes that utilize this source of NAD(+) to facilitate immune responses.
authors.affiliation: Trudeau Institute, 154 Algonquin Avenue, Saranac Lake, New York 12983, USA.
authors.forename: Stephen P
authors.initials: SP
authors.lastname: Goodrich
authors.forename: Hélène
authors.initials: H
authors.lastname: Muller-Steffner
authors.forename: Ahmed
authors.initials: A
authors.lastname: Osman
authors.forename: Marie-Jo
authors.initials: MJ
authors.lastname: Moutin
authors.forename: Kim
authors.initials: K
authors.lastname: Kusser
authors.forename: Alan
authors.initials: A
authors.lastname: Roberts
authors.forename: David L
authors.initials: DL
authors.lastname: Woodland
authors.forename: Troy D
authors.initials: TD
authors.lastname: Randall
authors.forename: Esther
authors.initials: E
authors.lastname: Kellenberger
authors.forename: Philip T
authors.initials: PT
authors.lastname: LoVerde
authors.forename: Francis
authors.initials: F
authors.lastname: Schuber
authors.forename: Frances E
authors.initials: FE
authors.lastname: Lund
mesh_terms: D036541:ADP-ribosyl Cyclase / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D000818:Animals; D001048:Aplysia / Q000201:enzymology / Q000235:genetics*; D001483:Base Sequence; D002118:Calcium / Q000378:metabolism*; D020013:Calcium Signaling / Q000235:genetics; D003001:Cloning, Molecular; D036563:Cyclic ADP-Ribose / Q000096:biosynthesis*; D015870:Gene Expression / Q000235:genetics*; D008969:Molecular Sequence Data; D009243:NAD / Q000378:metabolism; D009244:NAD+ Nucleosidase / Q000378:metabolism; D009249:NADP / Q000031:analogs & derivatives / Q000378:metabolism; D010802:Phylogeny; D012550:Schistosoma mansoni / Q000201:enzymology / Q000235:genetics / Q000276:immunology
chemical_list: D009243:NAD; D036563:Cyclic ADP-Ribose; D009249:NADP; C024376:NAADP; D036541:ADP-ribosyl Cyclase; D009244:NAD+ Nucleosidase; D002118:Calcium