title: ADP-ribosyl cyclase and CD38. Multi-functional enzymes in Ca+2 signaling.
abstract: Mobilization of internal Ca+2 is an important signaling mechanism in cells. In addition to the inositol trisphosphate pathway, cyclic ADP-ribose (cADPR) and nicotinic acid adenine dinucleotide (NAADP) have been shown to mobilize Ca+2 via independent mechanisms. Although the structures of cADPR and NAADP are totally distinct, both nucleotides can be synthesized by ADP-ribosyl cyclase or CD38, a lymphocyte antigen. Both enzymes cyclize NAD to cADPR. In the presence of nicotinic acid the two enzymes catalyze a base exchange reaction resulting in the synthesis of NAADP from NADP. The switch between these two modes of catalysis is regulated by pH. Furthermore, both enzymes can also cyclize nicotinamide guanine dinucleotide (NGD) to produce a fluorescent product, cyclic GDP-ribose (cGDPR), which has a site of cyclization different from cADPR. A model is proposed to account for the multi-functionality of these enzymes. In order to be able to verify the model, a soluble ADP-ribosyl cyclase has been crystallized and X-ray diffraction shows that it is a dimer. Solution of the crystal structure of the cyclase should provide valuable insight into the structural features necessary for its multiple catalytic functions.
authors.affiliation: Department of Physiology and Pharmacology, University of Minnesota, Minneapolis 55455, USA.
authors.forename: H C
authors.initials: HC
authors.lastname: Lee
authors.forename: R M
authors.initials: RM
authors.lastname: Graeff
authors.forename: T F
authors.initials: TF
authors.lastname: Walseth
mesh_terms: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000737:chemistry / Q000378:metabolism*; D002118:Calcium / Q000378:metabolism*; D002384:Catalysis; D018360:Crystallography, X-Ray; D006801:Humans; D006868:Hydrolysis; D008562:Membrane Glycoproteins; D009699:N-Glycosyl Hydrolases / Q000737:chemistry / Q000378:metabolism*; D011487:Protein Conformation; D015398:Signal Transduction
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D008562:Membrane Glycoproteins; D009699:N-Glycosyl Hydrolases; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D051997:ADP-ribosyl Cyclase 1; D002118:Calcium