title: Inhibition of NAD+ glycohydrolase and ADP-ribosyl cyclase activities of leukocyte cell surface antigen CD38 by gangliosides.
abstract: We have recently reported that gangliosides act as inhibitors of ADP-ribosyltransferases and NAD+ glycohydrolases (NADase) of pertussis toxin and the C3 exoenzyme from Clostridium botulinum (Hara-Yokoyama, M., Hirabayashi, Y., Irie, F., Syuto, B., Moriishi, K., Sugiya, H., and Furuyama, S. (1995) J. Biol. Chem. 270, 8115-8121). Here, we investigated the effect of gangliosides on the enzymatic activity of leukocyte cell surface antigen CD38, which is identified as an ecto-NADase (Kontani, K., Nishina, H., Ohoka, Y., Takahashi, K., and Katada, T. (1993) J. Biol. Chem. 268, 16895-16898). Gangliosides GM1a and GQ1balpha inhibited the NADase activity in the immunoprecipitate of anti-CD38 antibody from the membrane extract of retinoic acid-treated human leukemic HL-60 cells. Gangliosides also inhibited the NADase activity of the extracellular domain of CD38 antigen that was deprived of the transmembrane domain and was expressed in Escherichia coli as a fusion protein with maltose-binding protein (MBP-CD38). The order of the inhibitory effect of purified ganglioside species on the NADase activity on MBP-CD38 was as follows: GQ1balpha > GT1b, GQ1b > GD1a, GD1b, GM1a, GM1b, GD3, GM3. GQ1balpha inhibited the NADase of MBP-CD38 in a noncompetitive manner versus NAD+ with a Ki value of about 0.3 microM. Neither ceramide nor the oligosaccharide moiety of GQ1balpha had an effect on the NADase activity. GQ1balpha, GT1b, and GQ1b also efficiently inhibited the ADP-ribosyl cyclase activity of MBP-CD38. At present, gangliosides are the only endogenous species that can block the enzymatic activity of CD38 antigen. The present results suggest a potential role of gangliosides as inhibitors of the ecto-NADases.
authors.affiliation: Department of Physiology, Nihon University School of Dentistry at Matsudo, 2-870-1 Sakae-cho Nishi, Matsudo, Chiba 271, Japan.
authors.forename: M
authors.initials: M
authors.lastname: Hara-Yokoyama
authors.forename: I
authors.initials: I
authors.lastname: Kukimoto
authors.forename: H
authors.initials: H
authors.lastname: Nishina
authors.forename: K
authors.initials: K
authors.lastname: Kontani
authors.forename: Y
authors.initials: Y
authors.lastname: Hirabayashi
authors.forename: F
authors.initials: F
authors.lastname: Irie
authors.forename: H
authors.initials: H
authors.lastname: Sugiya
authors.forename: S
authors.initials: S
authors.lastname: Furuyama
authors.forename: T
authors.initials: T
authors.lastname: Katada
mesh_terms: D036541:ADP-ribosyl Cyclase; D051997:ADP-ribosyl Cyclase 1; D000818:Animals; D015703:Antigens, CD; D000943:Antigens, Differentiation / Q000187:drug effects*; D001048:Aplysia; D002417:Cattle; D002518:Ceramides / Q000737:chemistry; D005732:Gangliosides / Q000737:chemistry / Q000494:pharmacology*; D018922:HL-60 Cells; D006801:Humans; D006868:Hydrolysis; D008562:Membrane Glycoproteins; D009699:N-Glycosyl Hydrolases / Q000187:drug effects*; D009243:NAD / Q000378:metabolism; D009244:NAD+ Nucleosidase / Q000037:antagonists & inhibitors*; D009844:Oligosaccharides / Q000737:chemistry
chemical_list: D015703:Antigens, CD; D000943:Antigens, Differentiation; D002518:Ceramides; D005732:Gangliosides; D008562:Membrane Glycoproteins; D009844:Oligosaccharides; D009243:NAD; D009699:N-Glycosyl Hydrolases; D036541:ADP-ribosyl Cyclase; C498154:CD38 protein, human; D009244:NAD+ Nucleosidase; D051997:ADP-ribosyl Cyclase 1