Stimulation of ADP-ribosyl cyclase activity of the cell surface antigen CD38 by zinc ions resulting from inhibition of its NAD+ glycohydrolase activity

Eur J Biochem. 1996 Jul 1;239(1):177-82. doi: 10.1111/j.1432-1033.1996.0177u.x.


The lymphocyte cell surface antigen, CD38, which has an amino acid sequence similar to Aplysia ADP-ribosyl cyclase, catalyzes not only the hydrolysis of NAD+ and 1-(5-phospho-beta-D-ribosyl) adenosine 5'-phosphate cyclic anhydride (cyclic ADP-ribose) but also the formation of cyclic ADP-ribose from NAD+. To characterize the bifunctional enzyme properties, we produced the recombinant CD38 fused with a maltose-binding protein (MBP-CD38). Zinc ions stimulated the ADP-ribosyl cyclase activity of MBP-CD38, but inversely inhibited its NAD+ glycohydrolase activity which was approximately 100-fold dominant to the cyclase activity in the absence of Zn2+. Such dual effects of Zn2+ were also observed in the native membrane-bound CD38 of HL-60 cells which had been caused to differentiate by retinoic acid. Zinc ions inhibited the NAD+ glycohydrolase reaction catalyzed by MBP-CD38 in an uncompetitive manner, whereas they enhanced the ADP-ribosyl cyclase reaction without affecting the Km value for NAD+. There was an increase in the fluorescence intensity of a hydrophobic fluorescent probe, 8-anilino-1-naphthalenesulfonate, in the presence of MBP-CD38. The fluorescence increase was further enhanced by the addition of Zn2+ with a shift in the maximum emission wavelength from 484 nm to 470 nm, suggesting that Zn2+ caused conformational changes of MBP-CD38. These results indicate that Zn2+ directly interacts with CD38 to stimulate its ADP-ribosyl cyclase with inhibition of its NAD+ glycohydrolase, probably due to prevention of the access of water molecule to an intermediate of the enzymesubstrate complex.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ADP-ribosyl Cyclase
  • ADP-ribosyl Cyclase 1
  • Anilino Naphthalenesulfonates
  • Antigens, CD / chemistry
  • Antigens, CD / metabolism*
  • Antigens, Differentiation / chemistry
  • Antigens, Differentiation / metabolism*
  • Enzyme Activation
  • Fluorescent Dyes
  • HL-60 Cells
  • Humans
  • Kinetics
  • Membrane Glycoproteins
  • N-Glycosyl Hydrolases / chemistry
  • N-Glycosyl Hydrolases / metabolism*
  • NAD+ Nucleosidase / antagonists & inhibitors*
  • Zinc / pharmacology*


  • Anilino Naphthalenesulfonates
  • Antigens, CD
  • Antigens, Differentiation
  • Fluorescent Dyes
  • Membrane Glycoproteins
  • 1-anilino-8-naphthalenesulfonate
  • N-Glycosyl Hydrolases
  • ADP-ribosyl Cyclase
  • CD38 protein, human
  • NAD+ Nucleosidase
  • ADP-ribosyl Cyclase 1
  • Zinc