ADP-ribosyl cyclase; crystal structures reveal a covalent intermediate

Structure. 2004 Mar;12(3):477-86. doi: 10.1016/j.str.2004.02.006.


ADP-ribosyl cyclase catalyzes the elimination of nicotinamide from NAD and cyclization to cADPR, a known second messenger in cellular calcium signaling pathways. We have determined to 2.0 A resolution the structure of Aplysia cyclase with ribose-5-phosphate bound covalently at C3' and with the base exchange substrate (BES), pyridylcarbinol, bound to the active site. In addition, further refinement at 2.4 A resolution of the structure of nicotinamide-bound cyclase, which was previously reported, reveals that ribose-5-phosphate is also covalently bound in this structure, and a second nicotinamide site was identified. The structures of native and mutant Glu179Ala cyclase were also solved to 1.7 and 2.0 A respectively. It is proposed that the second nicotinamide site serves to promote cyclization by clearing the active site of the nicotinamide byproduct. Moreover, a ribosylation mechanism can be proposed in which the cyclization reaction proceeds through a covalently bound intermediate.

Publication types

  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • ADP-ribosyl Cyclase / chemistry*
  • ADP-ribosyl Cyclase / metabolism
  • Amino Acid Sequence
  • Animals
  • Aplysia / enzymology
  • Conserved Sequence
  • Crystallography, X-Ray
  • Molecular Sequence Data
  • Nicotinamide Mononucleotide / metabolism
  • Protein Structure, Secondary
  • Protein Structure, Tertiary
  • Ribosemonophosphates / metabolism
  • Sequence Alignment


  • Ribosemonophosphates
  • Nicotinamide Mononucleotide
  • ribose-5-phosphate
  • ADP-ribosyl Cyclase

Associated data

  • PDB/1R0S
  • PDB/1R12
  • PDB/1R15
  • PDB/1R16