Structural determinants for N1/N7 cyclization of nicotinamide hypoxanthine 5'-dinucleotide (NHD+) derivatives by ADP-ribosyl cyclase from aplysia californica: Ca2+-mobilizing activity of 8-substituted cyclic inosine 5'-diphosphoribose analogues in T-lymphocytes.
A series of nicotinamide hypoxanthine 5'-dinucleotide (NHD+) analogues modified at C-8 (2-5) and 7-deaza-NHD+ were synthesized, and cyclization in the presence of Aplysia ADP-ribosyl cyclase was studied. All 8-substituted NHD+ analogues were converted into their N1-cyclic forms by the enzyme, while in contrast, 7-deaza-NHD+ 17 was hydrolyzed into 7-deazainosine 5'-diphosphoribose (7-deaza-IDPR) 25. Correlations are made showing that the conformation of the NHD+ substrate is the key to successful cyclization. The pharmacological activities of these novel cIDPR derivatives were evaluated in both permeabilized and intact Jurkat T-lymphocytes. The results show that in permeabilized cells both 8-iodo 1g and 8-N3-N1-cIDPR 1d have an activity comparable to that of cADPR, while 8-iodo 1g and 8-phenyl-N1-cIDPR 1c have a small but significant effect in intact cells and can therefore be regarded as membrane-permeant; thus, cIDPR derivatives are emerging as important novel biological tools to study cADPR-mediated Ca2+ release in T-cells.
Moreau
Christelle
C
Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath, BA2 7AY, United Kingdom.
Wagner
Gerd K
GK
Weber
Karin
K
Guse
Andreas H
AH
Potter
Barry V L
BV
D036541:ADP-ribosyl Cyclase / Q000737:chemistry*; D000818:Animals; D001048:Aplysia / Q000201:enzymology*; D002118:Calcium / Q000378:metabolism*; D007289:Cyclic IMP / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D003500:Cyclization; D006801:Humans; D006868:Hydrolysis; D007290:Inosine Diphosphate / Q000138:chemical synthesis* / Q000737:chemistry; D019169:Jurkat Cells; D008968:Molecular Conformation; D013237:Stereoisomerism; D013329:Structure-Activity Relationship; D013601:T-Lymphocytes / Q000187:drug effects* / Q000378:metabolism
D007289:Cyclic IMP; D007290:Inosine Diphosphate; D036541:ADP-ribosyl Cyclase; D002118:Calcium