Aplysia californica mediated cyclisation of novel 3'-modified NAD+ analogues: a role for hydrogen bonding in the recognition of cyclic adenosine 5'-diphosphate ribose.
Cyclic ADP-ribose mobilizes intracellular Ca2+ in a variety of cells. To elucidate the nature of the interaction between the C3' substituent of cADP-ribose and the cADPR receptor, three analogues of NAD+ modified in the adenosine ribase (xyloNAD+ 3'F-xyloNAD+ and 3'F-NAD+ were chemically synthesised from D-xylose and adenine starting materials. 3'F-NAD+ was readily converted to cyclic 3'F-ADP ribose by the action of the cyclase enzyme derived from the mollusc Aplysia californica. XyloNAD+ and 3'F-xyloNAD+ were cyclised only reluctantly and in poor yield to afford unstable cyclic products. Biological evaluation of cyclic 3'F-ADP ribose for calcium release in sea urchin egg homogenate gave an EC(50) of 1.5+/-0.5 microM. This high value suggests that the ability of the C3' substituent to donate a hydrogen bond is crucial for agonism.
Mort
Christopher J W
CJ
Wolfson Laboratory of Medicinal Chemistry, Department of Pharmacy and Pharmacology, University of Bath, Claverton Down, Bath BA2 7AY, UK.
Migaud
Marie E
ME
Galione
Antony
A
Potter
Barry V L
BV
D036541:ADP-ribosyl Cyclase / Q000737:chemistry / Q000378:metabolism; D000818:Animals; D001048:Aplysia / Q000737:chemistry*; D001671:Biochemistry / Q000379:methods; D002118:Calcium / Q000378:metabolism; D036563:Cyclic ADP-Ribose / Q000737:chemistry*; D003500:Cyclization; D006860:Hydrogen Bonding; D007700:Kinetics; D009243:NAD / Q000031:analogs & derivatives* / Q000494:pharmacology; D010063:Ovum / Q000187:drug effects / Q000378:metabolism; D012617:Sea Urchins
D009243:NAD; D036563:Cyclic ADP-Ribose; D036541:ADP-ribosyl Cyclase; D002118:Calcium