Phosphonate and thiophosphate nucleotide analogues in studies of some enzyme reactions.
Enzymes which cleave P-O bonds can be blocked by phosphonate analogues of biological phosphates. alpha-Fluorophosphonates are more electronegative at the bridging carbon than simple methylenephosphonates which improves their use for the study of enzymes. Thus, the beta,gamma-difluoromethylene analogue of ATP is a viable substrate for (2----5)An synthetase which converts it into (2----5)An species having a 5'-beta,gamma-difluoromethylene-trisphosphate. This binds strongly to RNase L but does not activate it. The unsymmetrical Ap4Aases from Artemia and lupin are strongly inhibited by P2,P3-fluoromethylenebisphosphonate- and by P1,P4-dithiophosphate-analogues of diadenosyl-5',5"-P1,P4-tetraphosphate while anomalous, non-regiospecific cleavage of some P2,P3-bridged mimics is observed. Certain such analogues inhibit both platelet aggregation in vitro and arterial blood-clotting in rabbits. Separation of the diastereo-isomers of P1,P4-dithiophosphate analogues of Ap4A is achieved using reverse-phase hplc which provides direct access to beta,gamma-CHF-bridged analogues of ATP with resolved stereochemistry at the CHF centre.
Blackburn
G M
GM
Krebs Institute, Department of Chemistry, University of Sheffield, UK.
Guo
M J
MJ
Langston
S P
SP
Taylor
G E
GE
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives; D004798:Enzymes / Q000378:metabolism*; D015394:Molecular Structure; D009711:Nucleotides / Q000737:chemistry*; D063065:Organophosphonates / Q000737:chemistry*; D010710:Phosphates / Q000737:chemistry*
D004798:Enzymes; D009711:Nucleotides; D063065:Organophosphonates; D010710:Phosphates; D000255:Adenosine Triphosphate; C035638:thiophosphoric acid