5-Phosphoribosyl 1-pyrophosphate synthetase converts the acyclic nucleoside phosphonates 9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine and 9-(2-phosphonylmethoxyethyl)adenine directly to their antivirally active diphosphate derivatives.
The acyclic nucleoside phosphonates 9-(3-hydroxy-2-phosphonylmethoxypropyl)adenine (HPMPA) and 9-(2-phosphonylmethoxyethyl)adenine (PMEA) are potent inhibitors of DNA viruses and retroviruses, respectively. Unlike nucleoside triphosphates, the metabolically active (diphosphorylated) forms of HPMPA and PMEA (designated HPMPApp and PMEApp) are synthesized in a reversible reaction in which the pyrophosphate group of 5-phosphoribosyl 1-pyrophosphate (PRPP) is directly transferred to HPMPA and PMEA by purified PRPP synthetase. In this respect, PRPP synthetase does not act stereospecifically in that it recognizes both the S-enantiomer and the R-enantiomer of HPMPA as substrate. PRPP synthetase also recognizes other acyclic adenine and 2,6-diaminopurine riboside phosphonates as a substrate. It is now imperative to evaluate the potential role of PRPP synthetase, as activating enzyme, in the antiviral action of this type of molecules in intact cells.
Balzarini
J
J
Rega Institute for Medical Research, Katholieke Universiteit Leuven, Belgium.
De Clercq
E
E
D000225:Adenine / Q000031:analogs & derivatives* / Q000378:metabolism; D000998:Antiviral Agents / Q000378:metabolism*; D066298:In Vitro Techniques; D007700:Kinetics; D063065:Organophosphonates; D009943:Organophosphorus Compounds / Q000378:metabolism*; D010766:Phosphorylation; D012268:Ribose-Phosphate Pyrophosphokinase / Q000378:metabolism*; D013379:Substrate Specificity
D000998:Antiviral Agents; D063065:Organophosphonates; D009943:Organophosphorus Compounds; C053001:adefovir; C050127:9-(S)-(3-hydroxy-2-(phosphonomethoxy)propyl)adenine; D012268:Ribose-Phosphate Pyrophosphokinase; D000225:Adenine