Ribonucleotide reductase induced by varicella zoster virus. Characterization, and potentiation of acyclovir by its inhibition.
An enzyme that catalyzes the conversion of CDP to 2'-dCDP in the presence of dithiothreitol (DTT) was detected in ammonium sulfate fractionated-extracts of varicella zoster virus (VZV)-infected cells. This ribonucleotide reductase was antigenically distinguishable from the isofunctional eucaryotic enzyme as well as the ribonucleotide reductases induced by herpes simplex virus types 1 and 2 (HSV-1 and HSV-2). The VZV-induced enzyme was purified to the extent that most of the contaminating enzymes, which would significantly deplete the substrate, were removed. The VZV-induced ribonucleotide reductase exhibited maximum activity in the absence of ATP and/or magnesium and was only weakly inhibited by 2'-deoxynucleoside triphosphates. Furthermore, ADP, UDP and GDP competitively inhibited CDP reduction with Ki (Km) values of 15, 20, 1.8 and 0.88 microM, respectively. These kinetic properties were very similar to those of the correspondingly purified ribonucleotide reductases induced by HSV-1 [Averett et al., J. biol. Chem. 258, 9831 (1983)] and HSV-2 [Averett et al., J. Virol. 52, 981 (1984)] and were dissimilar to the allosterically regulated mammalian enzyme. A723U, an inactivator of HSV-1 ribonucleotide reductase that potentiates the anti-HSV-1 activity of acyclovir [Spector et al., Proc. natn. Acad. Sci. U.S.A. 82, 4254 (1985)], also appeared to inactivate this VZV-induced ribonucleotide reductase and to potentiate the anti-VZV activity of acyclovir.
Spector
T
T
Wellcome Research Laboratories, Research Triangle Park, NC 27709.
Stonehuerner
J G
JG
Biron
K K
KK
Averett
D R
DR
D000212:Acyclovir / Q000494:pharmacology*; D002478:Cells, Cultured; D002644:Chickenpox / Q000188:drug therapy / Q000201:enzymology*; D003565:Cytidine Diphosphate / Q000378:metabolism; D004357:Drug Synergism; D004790:Enzyme Induction; D014645:Herpesvirus 3, Human / Q000187:drug effects / Q000201:enzymology* / Q000254:growth & development; D006801:Humans; D007158:Immunologic Techniques; D007700:Kinetics; D011725:Pyridines / Q000494:pharmacology*; D012264:Ribonucleotide Reductases / Q000037:antagonists & inhibitors / Q000096:biosynthesis* / Q000302:isolation & purification; D013882:Thiosemicarbazones / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects
D011725:Pyridines; D013882:Thiosemicarbazones; C045577:compound A723U; D003565:Cytidine Diphosphate; D012264:Ribonucleotide Reductases; D000212:Acyclovir