Azidothymidine triphosphate is an inhibitor of both human immunodeficiency virus type 1 reverse transcriptase and DNA polymerase gamma.
The reverse transcriptase from human immunodeficiency virus type 1 was purified from the virus to near homogeneity. The enzyme was shown to possess both RNA-dependent and DNA-dependent DNA-synthesizing activity. Activated DNA as a heteropolymeric substrate was used as efficiently as was the homopolymeric substrate poly(rA)-oligo(dT). The Michaelis-Menten constants were determined for each of the four nucleotides needed to elongate a natural template primer. Azidothymidine triphosphate, a well-known inhibitor of the enzyme, inhibited the enzyme competitively with respect to dTTP and noncompetitively with respect to the other nucleotides. Azidothymidine triphosphate acted as an efficient inhibitor of cellular DNA polymerase gamma, whereas other enzymes of eucaryotic DNA metabolism, namely, DNA polymerase alpha-primase and DNA polymerase beta, were not inhibited. This finding may explain why some acquired immunodeficiency syndrome patients suffer side effects during azidothymidine therapy.
König
H
H
Paul Ehrlich Institut, Langen, Federal Republic of Germany.
Behr
E
E
Löwer
J
J
Kurth
R
R
D004258:DNA Polymerase III / Q000037:antagonists & inhibitors*; D019915:DNA Primase; D004279:DNA, Viral / Q000096:biosynthesis; D054306:Dideoxynucleotides; D004591:Electrophoresis, Polyacrylamide Gel; D015497:HIV-1 / Q000187:drug effects*; D007700:Kinetics; D019384:Nucleic Acid Synthesis Inhibitors; D009711:Nucleotides / Q000494:pharmacology; D012316:RNA Nucleotidyltransferases / Q000378:metabolism; D018894:Reverse Transcriptase Inhibitors; D013698:Templates, Genetic; D013942:Thymine Nucleotides / Q000494:pharmacology*; D015215:Zidovudine / Q000031:analogs & derivatives* / Q000494:pharmacology
D004279:DNA, Viral; D054306:Dideoxynucleotides; D019384:Nucleic Acid Synthesis Inhibitors; D009711:Nucleotides; D018894:Reverse Transcriptase Inhibitors; D013942:Thymine Nucleotides; D015215:Zidovudine; C052873:zidovudine triphosphate; D019915:DNA Primase; D012316:RNA Nucleotidyltransferases; D004258:DNA Polymerase III