Mechanism of inhibition of deoxyribonucleic acid synthesis by 1-beta-D-arabinofuranosyladenosine triphosphate and its potentiation by 6-mercaptopurine ribonucleoside 5'-monophosphate.
The mechanism of inhibition of DNA synthesis by 1-beta-D-arabinofuranosyl-ATP (ara-ATP) and the potentiation of this inhibition by 6-mercaptopurine ribonucleoside 5'-monophosphate (6-MPR-P) have been investigated with mammalian DNA polymerase delty by using poly(dA-dT) as the template. The inhibition of DNA synthesis by ara-ATP correlates with incorporation of ara-AMP into poly(dA-dT). Nearest-neighbor analysis indicates that ara-AMP does not act as an absolute chain terminator but rather that chains with 3'-terminal arabinosyl nucleotides are extended slowly. The inhibition of DNA synthesis by ara-ATP is markedly enhanced by the addition of the nucleotide derivative of 6-mercaptopurine, 6-mercaptopurine ribonucleoside 5'-monophosphate. The increased inhibition of DNA synthesis in the presence of 6-MPR-P is due to increased incorporation of ara-AMP. The mechanism by which 6-MPR-P increases the incorporation of ara-AMP is by selective inhibition of the 3' to 5' exonuclease activity of DNA polymerase, thereby preventing the removal of newly incorporated ara-AMP at 3' termini of DNA chains.
D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D001088:Arabinonucleotides / Q000031:analogs & derivatives; D001853:Bone Marrow / Q000201:enzymology; D004247:DNA / Q000096:biosynthesis*; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D007291:Inosine Monophosphate / Q000031:analogs & derivatives / Q000494:pharmacology*; D007292:Inosine Nucleotides / Q000494:pharmacology*; D007700:Kinetics; D011817:Rabbits; D013379:Substrate Specificity; D013873:Thionucleotides / Q000494:pharmacology*; D001084:Vidarabine Phosphate / Q000031:analogs & derivatives
D001088:Arabinonucleotides; D007292:Inosine Nucleotides; D013873:Thionucleotides; D001084:Vidarabine Phosphate; D007291:Inosine Monophosphate; C000101:ara-ATP; C003449:thioinosinic acid; D000255:Adenosine Triphosphate; D004247:DNA; D004259:DNA-Directed DNA Polymerase