Characterization of a novel inhibitor of human DNA polymerases: 3,4,5-tri-O-galloylquinic acid.
Various galloyl derivatives of quinic acid were found to be inhibitors of human DNA polymerases. Among them, 3,4,5-tri-O-galloylquinic acid (TGQA) was the most potent inhibitor of DNA polymerase alpha. Under identical conditions, this compound was 60-fold more potent than aphidicolin as an inhibitor of DNA polymerase alpha. The inhibition of DNA polymerase alpha by this compound was not competitive with either the template or any of the deoxynucleoside triphosphates with a Ki of 0.28 microM. Under similar reaction conditions, DNA polymerases beta and gamma were much less sensitive to the effects of these compounds and, in contrast to the effect seen with DNA polymerase alpha, the inhibition of DNA polymerases beta and gamma by TGQA was competitive with respect to the template with Ki values of 44.4 and 7.5 microM respectively. The potency of these compounds against DNA polymerase gamma varied according to the assay conditions used. The inhibition of DNA polymerase gamma by TGQA could be increased substantially by using MnCl2 in place of MgCl2 and by including 50 mM potassium phosphate, pH 7.5, in the assay mixture. DNA polymerase beta was also more sensitive to TGQA when measured with MnCl2. However, potassium phosphate had little, if any, effect on the inhibition by TGQA of either DNA polymerase alpha or beta. DNA polymerase alpha was less sensitive to TGQA when assayed with MnCl2. TGQA was not a potent inhibitor of human KB cell growth in culture, which could be due to its degradation or poor uptake. Nevertheless, this compound could serve as a model for developing antitumor drugs targeted at DNA polymerases.
Parker
W B
WB
Department of Pharmacology, School of Medicine, University of North Carolina, Chapel Hill 27599.
Nishizawa
M
M
Fisher
M H
MH
Ye
N
N
Lee
K H
KH
Cheng
Y C
YC
D002460:Cell Line; D004256:DNA Polymerase I / Q000037:antagonists & inhibitors; D004257:DNA Polymerase II / Q000037:antagonists & inhibitors; D004258:DNA Polymerase III / Q000037:antagonists & inhibitors; D005707:Gallic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D006801:Humans; D007700:Kinetics; D008954:Models, Biological; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors; D011801:Quinic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology; D018894:Reverse Transcriptase Inhibitors; D013329:Structure-Activity Relationship
D019384:Nucleic Acid Synthesis Inhibitors; D018894:Reverse Transcriptase Inhibitors; D011801:Quinic Acid; D005707:Gallic Acid; C061995:3,4,5-tri-O-galloylquinic acid; D004256:DNA Polymerase I; D004257:DNA Polymerase II; D004258:DNA Polymerase III