STUDIES ON INHIBITORS OF MAMMALIAN DNA-POLYMERASE-ALPHA AND DNA-POLYMERASE-BETA - SULFOLIPIDS FROM A PTERIDOPHYTE, ATHYRIUM NIPONICUM

Three sulfolipid compounds, 1, 2, and 3, have been isolated from a hig her plant, a pteridophyte, Athyrium niponicum, as potent inhibitors of the activities of calf DNA polymerase a and rat DNA polymerase beta. The inhibition by the sulfolipids was concentration dependent, and alm ost complete inhibition of DNA polymerase alpha and DNA polymerase bet a was achieved at 6 and 8 mu g/mL, respectively. The compounds did not influence the activities of calf thymus terminal deoxynucleotidyl tra nsferase, prokaryotic DNA polymerases such as the Klenow fragment of D NA polymerase I, T4 DNA polymerase and Taq polymerase, the DNA metabol ic enzyme DNase I, and even a DNA polymerase from a higher plant, caul iflower. Similarly, the compounds did not inhibit the activity of the human immunodeficiency virus type 1 reverse transcriptase. The kinetic studies of the compounds showed that DNA polymerase alpha was inhibit ed non-competitively with respect to the DNA template and substrate, w hereas DNA polymerase beta was inhibited competitively with both the D NA template and substrate. The binding to DNA polymerase beta could be stopped with non-ionic detergent, but the binding to DNA polymerase a lpha could not. (C) 1998 Elsevier Science Inc.