A plant phytotoxin, solanapyrone A, is an inhibitor of DNA polymerase β and λ

Abstract

Solanapyrone A, a phytotoxin and enzyme inhibitor isolated from a fungus (SUT 01B1-2) selectively inhibits the activities of mammalian DNA polymerase β and λ (pol β and λ) in vitro. The IC 50 values of the compound were 30 μM for pol β and 37 μM for pol λ. Because pol β and λ are in a family and their three-dimensional structures are thought to be highly similar to each other, we used pol β to analyze the biochemical relationship with solanapyrone A. On pol β, solanapyrone A antagonistically competed with both the DNA template and the nucleotide substrate. BIAcore analysis demonstrated that solanapyrone A bound selectively to the N-terminal 8-kDa domain of pol β. This domain is known to bind single-stranded DNA, provide 5′-phosphate recognition of gapped DNA, and cleave the sugar-phosphate bond 3′ to an intact apurinic/apyrimidinic (AP) site (i.e. AP lyase activity) including 5′-deoxyribose phosphate lyase activity. Solanapyrone A inhibited the single-stranded DNA-binding activity but did not influence the activities of the 5′-phosphate recognition in gapped DNA structures and the AP lyase. Based on these results, the inhibitory mechanism of solanapyrone A is discussed.