Formosusin A, a novel specific inhibitor of mammalian DNA polymerase β from the fungus Paecilomyces formosus

Variotin (1) and three novel compounds, formosusin A (2), B (3), and C (4), were isolated from the cultures of the fungus Paecilomyces formosus, and their structures were determined by spectroscopic analyses. Compound 2 is (6Z,8E,10E)-variotin, a new cis-olefin analog of compound 1. Compound 2 selectively inhibited the activity of mammalian DNA polymerase beta (pol beta) in vitro, with an IC50 of 35.6 mu M. By contrast, compounds 1, 3, and 4 did not influence the activity of pol beta. These four compounds showed no effect on the activities of other 10 mammalian pols (i.e., pols alpha, gamma, delta, epsilon, eta, iota, kappa, lambda, and mu, and terminal deoxynucleotidyl transferase). These compounds also did not inhibit the activities of fish, insect, plant, and prokaryotic pols and other DNA metabolic enzymes tested. These results suggested that compound 2 could be a selective inhibitor of mammalian pol beta. The compound 2-induced inhibition of rat pol beta activity was competitive and non-competitive with respect to the DNA template-primer substrate and the dNTP substrate, respectively. On the basis of these results, the relationship between the three-dimensional structure and pol beta inhibitory mechanism of compound 2 is discussed. (C) 2013 Elsevier Ltd. All rights reserved.