Hymenoic acid (
1) is a natural compound isolated from cultures of a fungus,
Hymenochaetaceae sp., and this structure was determined by spectroscopic analyses. Compound
1 is a novel sesquiterpene,
trans-4-[(1′
E,5′
S)-5′-carboxy-1′-methyl-1′-hexenyl]cyclohexanecarboxylic acid. This compound selectively inhibited the activity of human DNA polymerase λ (pol λ) in vitro, and 50%inhibition was observed at a concentration of 91.7 μM. Compound
1 did not influence the activities of the other seven mammalian pols (i.e., pols
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, γ, δ, ε, η, ι, and κ), but also showed no effect even on the activity of pol β, which is thought to have a very similar three-dimensional structure to the pol β-like region of pol λ. This compound also did not inhibit the activities of prokaryotic pols and other DNA metabolic enzymes tested. These results suggested that compound
1 could be a selective inhibitor of eukaryotic pol λ. This compound had no inhibitory activities against two N-terminal truncated pol λ, del-1 pol λ (lacking nuclear localization signal (NLS), BRCA1 C-terminus (BRCT) domain [residues 133–575]), and del-2 pol λ (lacking NLS, BRCT, domain and proline-rich region [residues 245–575]). The compound
1-induced inhibition of intact pol λ activity was non-competitive with respect to both the DNA template-primer and the dNTP substrate. On the basis of these results, the pol λ inhibitory mechanism of compound
1 is discussed.