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Structural relationship of curcumin derivatives binding to the BRCT domain of human DNA polymerase λ
Author(s) -
Takeuchi Toshifumi,
Ishidoh Tomomi,
Iijima Hiroshi,
Kuriyama Isoko,
Shimazaki Noriko,
Koiwai Osamu,
Kuramochi Kouji,
Kobayashi Susumu,
Sugawara Fumio,
Sakaguchi Kengo,
Yoshida Hiromi,
Mizushina Yoshiyuki
Publication year - 2006
Publication title -
genes to cells
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.912
H-Index - 115
eISSN - 1365-2443
pISSN - 1356-9597
DOI - 10.1111/j.1365-2443.2006.00937.x
Subject(s) - curcumin , biology , dna polymerase , processivity , polymerase , dna , in vitro , biochemistry , structure–activity relationship , microbiology and biotechnology , stereochemistry , chemistry
We previously reported that phenolic compounds, petasiphenol and curcumin (diferuloylmethane), were a selective inhibitor of DNA polymerase λ (pol λ) in vitro . The purpose of this study was to investigate the molecular structural relationship of curcumin and 13 chemically synthesized derivatives of curcumin. The inhibitory effect on pol λ (full‐length, i.e. intact pol λ including the BRCA1 C‐ terminal [BRCT] domain) by some derivatives was stronger than that by curcumin, and monoacetylcurcumin (compound 13) was the strongest pol λ inhibitor of all the compounds tested, achieving 50% inhibition at a concentration of 3.9 µ m . The compound did not influence the activities of replicative pols such as α, δ, and ɛ. It had no effect on pol β activity either, although the three‐dimensional structure of pol β is thought to be highly similar to that of pol λ. Compound 13 did not inhibit the activity of the C‐terminal catalytic domain of pol λ including the pol β‐like core, in which the BRCT motif was deleted from its N‐terminal region. MALDI‐TOF MS analysis demonstrated that compound 13 bound selectively to the N‐terminal domain of pol λ, but did not bind to the C‐terminal region. Based on these results, the pol λ‐inhibitory mechanism of compound 13 is discussed.