Structural relationship of curcumin derivatives binding to the BRCT domain of human DNA polymerase lambda.
We previously reported that phenolic compounds, petasiphenol and curcumin (diferuloylmethane), were a selective inhibitor of DNA polymerase lambda (pol lambda) 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 lambda (full-length, i.e. intact pol lambda including the BRCA1 C- terminal [BRCT] domain) by some derivatives was stronger than that by curcumin, and monoacetylcurcumin (compound 13) was the strongest pol lambda inhibitor of all the compounds tested, achieving 50% inhibition at a concentration of 3.9 microm. The compound did not influence the activities of replicative pols such as alpha, delta, and epsilon. It had no effect on pol beta activity either, although the three-dimensional structure of pol beta is thought to be highly similar to that of pol lambda. Compound 13 did not inhibit the activity of the C-terminal catalytic domain of pol lambda including the pol beta-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 lambda, but did not bind to the C-terminal region. Based on these results, the pol lambda-inhibitory mechanism of compound 13 is discussed.
Takeuchi
Toshifumi
T
Department of Applied Biological Science, Tokyo University of Science, Noda, Chiba, Japan.
Ishidoh
Tomomi
T
Iijima
Hiroshi
H
Kuriyama
Isoko
I
Shimazaki
Noriko
N
Koiwai
Osamu
O
Kuramochi
Kouji
K
Kobayashi
Susumu
S
Sugawara
Fumio
F
Sakaguchi
Kengo
K
Yoshida
Hiromi
H
Mizushina
Yoshiyuki
Y
D020816:Amino Acid Motifs; D019313:BRCA1 Protein / Q000378:metabolism*; D001665:Binding Sites; D003474:Curcumin / Q000031:analogs & derivatives / Q000378:metabolism* / Q000494:pharmacology; D019951:DNA Polymerase beta / Q000037:antagonists & inhibitors*; D004791:Enzyme Inhibitors / Q000378:metabolism* / Q000494:pharmacology; D006801:Humans; D007527:Isoenzymes / Q000037:antagonists & inhibitors / Q000378:metabolism; D008958:Models, Molecular; D015394:Molecular Structure; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D019032:Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization; D013329:Structure-Activity Relationship
D019313:BRCA1 Protein; D004791:Enzyme Inhibitors; D007527:Isoenzymes; C415367:DNA polymerase beta2; D019951:DNA Polymerase beta; D003474:Curcumin