Inhibition of mammalian DNA polymerases by resveratrol: mechanism and structural determinants.
Resveratrol, a natural compound found in many dietary plants and in red wine, plays an important role in the prevention of many human pathological processes, including inflammation, atherosclerosis and carcinogenesis. We have shown that the antiproliferative activity of resveratrol correlated with its ability to inhibit the replicative pols (DNA polymerases) alpha and delta in vitro [Stivala, Savio, Carafoli, Perucca, Bianchi, Maga, Forti, Pagnoni, Albini, Prosperi and Vannini (2001) J. Biol. Chem. 276, 22586-22594]. In this paper, we present the first detailed biochemical investigation on the mechanism of action of resveratrol towards mammalian pols. Our results suggest that specific structural determinants of the resveratrol molecule are responsible for selective inhibition of different mammalian pols, such as the family B pol alpha and the family X pol lambda. Moreover, the resveratrol derivative trans-3,5-dimethoxy-4-hydroxystilbene, which is endowed with a strong antiproliferative activity (Stivala et al., 2001), can inhibit pols alpha and lambda and also suppress the in vitro SV40 DNA replication. The potency of inhibition is similar to that of aphidicolin, an inhibitor of the three replicative pols alpha, delta and epsilon. Our findings establish the necessary background for the synthesis of resveratrol derivatives having more selective and potent antiproliferative activity.
Locatelli
Giada A
GA
Istituto di Genetica Molecolare IGM-CNR, 27100 Pavia, Italy.
Savio
Monica
M
Forti
Luca
L
Shevelev
Igor
I
Ramadan
Kristijan
K
Stivala
Lucia A
LA
Vannini
Vanio
V
Hübscher
Ulrich
U
Spadari
Silvio
S
Maga
Giovanni
G
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D004254:DNA Nucleotidyltransferases / Q000378:metabolism; D004261:DNA Replication; D004259:DNA-Directed DNA Polymerase / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008322:Mammals; D015394:Molecular Structure; D019384:Nucleic Acid Synthesis Inhibitors; D011485:Protein Binding; D000077185:Resveratrol; D013267:Stilbenes / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013379:Substrate Specificity
C439024:3,5-dihydroxy-4'-methoxystilbene; C506282:3,5-dimethoxy-4'-hydroxystilbene; D019384:Nucleic Acid Synthesis Inhibitors; D013267:Stilbenes; C010118:4,4'-dihydroxystilbene; D004254:DNA Nucleotidyltransferases; D004259:DNA-Directed DNA Polymerase; D000077185:Resveratrol