Abstract
A number of compounds used for cancer chemotherapy exert their effects by inhibiting DNA replication. New inhibitors of DNA polymerases, therefore, could be potential candidates for new anti-cancer drugs. This study tested the effects of two phenalenone-skeleton-based compounds, which were isolated from a marine-derived fungus Penicillium sp., sculezonone-B (SCUL-B) and sculezonone-A (SCUL-A), upon DNA polymerase activity. Both compounds inhibited bovine DNA polymerases α and γ, moderately affected the activity of DNA polymerase ε, and had almost no effect on HIV-reverse transcriptase and an E. coli DNA polymerase I Klenow fragment. Most notably, whereas SCUL-A inhibited pol β (IC50 = 17 μM), SCUL-B has only a weak influence upon this polymerase (IC50 = 90 μM). Kinetic studies showed that inhibition of both DNA polymerases α and β by either SCUL-A or SCUL-B was competitive with respect to dTTP substrate and noncompetitive with the template-primer. Whereas pol α inhibition by SCUL-B is competitive with respect to dATP, the inhibition by SCUL-A was found to be a mixed type with dATP substrate. The Ki values of SCUL-B were calculated to be 1.8 and 6.8 μM for DNA polymerases α and γ, respectively. The Ki of DNA polymerase β for SCUL-A was 12 μM and that for DNA polymerase α, 16 μM. Therefore, deletion of the OH-group at C12 enhanced inhibition of DNA polymerase β. Since computational analyses of these two inhibitors revealed a remarkable difference in the distribution of negative electrostatic charge on the surface of molecules, we infer that different electrostatic charges might elicit different inhibition spectra from these two compounds.
| Original language | English |
|---|---|
| Pages (from-to) | 7610-7616 |
| Number of pages | 7 |
| Journal | Biochemistry |
| Volume | 41 |
| Issue number | 24 |
| DOIs | |
| Publication status | Published - 18-06-2002 |
| Externally published | Yes |
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All Science Journal Classification (ASJC) codes
- Biochemistry
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Novel phenalenone derivatives from a marine-derived fungus exhibit. Distinct inhibition spectra against eukaryotic DNA polymerases. / Perpelescu, Marinela; Kobayashi, Jun'ichi; Furuta, Miho; Ito, Yasutomo; Izuta, Shunji; Takemura, Masaharu; Suzuki, Motoshi; Yoshida, Shonen.
In: Biochemistry, Vol. 41, No. 24, 18.06.2002, p. 7610-7616.Research output: Contribution to journal › Article
TY - JOUR
T1 - Novel phenalenone derivatives from a marine-derived fungus exhibit. Distinct inhibition spectra against eukaryotic DNA polymerases
AU - Perpelescu, Marinela
AU - Kobayashi, Jun'ichi
AU - Furuta, Miho
AU - Ito, Yasutomo
AU - Izuta, Shunji
AU - Takemura, Masaharu
AU - Suzuki, Motoshi
AU - Yoshida, Shonen
PY - 2002/6/18
Y1 - 2002/6/18
N2 - A number of compounds used for cancer chemotherapy exert their effects by inhibiting DNA replication. New inhibitors of DNA polymerases, therefore, could be potential candidates for new anti-cancer drugs. This study tested the effects of two phenalenone-skeleton-based compounds, which were isolated from a marine-derived fungus Penicillium sp., sculezonone-B (SCUL-B) and sculezonone-A (SCUL-A), upon DNA polymerase activity. Both compounds inhibited bovine DNA polymerases α and γ, moderately affected the activity of DNA polymerase ε, and had almost no effect on HIV-reverse transcriptase and an E. coli DNA polymerase I Klenow fragment. Most notably, whereas SCUL-A inhibited pol β (IC50 = 17 μM), SCUL-B has only a weak influence upon this polymerase (IC50 = 90 μM). Kinetic studies showed that inhibition of both DNA polymerases α and β by either SCUL-A or SCUL-B was competitive with respect to dTTP substrate and noncompetitive with the template-primer. Whereas pol α inhibition by SCUL-B is competitive with respect to dATP, the inhibition by SCUL-A was found to be a mixed type with dATP substrate. The Ki values of SCUL-B were calculated to be 1.8 and 6.8 μM for DNA polymerases α and γ, respectively. The Ki of DNA polymerase β for SCUL-A was 12 μM and that for DNA polymerase α, 16 μM. Therefore, deletion of the OH-group at C12 enhanced inhibition of DNA polymerase β. Since computational analyses of these two inhibitors revealed a remarkable difference in the distribution of negative electrostatic charge on the surface of molecules, we infer that different electrostatic charges might elicit different inhibition spectra from these two compounds.
AB - A number of compounds used for cancer chemotherapy exert their effects by inhibiting DNA replication. New inhibitors of DNA polymerases, therefore, could be potential candidates for new anti-cancer drugs. This study tested the effects of two phenalenone-skeleton-based compounds, which were isolated from a marine-derived fungus Penicillium sp., sculezonone-B (SCUL-B) and sculezonone-A (SCUL-A), upon DNA polymerase activity. Both compounds inhibited bovine DNA polymerases α and γ, moderately affected the activity of DNA polymerase ε, and had almost no effect on HIV-reverse transcriptase and an E. coli DNA polymerase I Klenow fragment. Most notably, whereas SCUL-A inhibited pol β (IC50 = 17 μM), SCUL-B has only a weak influence upon this polymerase (IC50 = 90 μM). Kinetic studies showed that inhibition of both DNA polymerases α and β by either SCUL-A or SCUL-B was competitive with respect to dTTP substrate and noncompetitive with the template-primer. Whereas pol α inhibition by SCUL-B is competitive with respect to dATP, the inhibition by SCUL-A was found to be a mixed type with dATP substrate. The Ki values of SCUL-B were calculated to be 1.8 and 6.8 μM for DNA polymerases α and γ, respectively. The Ki of DNA polymerase β for SCUL-A was 12 μM and that for DNA polymerase α, 16 μM. Therefore, deletion of the OH-group at C12 enhanced inhibition of DNA polymerase β. Since computational analyses of these two inhibitors revealed a remarkable difference in the distribution of negative electrostatic charge on the surface of molecules, we infer that different electrostatic charges might elicit different inhibition spectra from these two compounds.
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U2 - 10.1021/bi020115a
DO - 10.1021/bi020115a
M3 - Article
VL - 41
SP - 7610
EP - 7616
JO - Biochemistry
JF - Biochemistry
SN - 0006-2960
IS - 24
ER -