Structural homology between DNA binding sites of DNA polymerase β and DNA topoisomerase II

Mizushina, Yoshiyuki; Sugawara, Fumio; Iida, Akira; Sakaguchi, Kengo

doi:10.1006/jmbi.2000.4223

Cited by 23 publications

(16 citation statements)

References 38 publications

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“…3). Mizushina and co-workers [24] found this to be the preferred binding site for unsaturated fatty acids with yeast topoisomerase II. Not surprisingly, the nature of binding of these lipophilic triterpenoids is largely hydrophobic, and the triterpenoids can dock in various orientations in this binding pocket.…”

Section: Resultsmentioning

confidence: 95%

Non-Intercalative Triterpenoid Inhibitors of Topoisomerase II: A Molecular Docking Study

Setzer¹

2008

Open Bioact Compd J

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Abstract:Theoretical flexible docking studies were carried out on a number of triterpenoids previously shown to be inhibitors of topoisomerase II in order to assess the nature of binding of these non-intercalative inhibitors to the enzyme. The molecular docking results suggest that most of the triterpenoids preferentially bind to the DNA binding site of topoisomerase II, while a few also bind to the ATP binding site. These results provide some insight into the mode of activity of these cytotoxic natural products.

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Section: Resultsmentioning

confidence: 95%

Non-Intercalative Triterpenoid Inhibitors of Topoisomerase II: A Molecular Docking Study

Setzer¹

2008

Open Bioact Compd J

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“…The fatty acid shuttling function of L-FABP could be similar to that of CRBP, which shares structural homology with L-FABP (70). It is important to note that L-FABP may also provide a specific pool of fatty acids for nuclear utilization to modify the activity of certain nuclear enzymes, including DNA nucleotidase and DNA-dependent RNA polymerase (38) as well as DNA polymerases (72) and DNA topoisomerase II (73,74). Because L-FABP expression is regulated by fatty acid-induced PPAR␣ transcriptional activity (75), L-FABP may also regulate its own transcription by enhancing LCFA targeting to the nucleus.…”

Section: L-fabp Expression Stimulates Uptake and Nuclear Distributionmentioning

confidence: 99%

Liver Fatty Acid-binding Protein Targets Fatty Acids to the Nucleus

Huang¹,

Starodub²,

McIntosh³

et al. 2002

Journal of Biological Chemistry

130

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Because the nuclear peroxisome proliferator-activated receptors (PPAR) 1 regulate expression of genes involved in fatty acid oxidation (PPAR␣) and adiposity (PPAR␥), it has been postulated that PPARs play important roles in diabetes, atherosclerosis, and obesity (reviewed in Refs. 1-6). In support of this hypothesis, fatty acid oxidation is diminished in PPAR␣ geneablated mice (7-9) accompanied by fat accumulation (heart (10), centrilobular regions of the liver (7, 8), adipose tissue (11)), hypercholesterolemia (12), and hypoglycemia (10). (13). These data strongly support the possibility that LCFAs may be natural ligands for PPARs and that LCFAs may be more specific ligands for PPAR␣ as compared with other PPARs. Unfortunately, physiological significance of these findings is not yet clear since it is not known whether unesterified, unbound LCFAs are present in the cell and that their concentration in the nucleus is at least in the nanomolar range.A variety of studies suggest that unesterified LCFAs are present within the cell at levels physiologically significant for regulating PPAR␣ activity. Based on the Michaelis constant of long chain fatty acyl-CoA synthetase, the total cellular unesterified LCFA concentration has been estimated near 20 M (18). However, because of the presence of intracellular fatty acid-binding proteins (FABPs) (reviewed in Ref. 19), the intracellular concentration of unbound, unesterified LCFAs is thought to be nearly 3 orders of magnitude lower, near 7-50 nM in liver, heart, and intestine (20, 21). Whether nuclear levels of unbound LCFAs are also in the nanomolar range is not known. Another key question is the origin of nuclear unesterified LCFAs. Nuclei do not synthesize LCFAs but must import them from the cytosol (22-24) by as yet unresolved transport systems. Nearly 20 and 4% of the plasma-derived unesterified LCFAs appear in nuclei isolated from hepatocytes (23) and cerebral cortex or leukemic lymphocytes (22, 24 -26), respectively. Despite data suggesting the presence of high (up to 40% of nuclear lipids) levels of unesterified LCFAs in isolated nuclei (27), subcellular fractionation studies may be complicated by LCFAs derived from lipolytic release, transfer from other intracellular sites, or cross-contamination with other mem-

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“…6 o study the in vivo roles of mammalian DNA polymerases, we have tried to screen and isolate selective inhibitors from natural products. In the process, we found that many of the newly found polymerase inhibitors were also inhibitors of eukaryotic DNA topoisomerases, 1,2) and both the polymerases and the topoisomerases have a three-dimensionally very similar pocket accepting DNA. 1) Importantly, the 3D structures of the pockets might be slightly different among the enzyme species, and based on the micro-heterogeneity, specific inhibition might occur.…”

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confidence: 99%

“…1) Importantly, the 3D structures of the pockets might be slightly different among the enzyme species, and based on the micro-heterogeneity, specific inhibition might occur. 1) We report here the discovery of a new, potent DNA topoisomerase II (topo II) inhibitor in a traditional Chinese medicinal plant.…”

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confidence: 99%

A novel DNA topoisomerase inhibitor: dehydroebriconic acid, one of the lanostane‐type triterpene acids from Poria cocos

et al. 2004

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Traditional Chinese medicinal plants are a treasure house for screening novel inhibitors of DNA polymerases and DNA topoisomerases from mammals; in the present study, nine lanostanetype triterpene acids were found in sclerotium of Poria cocos. Among the nine compounds, only dehydroebriconic acid could potently inhibit DNA topoisomerase II (topo II) activity (IC50=4.6 μM), while the compound moderately inhibited the activities of DNA polymerases α, β, γ, δ, ɛ, η, iota;, κ and λ only from mammals, to similar extents. Another compound, dehydrotrametenonic acid, also showed moderate inhibitory effects against topo II (IC50=37.5 μM) and weak effects against all the polymerases tested. Both compounds showed no inhibitory effect against topo I, higher plant (cauliflower) DNA polymerase I (α‐like polymerase) or II (βlike polymerase), calf thymus terminal deoxynucleotidyl transferase, human immunodeficiency virus type‐1 reverse transcriptase, prokaryotic DNA polymerases such as the Klenow fragment of E. coli DNA polymerase I, Taq DNA polymerase and T4 DNA polymerase, or DNA metabolic enzymes such as T7 RNA polymerase, T4 polynucleotide kinase and bovine deoxyribonu‐clease I. These findings suggest that dehydroebriconic acid and dehydrotrametenonic acid should be designated as topo II‐preferential inhibitors, although they also moderately inhibited all the mammalian DNA polymerases tested. Both dehydrotrametenonic acid and dehydroebriconic acid could prevent the growth of human gastric cancer cells, and their LD50 values were 63.6 and 38.4 μM, respectively. The cells were halted at the G1 phase in the cell cycle. The relation between the structure of triterpene acids and their inhibitory activities is discussed.

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Structural homology between DNA binding sites of DNA polymerase β and DNA topoisomerase II

Cited by 23 publications

References 38 publications

Non-Intercalative Triterpenoid Inhibitors of Topoisomerase II: A Molecular Docking Study

Non-Intercalative Triterpenoid Inhibitors of Topoisomerase II: A Molecular Docking Study

Liver Fatty Acid-binding Protein Targets Fatty Acids to the Nucleus

A novel DNA topoisomerase inhibitor: dehydroebriconic acid, one of the lanostane‐type triterpene acids from Poria cocos

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