Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase

Sánchez‐del‐Campo, Luis; Saez-Ayala, Magali; Chazarra, Soledad; Cabezas‐Herrera, Juan; Rodrı́guez-López, José Neptuno

doi:10.3390/ijms10125398

Cited by 26 publications

(19 citation statements)

References 31 publications

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“…The decrease could be explained by the fact that some polyphenols inhibit intestinal folate uptake [40] or influence the activity of dihydrofolate reductase which is an enzyme necessary for maintaining intracellular pools of tetrahydrofolate [41], [42].…”

Section: Discussionmentioning

confidence: 99%

Hydroxytyrosol supplementation increases vitamin C levels in vivo. A human volunteer trial

López‐Huertas

Fonolla

2017

Redox Biology

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Hydroxytyrosol (HT) is a main phenolic component of olive oil. In this study, we investigated the safety and effects produced by HT purified (99.5%) from olive mill waste. HT was administered at a daily dosage of 45 mg for 8 weeks to volunteers with mild hyperlipidemia (n=14). We measured markers of cardiovascular disease risk, enzyme markers of several clinical conditions, hematology, antioxidant parameters, vitamins and minerals at baseline (T0), 4 weeks (T4) and 8 weeks (T8). The values obtained at T4 and T8 were compared with baseline. We found that the HT dose administered was safe and mostly did not influence markers of cardiovascular disease, blood lipids, inflammatory markers, liver or kidney functions and the electrolyte balance. Serum iron levels remained constant but a significant (P<0.05) decrease in ferritin at T4 and T8 was found. Serum folate and red blood cell folate levels were also reduced at T4 and T8. Finally, vitamin C increased by two-fold at T4 and T8 compared with levels at baseline. These results indicate a physiologically relevant antioxidant function for HT through increasing endogenous vitamin C levels.

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Section: Discussionmentioning

confidence: 99%

Hydroxytyrosol supplementation increases vitamin C levels in vivo. A human volunteer trial

López‐Huertas

Fonolla

2017

Redox Biology

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“…Fluorescence quenching experiments demonstrated that the ester bond containing tea polyphenols EGCG and ECG are effective inhibitors of DHFR with K d of 0.9 and 1.8 µM, respectively, while polyphenols lacking the ester bond containing galloyl moiety (e.g., EGC and EC) did not bind to this enzyme [54]. The binding constant of EGCG to catalase was determined fluorimetrically to be 2.27×10 6 M −1 ( K d of 0.44 µM).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Catalase by Tea Catechins in Free and Cellular State: A Biophysical Approach

2014

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Tea flavonoids bind to variety of enzymes and inhibit their activities. In the present study, binding and inhibition of catalase activity by catechins with respect to their structure-affinity relationship has been elucidated. Fluorimetrically determined binding constants for (−)-epigallocatechin gallate (EGCG) and (−)-epicatechin gallate (ECG) with catalase were observed to be 2.27×106 M−1 and 1.66×106 M−1, respectively. Thermodynamic parameters evidence exothermic and spontaneous interaction between catechins and catalase. Major forces of interaction are suggested to be through hydrogen bonding along with electrostatic contributions and conformational changes. Distinct loss of α-helical structure of catalase by interaction with EGCG was captured in circular dichroism (CD) spectra. Gallated catechins demonstrated higher binding constants and inhibition efficacy than non-gallated catechins. EGCG exhibited maximum inhibition of pure catalase. It also inhibited cellular catalase in K562 cancer cells with significant increase in cellular ROS and suppression of cell viability (IC50 54.5 µM). These results decipher the molecular mechanism by which tea catechins interact with catalase and highlight the potential of gallated catechin like EGCG as an anticancer drug. EGCG may have other non-specific targets in the cell, but its anticancer property is mainly defined by ROS accumulation due to catalase inhibition.

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“…Quercetin 3-O-xyloside binds dihydrofolate reductase (DHFR), which is a key enzyme for the biosynthesis of DNA, RNA, and amino acids and has potential as an anticancer drug (31,32). It also shows promise against complications associated with diabetes by inhibiting lens aldol reductase (33).…”

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confidence: 99%

Synthesis of Flavonoid O -Pentosides by Escherichia coli through Engineering of Nucleotide Sugar Pathways and Glycosyltransferase

Han

Kim

Yoon

et al. 2014

Appl Environ Microbiol

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Plants produce two flavonoid O-pentoses, flavonoid O-xyloside and flavonoid O-arabinoside. However, analyzing their biological properties is difficult because flavonoids are not naturally produced in sufficient quantities. In this study, Escherichia coli was used to synthesize the plant-specific flavonoid O-pentosides quercetin 3-O-xyloside and quercetin 3-O-arabinoside. Two strategies were used. First, E. coli was engineered to express components of the biosynthetic pathways for UDP-xylose and UDP-arabinose. For UDP-xylose biosynthesis, two genes, UXS (UDP-xylose synthase) from Arabidopsis thaliana and ugd (UDP-glucose dehydrogenase) from E. coli, were overexpressed. In addition, the gene encoding ArnA (UDP-L-Ara4N formyltransferase/UDPGlcA C-4؆-decarboxylase), which competes with UXS for UDP-glucuronic acid, was deleted. For UDP-arabinose biosynthesis, UXE (UDP-xylose epimerase) was overexpressed. Next, we engineered UDP-dependent glycosyltransferases (UGTs) to ensure specificity for UDP-xylose and UDP-arabinose. The E. coli strains thus obtained synthesized approximately 160 mg/liter of quercetin 3-O-xyloside and quercetin 3-O-arabinoside.

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Binding of Natural and Synthetic Polyphenols to Human Dihydrofolate Reductase

Cited by 26 publications

References 31 publications

Hydroxytyrosol supplementation increases vitamin C levels in vivo. A human volunteer trial

Hydroxytyrosol supplementation increases vitamin C levels in vivo. A human volunteer trial

Inhibition of Catalase by Tea Catechins in Free and Cellular State: A Biophysical Approach

Synthesis of Flavonoid O -Pentosides by Escherichia coli through Engineering of Nucleotide Sugar Pathways and Glycosyltransferase

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