Flavonoids: True or promiscuous inhibitors of enzyme? The case of deoxyxylulose phosphate reductoisomerase

Tritsch, Denis; Zinglé, Catherine; Rohmer, Michel; Grosdemange-Billiard, Catherine

doi:10.1016/j.bioorg.2015.02.008

Cited by 26 publications

(23 citation statements)

References 45 publications

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“…25 We observed no change in the percentage inhibition and IC 50 of the compounds for all the three enzymes (Table 2) except in the case of compound 3f where a considerable loss of enzyme inhibitory activity was recorded.…”

Section: Resultsmentioning

confidence: 58%

Triblock Conjugates: Identification of a Highly Potent Antiinflammatory Agent

et al. 2015

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Rationally designed conjugates of chrysin, indole, and barbituric acid were synthesized and screened for their antiinflammatory activities through in vitro and in vivo experiments. Improved over the previously reported chrysin-indole-pyrazole conjugates and also in comparison to the chrysin, indole, and barbituric acid based COX-2 inhibitors, the new compounds have displayed significantly better IC50 for COX-2 and some of them also exhibited inhibition of 5-LOX enzyme. For one of the test compounds, IC50 for COX-2 and 5-LOX was 1 and 1.5 nM, respectively. Investigations of Swiss Albino mice through capsaicin induced paw lickings and dextran induced inflammation showed that these compounds possess appreciable analgesic and antiinflammatory activities. Ki, Ka, and ΔG for the enzyme-compound interaction were calculated and found to be in agreement with the biological data. The experimental results were supported by the molecular docking studies of the compounds in the active site of COX-2 and 5-LOX. Overall, a highly promising antiinflammatory agent was identified.

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Section: Resultsmentioning

confidence: 58%

Triblock Conjugates: Identification of a Highly Potent Antiinflammatory Agent

et al. 2015

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“…These species efficiently quench ThT fluorescence and are potentially false positives in many assays (Coelho-Cerqueira et al 2014). Furthermore, some flavonoids, including myricetin, are believed to derive their promiscuous activity from their ability to form aggregates at micro-molar concentrations (Tritsch et al 2015). If a more drug-like scaffold could access this type of chemical chaperone activity as proposed for EGCG, it could have powerful implications.…”

Section: Aggregation Inhibitorsmentioning

confidence: 99%

Interactions between Microtubule-Associated Protein Tau (MAPT) and Small Molecules

Rauch

Olson

Gestwicki

2016

Cold Spring Harb Perspect Med

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Tau aggregation is linked to multiple neurodegenerative disorders that are collectively termed tauopathies. Small molecules are powerful probes of the aggregation process, helping to reveal the key steps and serving as diagnostics and reporters. Moreover, some of these small molecules may have potential as therapeutics. This review details how small molecules and chemical biology have helped to elucidate the mechanisms of tau aggregation and how they are being used to detect and prevent tau aggregation. In addition, we comment on how new insights into tau prions are changing the approach to small molecule discovery.

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“…It has been reported recently that some flavonoids could produce promiscuous inhibition against DXR when using DMSO as a co-solvent16. Triton X-100 is often used as a dispersing agent to discriminate between the specific and non-specific inhibitions171819.…”

Section: Resultsmentioning

confidence: 99%

“…Then, we set two distinct concentrations for each of the theaflavins to evaluate its inhibition against DXR, one was close to its IC 50 value and the other was about twice of it. We also selected baicalein as a positive control since it has been demonstrated to be a non-specific inhibitor of DXR16. The data shown in Table 3 exhibit that for all four theaflavins, no noticeable difference in inhibition could be observed in the presence and absence of the detergent at either concentration, but for baicalein, the presence of Triton X-100 could significantly reduce its inhibition potency.…”

Section: Resultsmentioning

confidence: 99%

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Antimicrobial mechanism of theaflavins: They target 1-deoxy-D-xylulose 5-phosphate reductoisomerase, the key enzyme of the MEP terpenoid biosynthetic pathway

Xian

Qiao

Zhang

et al. 2016

Sci Rep

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1-Deoxy-D-xylulose 5-phosphate reductoisomerase (DXR) is the first committed enzyme in the 2-methyl-D-erythritol 4-phosphate (MEP) terpenoid biosynthetic pathway and is also a validated antimicrobial target. Theaflavins, which are polyphenolic compounds isolated from fermented tea, possess a wide range of pharmacological activities, especially an antibacterial effect, but little has been reported on their modes of antimicrobial action. To uncover the antibacterial mechanism of theaflavins and to seek new DXR inhibitors from natural sources, the DXR inhibitory activity of theaflavins were investigated in this study. The results show that all four theaflavin compounds could specifically suppress the activity of DXR, with theaflavin displaying the lowest effect against DXR (IC50 162.1 μM) and theaflavin-3,3′-digallate exhibiting the highest (IC50 14.9 μM). Moreover, determination of inhibition kinetics of the theaflavins demonstrates that they are non-competitive inhibitors of DXR against 1-deoxy-D-xylulose 5-phosphate (DXP) and un-competitive inhibitors with respect to NADPH. The possible interactions between DXR and the theaflavins were simulated via docking experiments.

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Flavonoids: True or promiscuous inhibitors of enzyme? The case of deoxyxylulose phosphate reductoisomerase

Cited by 26 publications

References 45 publications

Triblock Conjugates: Identification of a Highly Potent Antiinflammatory Agent

Triblock Conjugates: Identification of a Highly Potent Antiinflammatory Agent

Interactions between Microtubule-Associated Protein Tau (MAPT) and Small Molecules

Antimicrobial mechanism of theaflavins: They target 1-deoxy-D-xylulose 5-phosphate reductoisomerase, the key enzyme of the MEP terpenoid biosynthetic pathway

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