Anti-malarial drug targets: Screening for inhibitors of 2C-methyl-d-erythritol 4-phosphate synthase (IspC protein) in Mediterranean plants

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.

show abstract

“…3A, the insert) with an IC 50 of 0.27 μM. These data are in good agreement with the previously published results515.…”

Section: Resultssupporting

confidence: 92%

“…Kaiser et al . have found that the leaf extracts of Cercis siliquastrum , a Mediterranean plant, exhibit strong inhibitory activity against DXR5.…”

mentioning

confidence: 99%

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

View full text Add to dashboard Cite

show abstract

“…This pivotal finding not only exemplifies the diversity of pathways involved in natural product biosynthesis, but also has provided new antimicrobial and antimalarial drug targets that are being actively explored using compounds such as fosmidomycin. 15,58 A number of isotope tracer studies have also confirmed close relationships between primary and secondary metabolisms, as shown in the shunt pathway that connects HMG-CoA and the branched-chain fatty acid precursor, isovaleryl-CoA. Other studies have demonstrated inter-relationships between different metabolic pathways, such as the convergence of isoprene and polyketide biosynthesis through the HMG-CoA synthase homologues.…”

Section: The Discovery Of the 2-epi-5-epi-valiolone Pathwaymentioning

confidence: 88%

Isotope tracer investigations of natural products biosynthesis: the discovery of novel metabolic pathways

Mahmud

2007

Labelled Comp Radiopharmac

View full text Add to dashboard Cite

Feeding experiments using isotopically labeled precursors remain crucial elements in the study of natural product biosynthesis. Through careful isotope tracer studies, a number of previously unrecognized biosynthetic pathways have now become obvious. One of the remarkable examples is the discovery of the non-mevalonate pathway in plants, bacteria, algae, and plasmodium, whereas others include the discovery of a new shunt pathway that connects the mevalonate pathway and branched-chain fatty acids in myxobacteria and the involvement of an unusual HMG-CoA synthase-like mechanism in polyketide biosynthesis. Significant progress has also been made in the biosynthetic studies of aminocyclitol-derived natural products and other bioactive secondary metabolites. This review highlights some of the more recent discoveries of novel mechanisms and metabolic pathways involved in natural product biosynthesis based on isotope tracer experiments.

show abstract

“…Also, the water extract was effective against B. subtilis at the same concentration. [26] The results showed that butanol extracts had a strong antimicrobial activity against all species, whereas the chloroform extract had a moderate activity and petroleum ether extract was inactive. In addition, both extracts did not provide good antimicrobial activity with a MIC value of 1250 lg/ml concentration against the upper respiratory tract infections caused by Haemophilus influenzae.…”

Section: Antioxidant Activitymentioning

confidence: 97%

Phytochemical Profile and Biological Activities of Helianthemum canum l. baumg. from Turkey

Baldemir

Gökşen

Ildız

et al. 2017

Chemistry & Biodiversity

View full text Add to dashboard Cite

In the current study, antioxidant, antibacterial activities, and the phenolic compositions of extracts from Helianthemum canum L. Baumg. (Apiaceae) aerial parts were investigated for the first time. The H. canum was extracted with 70% methanol (HCMeOH) and water (HCW). Both extracts were determined by total phenolic contents (3 mg/ml), flavonoids (1.5 mg/ml), flavonols (1.5 mg/ml), qualitative-quantitative compositions, iron (II) chelation activities (0.1 - 5 mg/ml), free radical scavenging activities (DPPH : 0.01 - 0.6 mg/ml and ABTS : 0.125 - 0.5 mg/ml) and the effect upon inhibition of β-carotene/linoleic acid co-oxidation (1 mg/ml). The peroxidation level was also determined using the thiobarbituric acid method (0.01 - 1.5 mg/ml). The results of the activity tests given as IC values were estimated from non-linear algorithm and compared with standards. Antibacterial activities of extracts and standards were evaluated against Gram-negative and -positive ten standard strains using disc diffusion and broth microdilution methods. The MIC results (312.5 - 2500 μg/ml) against tested microorganisms varied from 625 to 2500 μg/ml. In HPLC analysis, 3,5-dihydroxybenzoic acid was found as the main substance in both extracts. These results showed that HCMeOH was richer in phenolic compounds (284.13 ± 0.30 mg GAE/g extract) from HCW (244.55 ± 0.35 mg GAE/g extract) In conclusion, H. canum extracts showed in vitro antibacterial and antioxidant activities.

show abstract

Anti-malarial drug targets: Screening for inhibitors of 2C-methyl-d-erythritol 4-phosphate synthase (IspC protein) in Mediterranean plants

Cited by 23 publications

References 35 publications

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

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

Isotope tracer investigations of natural products biosynthesis: the discovery of novel metabolic pathways

Phytochemical Profile and Biological Activities of Helianthemum canum l. baumg. from Turkey

Contact Info

Product

Resources

About