Chicoric Acid: Natural Occurrence, Chemical Synthesis, Biosynthesis, and Their Bioactive Effects.
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ABSTRACT:
SUBMITTER: Yang M
PROVIDER: S-EPMC9262330 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Purple coneflower (Echinacea purpurea (L.) Moench) is a popular native North American herbal plant. Its major bioactive compound, chicoric acid, is reported to have various potential physiological functions, but little is known about its biosynthesis. Here, taking an activity-guided approach, we identify two cytosolic BAHD acyltransferases that form two intermediates, caftaric acid and chlorogenic acid. Surprisingly, a unique serine carboxypeptidase-like acyltransferase uses chlorogenic acid as its acyl donor and caftaric acid as its acyl acceptor to produce chicoric acid in vacuoles, which has evolved its acyl donor specificity from the better-known 1-O-β-D-glucose esters typical for this specific type of acyltransferase to chlorogenic acid. This unusual pathway seems unique to Echinacea species suggesting convergent evolution of chicoric acid biosynthesis. Using these identified acyltransferases, we have reconstituted chicoric acid biosynthesis in tobacco. Our results emphasize the flexibility of acyltransferases and their roles in the evolution of specialized metabolism in plants.
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Project description:The prodiginine family of bacterial alkaloids is a diverse set of heterocyclic natural products that have likely been known to man since antiquity. In more recent times, these alkaloids have been discovered to span a wide range of chemical structures that possess a number of interesting biological activities. This review provides a comprehensive overview of research undertaken toward the isolation and structural elucidation of the prodiginine family of natural products. Additionally, research toward chemical synthesis of the prodiginine alkaloids over the last several decades is extensively reviewed. Finally, the current, evidence-based understanding of the various biosynthetic pathways employed by bacteria to produce prodiginine alkaloids is summarized.
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Project description:Biosynthesis of the leukotriene A (LTA) class of epoxide is a lipoxygenase-catalyzed transformation requiring a fatty acid hydroperoxide substrate containing at least three double bonds. Here, we report on biosynthesis of a dienoic analog of LTA epoxides via a different enzymatic mechanism. Beginning with homolytic cleavage of the hydroperoxide moiety, a catalase/peroxidase-related hemoprotein from Anabaena PCC 7120, which occurs in a fusion protein with a linoleic acid 9R-lipoxygenase, dehydrates 9R-hydroperoxylinoleate to a highly unstable epoxide. Using methods we developed for isolating extremely labile compounds, we prepared and purified the epoxide and characterized its structure as 9R,10R-epoxy-octadeca-11E,13E-dienoate. This epoxide hydrolyzes to stable 9,14-diols that were reported before in linoleate autoxidation (Hamberg, M. 1983. Autoxidation of linoleic acid: Isolation and structure of four dihydroxy octadecadienoic acids. Biochim. Biophys. Acta 752: 353-356) and in incubations with the Anabaena enzyme (Lang, I., C. Göbel, A. Porzel, I. Heilmann, and I. Feussner. 2008. A lipoxygenase with linoleate diol synthase activity from Nostoc sp. PCC 7120. Biochem. J. 410: 347-357). We also prepared an equivalent epoxide from 13S-hydroperoxylinoleate using a "biomimetic" chemical method originally described for LTA(4) synthesis and showed that like LTA(4), the C18.2 epoxide conjugates readily with glutathione, a potential metabolic fate in vivo. We compare and contrast the mechanisms of LTA-type allylic epoxide synthesis by lipoxygenase, catalase/peroxidase, and chemical transformations. These findings provide new insights into the reactions of linoleic acid hydroperoxides and extend the known range of catalytic activities of catalase-related hemoproteins.
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Project description:Glucosinolates (GSLs) are secondary plant metabolites abundantly found in plant order Brassicales. GSLs are constituted by an S-?-d-glucopyrano unit anomerically connected to O-sulfated (Z)-thiohydroximate moiety. The side-chain of the O-sulfate thiohydroximate moiety, which is derived from a different amino acid, contributes to the diversity of natural GSL, with more than 130 structures identified and validated to this day. Both the structural diversity of GSL and their biological implication in plants have been biochemically studied. Although chemical syntheses of GSL have been devised to give access to these secondary metabolites, direct extraction from biomass remains the conventional method to isolate natural GSL. While intact GSLs are biologically inactive, various products, including isothiocyanates, nitriles, epithionitriles, and cyanides obtained through their hydrolysis of GSLs, exhibit many different biological activities, among which several therapeutic benefits have been suggested. This article reviews natural occurrence, accessibility via chemical, synthetic biochemical pathways of GSL, and the current methodology of extraction, purification, and characterization. Structural information, including the most recent classification of GSL, and their stability and storage conditions will also be discussed. The biological perspective will also be explored to demonstrate the importance of these prominent metabolites.
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Project description:Thiocarboxylic acid-containing natural products are rare and their biosynthesis and biological significance remain unknown. Thioplatensimycin (thioPTM) and thioplatencin (thioPTN), thiocarboxylic acid congeners of the antibacterial natural products platensimycin (PTM) and platencin (PTN), were recently discovered. Here we report the biosynthetic origin of the thiocarboxylic acid moiety in thioPTM and thioPTN. We identify a thioacid cassette encoding two proteins, PtmA3 and PtmU4, responsible for carboxylate activation by coenzyme A and sulfur transfer, respectively. ThioPTM and thioPTN bind tightly to ?-ketoacyl-ACP synthase II (FabF) and retain strong antibacterial activities. Density functional theory calculations of binding and solvation free energies suggest thioPTM and thioPTN bind to FabF more favorably than PTM and PTN. Additionally, thioacid cassettes are prevalent in the genomes of bacteria, implicating that thiocarboxylic acid-containing natural products are underappreciated. These results suggest that thiocarboxylic acid, as an alternative pharmacophore, and thiocarboxylic acid-containing natural products may be considered for future drug discovery.
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Project description:L-5-hydroxytryptophan (5-HTP) is both a drug and a natural component of some dietary supplements. 5-HTP is produced from tryptophan by tryptophan hydroxylase (TPH), which is present in two isoforms (TPH1 and TPH2). Decarboxylation of 5-HTP yields serotonin (5-hydroxytryptamine, 5-HT) that is further transformed to melatonin (N-acetyl-5-methoxytryptamine). 5-HTP plays a major role both in neurologic and metabolic diseases and its synthesis from tryptophan represents the limiting step in serotonin and melatonin biosynthesis. In this review, after an look at the main natural sources of 5-HTP, the chemical analysis and synthesis, biosynthesis and microbial production of 5-HTP by molecular engineering will be described. The physiological effects of 5-HTP are discussed in both animal studies and human clinical trials. The physiological role of 5-HTP in the treatment of depression, anxiety, panic, sleep disorders, obesity, myoclonus and serotonin syndrome are also discussed. 5-HTP toxicity and the occurrence of toxic impurities present in tryptophan and 5-HTP preparations are also discussed.
| S-EPMC7796270 | biostudies-literature
Project description:BackgroundCurrent research on skin tissue engineering has been focusing on novel therapies for the effective management of chronic wounds. A critical aspect is to develop matrices that promote growth and uniform distribution of cells across the wound area, and at the same time offer protection, as well as deliver drugs that help wound healing and tissue regeneration. In this context, we aimed at developing electrospun scaffolds that could serve as carriers for the bioactive natural products alkannin and shikonin (A/S).MethodsA series of polymeric nanofibers composed of cellulose acetate (CA) or poly(ε-caprolactone) (PCL) and varying ratios of a mixture of A/S derivatives, has been successfully fabricated and their physico-chemical and biological properties have been explored.ResultsScanning electron microscopy revealed a uniform and bead-free morphology for CA scaffolds, while for PCL beads along the fibers were observed. The average diameters for all nanofibers ranged between 361 ± 47 and 487 ± 88 nm. During the assessment of physicochemical characteristics, CA fiber mats exhibited a more favored profile, while the assessment of the biological properties of the scaffolds showed that CA samples containing A/S mixture up to 1 wt.% achieved to facilitate attachment, survival and migration of Hs27 fibroblasts. With respect to the antimicrobial properties of the scaffolds, higher drug-loaded (1 and 5 wt.%) samples succeeded in inhibiting the growth of Staphylococcus epidermidis and S. aureus around the edges of the fiber mats. Finally, carrying out a structure-activity relationship study regarding the biological activities (fibroblast toxicity/proliferation and antibacterial activity) of pure A/S compounds - present in the A/S mixture - we concluded that A/S ester derivatives and the dimeric A/S augmented cell proliferation after 3 days, whereas shikonin proved to be toxic at 500 nM and 1 μM and alkannin only at 1 μM. Additionally, alkannin, shikonin and acetyl-shikonin showed more pronounced antibacterial properties than the other esters, the dimeric derivative and the A/S mixture itself.ConclusionsTaken together, these findings indicate that embedding A/S derivatives into CA nanofibers might be an advantageous drug delivery system that could also serve as a potential candidate for biomedical applications in the field of skin tissue engineering.
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Project description:Natural products containing carbon-phosphorus bonds (phosphonic and phosphinic acids) have found widespread use in medicine and agriculture. Recent years have seen a renewed interest in the biochemistry and biology of these compounds with the cloning of the biosynthetic gene clusters for several family members. This review discusses the commonalities and differences in the molecular logic that lie behind the biosynthesis of these compounds. The current knowledge regarding the metabolic pathways and enzymes involved in the production of a number of natural products, including the approved antibiotic fosfomycin, the widely used herbicide phosphinothricin (PT), and the clinical candidate for treatment of malaria FR-900098, is presented. Many of the enzymes involved in the biosynthesis of these compounds catalyze chemically and biologically unprecedented transformations, and a wealth of new biochemistry has been revealed through their study. These investigations have also suggested new strategies for natural product discovery.
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Project description:The controversial anti-proliferative effects of Echinacea purpurea (L.) Moench (Asteraceae) might be related to different plant metabolites contained in plant samples, extracts and products. The influence of bacterial endophytes on the synthesis of bioactive compounds in the medicinal plants has been previously demonstrated but there are only few studies addressing anticancer effects and mechanisms of E. purpurea extracts following endophytic colonization. The present study aimed to test and compare the lactate dehydrogenase (LDH) inhibition potential of n-hexane and methanol extracts from in vitro endophyte non-inoculated and inoculated E. purpurea plants. An in vitro model was previously set up to perform the infection of axenic E. purpurea plants with bacterial endophytic strains isolated from E. purpurea aerial part. Only methanol extracts showed LDH5 inhibition, in particular the richest in chicoric acid and most strongly inhibiting extract was obtained from inoculated stem and leaves of E. purpurea (IC50 = 0.9 mg/ml). Chicoric acid showed an IC50 value (66.7 µM) in enzymatic assays better than that of the reference compound galloflavin. Modeling studies were carried out to suggest the putative interaction mode of chicoric acid in the enzyme active site. This in vitro model on plant-bacterial interaction may lead to obtain extracts from plants enriched in bioactive compounds and it is a new approach for the discovery of novel anticancer compounds.
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Project description:Epoxy PUFAs are endogenous cytochrome P450 (P450) metabolites of dietary PUFAs. Although these metabolites exert numerous biological effects, attempts to study their complex biology have been hampered by difficulty in obtaining the epoxides as pure regioisomers and enantiomers. To remedy this, we synthesized 19,20- and 16,17-epoxydocosapentaenoic acids (EDPs) (the two most abundant EDPs in vivo) by epoxidation of DHA with WT and the mutant (F87V) P450 enzyme BM3 from Bacillus megaterium WT epoxidation yielded a 4:1 mixture of 19,20:16,17-EDP exclusively as (S,R) enantiomers. Epoxidation with the mutant (F87V) yielded a 1.6:1 mixture of 19,20:16,17-EDP; the 19,20-EDP fraction was ∼9:1 (S,R):(R,S), but the 16,17-EDP was exclusively the (S,R) enantiomer. To access the (R,S) enantiomers of these EDPs, we used a short (four-step) chemical inversion sequence, which utilizes 2-(phenylthio)ethanol as the epoxide-opening nucleophile, followed by mesylation of the resulting alcohol, oxidation of the thioether moiety, and base-catalyzed elimination. This short synthesis cleanly converts the (S,R)-epoxide to the (R,S)-epoxide without loss of enantiopurity. This method, also applicable to eicosapentaenoic acid and arachidonic acid, provides a simple, cost-effective procedure for accessing larger amounts of these metabolites.
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