Structure–activity relationships of tulipalines, tuliposides, and related compounds as inhibitors of MurA

Mendgen, Thomas; Scholz, Therese; Klein, Christian D.

doi:10.1016/j.bmcl.2010.07.139

Cited by 35 publications

(27 citation statements)

References 16 publications

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“…Tulipalins A and B show antimicrobial activities against a broad range of strains of bacteria and fungi, where tulipalin A functions as an antifungal agent rather than antibacterial and tulipalin B functions in the opposite manner (Bergman, 1966;Bergman et al, 1967;Bergman and Beijersbergen, 1968;Tschesche et al, 1968Tschesche et al, , 1969Beijersbergen, 1972;Beijersbergen and Lemmers, 1972;Schönbeck and Schroeder, 1972;Mendgen et al, 2010;Shigetomi et al, 2010Shigetomi et al, , 2011. In addition, tulipalin A has been reported to exhibit high insecticidal activity (Kim et al, 1998(Kim et al, , 1999.…”

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confidence: 99%

A Novel Lactone-Forming Carboxylesterase: Molecular Identification of a Tuliposide A-Converting Enzyme in Tulip

2012

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Tuliposides, the glucose esters of 4-hydroxy-2-methylenebutanoate and 3,4-dihydroxy-2-methylenebutanoate, are major secondary metabolites in tulip (Tulipa gesneriana). Their lactonized aglycons, tulipalins, function as defensive chemicals due to their biological activities. We recently found that tuliposide-converting enzyme (TCE) purified from tulip bulbs catalyzed the conversion of tuliposides to tulipalins, but the possibility of the presence of several TCE isozymes was raised: TCE in tissues other than bulbs is different from bulb TCE. Here, to prove this hypothesis, TCE was purified from petals, which have the second highest TCE activity after bulbs. The purified enzyme, like the bulb enzyme, preferentially accepted tuliposides as substrates, with 6-tuliposide A the best substrate, which allowed naming the enzyme tuliposide A-converting enzyme (TCEA), but specific activity and molecular mass differed between the petal and bulb enzymes. After peptide sequencing, a novel cDNA (TgTCEA) encoding petal TCEA was isolated, and the functional characterization of the recombinant enzyme verified that TgTCEA catalyzes the conversion of 6-tuliposide A to tulipalin A. TgTCEA was transcribed in all tulip tissues but not in bulbs, indicating the presence of a bulb-specific TgTCEA, as suggested by the distinct enzymatic characters between the petal and bulb enzymes. Plastidial localization of TgTCEA enzyme was revealed, which allowed proposing a cytological mechanism of TgTCE-mediated tulipalin formation in the tulip defensive strategy. Site-directed mutagenesis of TgTCEA suggested that the oxyanion hole and catalytic triad characteristic of typical carboxylesterases are essential for the catalytic process of TgTCEA enzyme. To our knowledge, TgTCEA is the first identified member of the lactone-forming carboxylesterases, specifically catalyzing intramolecular transesterification.

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A Novel Lactone-Forming Carboxylesterase: Molecular Identification of a Tuliposide A-Converting Enzyme in Tulip

2012

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“…In addition to terreic acid, two other classes of natural products, cnicins and tuliposides, have recently been demonstrated to inactivate MurA in vitro through covalent modification of Cys115. It was concluded that the antibiotic activity of these compounds primarily results from inhibition of MurA . However, the present study clearly demonstrates the divergence between in vitro potency and MurA selectivity; thus, it remains to be seen whether cnicins and tuliposides indeed target MurA in the cell.…”

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confidence: 55%

Differential antibacterial properties of the MurA inhibitors terreic acid and fosfomycin

et al. 2013

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Terreic acid is a metabolite with antibiotic properties produced by the fungus Aspergillus terreus, but its cellular target remains unknown. We recently reported that terreic acid inactivates the bacterial cell wall biosynthetic enzyme MurA in vitro by covalent reaction with residue Cys115 in a similar manner as the MurA-specific antibiotic fosfomycin. To address if terreic acid also targets MurA in vivo, we conducted antibacterial studies using selected E. coli strains in parallel with fosfomycin. While overexpression of MurA conferred resistance to fosfomycin, it did not protect cells treated with terreic acid. Furthermore, flow cytometry revealed that the antibiotic action of terreic acid appears to be primarily bacteriostatic, as opposed to the bactericidal action observed for fosfomycin. Combined, the data suggest that MurA is not the molecular target of terreic acid and that the antibiotic activity of terreic acid proceeds through a different mechanism of action. The methodology applied here provides a reliable and convenient tool to rapidly assess the potential of newly discovered in vitro inhibitors to target residue Cys115 of MurA in the cell.

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“…[7][8][9] Although PaA and PaB show antimicrobial activities against a broad range of strains of bacteria and fungi, their properties are distinctly different: PaA functions as an antifungal agent, while PaB is an antibacterial. 4,5,[7][8][9][10][11][12][13][14][15] PaA and PaB are formed in nature from the precursor sugar esters, 6-tuliposides A (PosA) and B (PosB), respectively (Fig. 1).…”

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confidence: 99%

Environmentally benign process for the preparation of antimicrobial α-methylene-β-hydroxy-γ-butyrolactone (tulipalin B) from tulip biomass

Nomura

Hayashi

Kawakami

et al. 2015

Bioscience, Biotechnology, and Biochemistry

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Tulipalin B (α-methylene-β-hydroxy-γ-butyrolactone, PaB) is an antimicrobial natural product occurring in tulip (Tulipa gesneriana). PaB is directly formed from the precursor glucose ester 6-tuliposide B (PosB) by endogenous Pos-converting enzyme (TCE). Despite the potential usefulness of antibacterial PaB in various industrial applications, lack of facile synthetic schemes hampers its practical use. Herein, we describe an environmentally benign and facile process for the preparation of PaB using tulip biomass materials based on one-step enzyme reaction catalyzed by TCE without the use of petroleum-derived solvents. By screening 115 tulip cultivars, we found three elite cultivars, which accumulated PosB almost exclusively in flower tissues. The flower extracts with aqueous ethanol were partially purified with activated charcoal and subjected to the enzyme reaction with reusable immobilized TCE prepared from bulb crude extracts. The reaction was completed in a few hours at room temperature, and PaB was purified with activated charcoal and ethanol in a batch-wise manner.

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Structure–activity relationships of tulipalines, tuliposides, and related compounds as inhibitors of MurA

Cited by 35 publications

References 16 publications

A Novel Lactone-Forming Carboxylesterase: Molecular Identification of a Tuliposide A-Converting Enzyme in Tulip

A Novel Lactone-Forming Carboxylesterase: Molecular Identification of a Tuliposide A-Converting Enzyme in Tulip

Differential antibacterial properties of the MurA inhibitors terreic acid and fosfomycin

Environmentally benign process for the preparation of antimicrobial α-methylene-β-hydroxy-γ-butyrolactone (tulipalin B) from tulip biomass

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