Natural products with calmodulin inhibitor properties

Martínez-Luis, Sergio; Pérez-Vásquez, Araceli; Mata, Rachel

doi:10.1016/j.phytochem.2007.02.025

Cited by 44 publications

(24 citation statements)

References 88 publications

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“…This finding is of particular importance, as it proposes an intracellular target site for SPC and also suggests an utterly novel type of in vivo regulation for the well-known Ca 2ϩ sensor protein CaM. The so far characterized CaM inhibitors are all synthetic (6 -8) or occur only in specific species (9,10), while SPC is presumably present in most eukaryotic cells as an intermediate of sphingolipid metabolism (11,12). Moreover, we have demonstrated that SPC can bind to CaM efficiently only if it is clustered, which form is manifested in micelles in vitro, raising several intriguing questions about lipid-protein interactions.…”

Section: Discussionmentioning

confidence: 97%

Structure and mechanism of calmodulin binding to a signaling sphingolipid reveal new aspects of lipid‐protein interactions

et al. 2010

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Lipid-protein interactions are rarely characterized at a structural molecular level due to technical difficulties; however, the biological significance of understanding the mechanism of these interactions is outstanding. In this report, we provide mechanistic insight into the inhibitory complex formation of the lipid mediator sphingosylphosphorylcholine with calmodulin, the most central and ubiquitous regulator protein in calcium signaling. We applied crystallographic, thermodynamic, kinetic, and spectroscopic approaches using purified bovine calmodulin and bovine cerebral microsomal fraction to arrive at our conclusions. Here we present 1) a 1.6-Å resolution crystal structure of their complex, in which the sphingolipid occupies the conventional hydrophobic binding site on calmodulin; 2) a peculiar stoichiometry-dependent binding process: at low or high protein-to-lipid ratio calmodulin binds lipid micelles or a few lipid molecules in a compact globular conformation, respectively, and 3) evidence that the sphingolipid displaces calmodulin from its targets on cerebral microsomes. We have ascertained the specificity of the interaction using structurally related lipids as controls. Our observations reveal the structural basis of selective calmodulin inhibition by the sphingolipid. On the basis of the crystallographic and biophysical characterization of the calmodulin-sphingosylphosphorylcholine interaction, we propose a novel lipid-protein binding model, which might be applicable to other interactions as well.

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Section: Discussionmentioning

confidence: 97%

Structure and mechanism of calmodulin binding to a signaling sphingolipid reveal new aspects of lipid‐protein interactions

et al. 2010

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“…Although anti-CaM drugs can interact with CaM in a versatile manner (9,10), the binding to apoCaM has only been demonstrated in case of KAR-2. Natural products with anti-CaM properties also exist, but can mainly be found in certain plant species and animal venoms (11). We have shown that the putative lipid second messenger sphingosylphosphorylcholine (SPC) (12,13) binds specifically to both apo-and Ca 2ϩ -saturated CaM, and inhibits the action of the protein on the target enzymes phosphodiesterase and calcineurin (14).…”

Section: Calmodulin (Cam)mentioning

confidence: 99%

Dissociation of Calmodulin-Target Peptide Complexes by the Lipid Mediator Sphingosylphosphorylcholine

Kovács¹,

Tóth²,

Vértessy

et al. 2010

Journal of Biological Chemistry

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“…Some studies have demonstrated that coumarin could be used by Penicillium jenseni and P. nigricans, Rhodotorula rosea, Arthrobacter sp. and regulate the growth of moulds and inhibit the growth of gram-positive microorganisms (Bellis 1958;Knypl and Szopa 1960;Knypl 1963;Levy and Weinstein 1964;Dadak 1965;Frost and Levy 1966;Martinez-Luis et al 2007). However, little has been known of direct and specific effect of pure coumarin added into media on growth, biomass, sporulation, conidia germination, mycotoxin and phytopathogenic enzymes particularly mycotoxin production and phytopathogenic enzymes of Fusarium sp.…”

Section: Introductionmentioning

confidence: 99%

Allelopathic impact of artificially applied coumarin on Fusarium oxysporum f.sp. niveum

Raza

Liu

et al. 2007

World J Microbiol Biotechnol

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Watermelon production is threatened by fusarium wilt caused by Fusarium oxysporum f.sp. niveum (FON) in continuous cultivation system. Some elements, mainly allelochemicals, released from living roots or decayed plants might be associated with the disease. The purpose of this work was to evaluate the possible impact of coumarin, one kind of watermelon allelochemical, on FON. Furthermore, possible new mechanisms might be investigated during the ecological interactions of plant-microbe. Results showed that coumarin strongly inhibited growth of FON leading to a decrease in its biomass, dry weight of mycelia of FON in a liquid culture. The dry weight was decreased by 62.9% compared with control. The hyphal growth of FON on plates was stopped at high ([400 mg l -1 ) concentrations of coumarin. At 320 mg l -1 , sporulation and enzyme activities of FON were also severely suppressed by coumarin. The yield of conidia, and the activities of proteinase, cellulase, and amylase were reduced by 98.9%, 79.7%, 29.8% and 15.9% respectively. However, conidial germination and mycotoxin (MT) production of FON were greatly stimulated, being increased by 55.7% and 14.9 fold at 320 mg l -1 respectively. We conclude that coumarin acted as an allelochemical substance to inhibit growth and pathogenic enzyme activities of FON but to stimulate mycotoxin production and conidial germination. It was suggested that coumarin acted as a signal transduction element bridging plant and pathogen in the process of plant-microbe interactions.

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Natural products with calmodulin inhibitor properties

Cited by 44 publications

References 88 publications

Structure and mechanism of calmodulin binding to a signaling sphingolipid reveal new aspects of lipid‐protein interactions

Structure and mechanism of calmodulin binding to a signaling sphingolipid reveal new aspects of lipid‐protein interactions

Dissociation of Calmodulin-Target Peptide Complexes by the Lipid Mediator Sphingosylphosphorylcholine

Allelopathic impact of artificially applied coumarin on Fusarium oxysporum f.sp. niveum

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