The Molecular Mechanism of Bee Venom Phospholipase A<sub>2</sub> Inactivation by Bolinaquinone

Monti, Maria Chiara; Casapullo, Agostino; Santomauro, Cosima; D’Auria, Maria Valeria; Riccio, Raffaele; Gomez‐Paloma, Luigi

doi:10.1002/cbic.200500454

Cited by 18 publications

(28 citation statements)

References 54 publications

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“…As discussed previously, the quinone moieties may be the active part in Michael addition reactions that interfere with regulatory molecules in living cells. 15 In addition to the quinone moiety of corallidictyals A/B (4/5), the aldehyde moiety may play an important role in the cytotoxic activity of siphonodictyal G (11) as compared to siphonodictyol G (2).…”

Section: Resultsmentioning

confidence: 99%

Bioactive Metabolites from the Caribbean Sponge Aka coralliphagum

et al. 2007

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The chemistry of the burrowing sponge Aka coralliphagum was investigated to identify chemically labile secondary metabolites. The HPLC-MS analysis of the two growth forms typica and incrustans revealed different metabolites. The previously unknown sulfated compounds siphonodictyals B1 to B3 (6-8), corallidictyals C (9) and D (10), and siphonodictyal G (11) were isolated, and their structures were elucidated by NMR and MS experiments. The compounds were tested in a DPPH assay, in antimicrobial assays against bacteria, yeasts, and fungi, and in antiproliferation assays using cultures of mouse fibroblasts. The biological activity was linked to the presence of the ortho-hydroquinone moiety.The burrowing sponge Aka coralliphagum ()Siphonodictyon coralliphagum) is a bright yellow colored sponge that burrows into corals. Four distinct morphological growth forms have been described for Aka coralliphagum from the Caribbean: forma typica, f. tubulosa, f. obruta, and f. incrustans. 1 Several bioactive sesquiterpene hydroquinones, such as the siphonodictyals (B, 1) and siphonodictyols, 2 were obtained from the forms tubulosa and typica. Although the isolation of labile compounds such as siphonodictyols G (2) and H (3) suggested the existence of additional sulfated phenolic compounds in A. coralliphagum, compounds such as the siphonodictyals were isolated without respect to the occurrence of sulfated metabolites. Past isolation and purification methods did not account for the problem of compound hydrolysis. 2a,b This paper describes the isolation, structure elucidation, and biological testing of the new, labile metabolites siphonodictyals B1 to B3 (6-8), corallidictyals C (9) and D (10), and siphonodictyal G (11) from the Aka growth form incrustans. In order to compare the secondary metabolites of the two growth forms incrustans and typica, an HPLC analysis of their crude extracts was performed. These two forms of Aka occur in different habitats, with typica predominating on shallow water reefs (10-15 m) while incrustans occurs on deep water vertical slopes (20-25 m). It was deemed important to isolate the labile natural products of these two growth forms in their naturally occurring forms in order to understand more about their biological and ecological function. Results and DiscussionExtracts of sponge samples were investigated by an HPLC-MS screening. The two growth forms of Aka coralliphagum (typica and incrustans) showed differences in HPLC fingerprints and their major metabolites (Figure 1). While forma typica contained more polar compounds (shorter retention times), forma incrustans contained three main compounds with a less polar character. Further characterization by HPLC-API-CID-MS/MS showed a single or double sulfation of compounds with shorter retention times. This was deduced by loss of m/z 80 under MS/MS conditions and detection of a [SO 3 ] -ion at m/z 80 (see Supporting Information) 3 as well as a sulfur-specific isotopic pattern. These results indicate that the two growth forms have considerable differences...

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Section: Resultsmentioning

confidence: 99%

Bioactive Metabolites from the Caribbean Sponge Aka coralliphagum

et al. 2007

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“…Plants, mammals, snakes and bee venoms can be the source of PLA 2 and according to their cellular location, these enzymes can be classified as cytosolic (cPLA 2 ), calcium independent (iPLA 2 ) and secretory (sPLA 2 ) [5]. Considering the three types of PLA 2 mentioned, studies revealed that sPLA 2 is deeply involved in the inflammatory process of several conditions [3,6] such as rheumatoid arthritis, atherosclerosis, respiratory distress syndrome and septic shock [4,5,7]. Most precisely, sPLA 2 leads to the formation of lipid inflammatory mediators through its lipolytic activity and also by activation of iPLA 2 [7].…”

Section: Introductionmentioning

confidence: 98%

“…Arachidonic acid (AA) is among the free fatty acids released representing a possible store of energy [2] and being involved in the biosynthesis of prostaglandins, prostacyclins, thromboxanes and interleukins -eicosanoids, known as mediators of inflammation and signal transduction [2][3][4]. Plants, mammals, snakes and bee venoms can be the source of PLA 2 and according to their cellular location, these enzymes can be classified as cytosolic (cPLA 2 ), calcium independent (iPLA 2 ) and secretory (sPLA 2 ) [5].…”

Section: Introductionmentioning

confidence: 99%

A biophysical approach to phospholipase A2 activity and inhibition by anti-inflammatory drugs

Gaspar

Lúcio

Wagner

et al. 2010

Biophysical Chemistry

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The present study describes the interaction of two nonsteroidal anti-inflammatory drugs (ibuprofen and piroxicam) with PLA(2) from Naja mossambica mossambica and seeks to deepen the knowledge about the influence of the biophysical properties of biomembranes, and the inhibitory effect of the drugs on the enzymatic activity. Fluorescent techniques with and without the use of probes, surface pressure/molecular area isotherms, surface pressure/time and molecular area/time measurements combined with circular dichroism spectroscopy and direct techniques of visualization of lipid membranes (Brewster angle microscopy), revealed that both drugs inhibit PLA(2). Additionally, the structure and characteristics of the lipid bilayer, as well as, the direct interaction of drugs with the enzyme seem to play an important role on the hydrolytic activity of PLA(2) towards membrane model systems. These results open a way of finding new and better strategies that can contribute to the development of suitable agents for relieving inflammatory conditions.

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“…Following our on-going extensive investigation on the PLA 2 inactivation mechanism by anti-inflammatory marine natural products (Monti et al, 2004a,b;Monti et al, 2006;Monti et al, 2009), and attracted by the perspective of a rational design of novel inhibitors as new potential lead compounds against inflammation-related diseases (Guerrero et al, 2007;Aquino et al, 2008), we have investigated the molecular mechanism of sPLA 2 -IIA inhibition by BLQ. The opportunity of exploring the reactivity of the p-quinone systems in this biological context and the latest findings of an oncogenic action of PLA 2 in prostate cancer (Mirtti et al, 2009) offered further motivations for this project.…”

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The molecular mechanism of human group IIA phospholipase A2 inactivation by bolinaquinone

Monti

Chini

Margarucci

et al. 2009

J of Molecular Recognition

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The molecular basis of the human group IIA secretory phospholipase A(2) inactivation by bolinaquinone (BLQ), a hydroxyquinone marine terpenoid, has been investigated for the comprehension of its relevant antiinflammatory properties, through the combination of spectroscopic techniques, biosensors analysis, mass spectrometry (MS) and molecular docking. Indeed, sPLA(2)s are well known to be implicated in the pathogenesis of inflammation such as rheumatoid arthritis, septic shock, psoriasis and asthma. Our results suggest a mechanism of competitive inhibition guided by a non-covalent molecular recognition event, disclosing the key role of the BLQ hydroxyl-quinone moiety in the chelation of the catalytic Ca(2+) ion inside the enzyme active site.The understanding of the sPLA(2)-IIA inactivation mechanism by BLQ could be useful for the development of a new chemical class of PLA(2) inhibitors, able to specifically target the enzyme active site.

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The Molecular Mechanism of Bee Venom Phospholipase A₂ Inactivation by Bolinaquinone

Cited by 18 publications

References 54 publications

Bioactive Metabolites from the Caribbean Sponge Aka coralliphagum

Bioactive Metabolites from the Caribbean Sponge Aka coralliphagum

A biophysical approach to phospholipase A2 activity and inhibition by anti-inflammatory drugs

The molecular mechanism of human group IIA phospholipase A2 inactivation by bolinaquinone

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The Molecular Mechanism of Bee Venom Phospholipase A2 Inactivation by Bolinaquinone

Cited by 18 publications

References 54 publications

Bioactive Metabolites from the Caribbean Sponge Aka coralliphagum

Bioactive Metabolites from the Caribbean Sponge Aka coralliphagum

A biophysical approach to phospholipase A2 activity and inhibition by anti-inflammatory drugs

The molecular mechanism of human group IIA phospholipase A2 inactivation by bolinaquinone

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The Molecular Mechanism of Bee Venom Phospholipase A₂ Inactivation by Bolinaquinone