The binding mode of petrosaspongiolide M to the human group IIA phospholipase A2: Exploring the role of covalent and noncovalent interactions in the inhibition process

Maria Chiara Monti; Agostino Casapullo; Claudio N. Cavasotto; Alessandra Tosco; Fabrizio Dal Piaz; Arturas Ziemys; Luigi Margarucci; Raffaele Riccio

doi:10.1002/chem.200801512

The binding mode of petrosaspongiolide M to the human group IIA phospholipase A₂: Exploring the role of covalent and noncovalent interactions in the inhibition process

Maria Chiara Monti, Agostino Casapullo, Claudio N. Cavasotto, Alessandra Tosco, Fabrizio Dal Piaz, Arturas Ziemys, Luigi Margarucci, Raffaele Riccio

Research output: Contribution to journal › Article › peer-review

35 Scopus citations

Abstract

We report an analysis of the mechanism of human group HA secretory phospholipase A₂ (sPLA₂-IIA) inhibition by the natural anti-inflammatory sesterterpene petrosaspongiolide M (PM). The amphiphilic PM, a λ-hydroxybutenolide marine terpenoid, selectively reacts with the sPLA,-IIA Lys67 residue, located near the enzyme-membrane interfacial binding surface, and covalently modifies the enzyme through imine formation. Furthermore, PM is able to target the active site of SPLA₂-IIA through several van der Waals/electrostatic complementarities. The two events cannot cooccur on a single PLA₂ molecule, so they may contribute separately to enzyme inhibiton. A more intriguing hypothesis suggests a double interaction of PM with two enzyme molecules, one of them covalently modified and the other contacting the inhibitor through its active site. We have explored the occurrence of this unusual binding mode leading to PM-induced PLA ₂ supramolecular complexes. These insights could suggest new PLA,-inhibition-based therapeutic strategies.

Original language	English (US)
Pages (from-to)	1155-1163
Number of pages	9
Journal	Chemistry - A European Journal
Volume	15
Issue number	5
DOIs	https://doi.org/10.1002/chem.200801512
State	Published - Jan 19 2009

Keywords

Enzymes
Inhibitors
Natural products
Phospholipases
Protein interactions

ASJC Scopus subject areas

General Chemistry

Access to Document

10.1002/chem.200801512

Cite this

Monti, M. C., Casapullo, A., Cavasotto, C. N., Tosco, A., Dal Piaz, F., Ziemys, A., Margarucci, L., & Riccio, R. (2009). The binding mode of petrosaspongiolide M to the human group IIA phospholipase A₂: Exploring the role of covalent and noncovalent interactions in the inhibition process. Chemistry - A European Journal, 15(5), 1155-1163. https://doi.org/10.1002/chem.200801512

The binding mode of petrosaspongiolide M to the human group IIA phospholipase A₂: Exploring the role of covalent and noncovalent interactions in the inhibition process. / Monti, Maria Chiara; Casapullo, Agostino; Cavasotto, Claudio N. et al.
In: Chemistry - A European Journal, Vol. 15, No. 5, 19.01.2009, p. 1155-1163.

Research output: Contribution to journal › Article › peer-review

Monti, MC, Casapullo, A, Cavasotto, CN, Tosco, A, Dal Piaz, F, Ziemys, A, Margarucci, L & Riccio, R 2009, 'The binding mode of petrosaspongiolide M to the human group IIA phospholipase A₂: Exploring the role of covalent and noncovalent interactions in the inhibition process', Chemistry - A European Journal, vol. 15, no. 5, pp. 1155-1163. https://doi.org/10.1002/chem.200801512

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abstract = "We report an analysis of the mechanism of human group HA secretory phospholipase A2 (sPLA2-IIA) inhibition by the natural anti-inflammatory sesterterpene petrosaspongiolide M (PM). The amphiphilic PM, a λ-hydroxybutenolide marine terpenoid, selectively reacts with the sPLA,-IIA Lys67 residue, located near the enzyme-membrane interfacial binding surface, and covalently modifies the enzyme through imine formation. Furthermore, PM is able to target the active site of SPLA2-IIA through several van der Waals/electrostatic complementarities. The two events cannot cooccur on a single PLA2 molecule, so they may contribute separately to enzyme inhibiton. A more intriguing hypothesis suggests a double interaction of PM with two enzyme molecules, one of them covalently modified and the other contacting the inhibitor through its active site. We have explored the occurrence of this unusual binding mode leading to PM-induced PLA 2 supramolecular complexes. These insights could suggest new PLA,-inhibition-based therapeutic strategies.",

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