TY - JOUR
T1 - The binding mode of petrosaspongiolide M to the human group IIA phospholipase A2
T2 - Exploring the role of covalent and noncovalent interactions in the inhibition process
AU - Monti, Maria Chiara
AU - Casapullo, Agostino
AU - Cavasotto, Claudio N.
AU - Tosco, Alessandra
AU - Dal Piaz, Fabrizio
AU - Ziemys, Arturas
AU - Margarucci, Luigi
AU - Riccio, Raffaele
PY - 2009/1/19
Y1 - 2009/1/19
N2 - 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.
AB - 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.
KW - Enzymes
KW - Inhibitors
KW - Natural products
KW - Phospholipases
KW - Protein interactions
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U2 - 10.1002/chem.200801512
DO - 10.1002/chem.200801512
M3 - Article
C2 - 19065693
AN - SCOPUS:58449114054
VL - 15
SP - 1155
EP - 1163
JO - Chemistry - A European Journal
JF - Chemistry - A European Journal
SN - 0947-6539
IS - 5
ER -