64222-94-2Relevant articles and documents
Δ12-Prostaglandin J2 as a product and ligand of human serum albumin: Formation of an unusual covalent adduct at His146
Yamaguchi, Satoru,Aldini, Giancarlo,Ito, Sohei,Morishita, Nozomi,Shibata, Takahiro,Vistoli, Giulio,Carini, Marina,Uchida, Koji
, p. 824 - 832 (2010)
Human serum albumin (HSA), the most abundant protein in plasma, has a very unique function, catalyzing the conversion of prostaglandin J2 (PGJ2), a dehydration product of PGD2, to yield Δ12-PGJ2. These PGD2 metabolites are actively transported into cells and accumulated in the nuclei, where they act as potent inducers of cell growth inhibition and cell differentiation, and exhibit their own unique spectrum of biological effects. The facts that (i) arachidonic acid metabolites bind to human serum albumin (HSA) and the metabolism of these molecules is altered as a result of binding, (ii) HSA catalyzes the transformation of PGJ2 into Δ12-PGJ2, and (iii) Δ12-PGJ2 is stable in serum suggest that HSA may bind and stabilize Δ12-PGJ2 in a specific manner. A molecular interaction analysis using surface plasmon resonance (Biacore) indeed suggested the presence of a specific Δ12-PGJ 2-binding site in HSA. To investigate the molecular details of the binding of this PGD2 metabolite to albumin, we analyzed the cocrystal structure of the HSA-Δ12-PGJ2-myristate complex by X-ray crystallography and found that two Δ12-PGJ12 molecules bind to a primary site in subdomain IB of the protein. The electron density results suggested that one of the two Δ12-PGJ 12 molecules that specifically bind to the site covalently interacted with a histidine residue (His146). Using nano-LC-MS/MS analysis of the HSA-Δ12-PGJ2 complex, the formation of an unusual Δ12-PGJ2-histidine adduct at His146 was confirmed. Thus, our crystallographic and mass spectrometric analyses of the HSA-Δ12-PGJ2 complex provided intriguing new insights into the molecular details of how this electrophilic ligand interacts with its primary producer and transporter.
