title: Structural evidence of the species-dependent albumin binding of the modified cyclic phosphatidic acid with cytotoxic properties.
abstract: Cyclic phosphatidic acids (cPAs) are naturally occurring, very active signalling molecules, which are involved in several pathological states, such as cancer, diabetes or obesity. As molecules of highly lipidic character found in the circulatory system, cPAs are bound and transported by the main extracellular lipid binding protein-serum albumin. Here, we present the detailed interactions between human serum albumin (HSA) and equine serum albumin (ESA) with a derivative of cPA, 1-O-myristoyl-sn-glycerol-2,3-cyclic phosphorodithioate (Myr-2S-cPA). Initial selection of the ligand used for the structural study was made by the analysis of the therapeutically promising properties of the sulfur containing analogues of cPA in respect to the unmodified lysophospholipids (LPLs). Substitution of one or two non-bridging oxygen atoms in the phosphate group with one or two sulfur atoms increases the cytotoxic effect of cPAs up to 60% on the human prostate cancer (PC) cells. Myr-2S-cPA reduces cancer cell viability in a dose-dependent manner, with IC50 value of 29.0 μM after 24 h incubation, which is almost 30% lower than IC50 of single substituted phosphorothioate cPA. Although, the structural homology between HSA and ESA is big, their crystal complexes with Myr-2S-cPA demonstrate significantly different mode of binding of this LPL analogue. HSA binds three molecules of Myr-2S-cPA, whereas ESA only one. Moreover, none of the identified Myr-2S-cPA binding sites overlap in both albumins.
authors.affiliation: Institute of Technical Biochemistry, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90-924 Lodz, Poland.
authors.forename: Bartosz
authors.initials: B
authors.lastname: Sekula
authors.affiliation: Institute of Technical Biochemistry, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90-924 Lodz, Poland.
authors.forename: Anna
authors.initials: A
authors.lastname: Ciesielska
authors.affiliation: Institute of Technical Biochemistry, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90-924 Lodz, Poland.
authors.forename: Przemyslaw
authors.initials: P
authors.lastname: Rytczak
authors.affiliation: Institute of Technical Biochemistry, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90-924 Lodz, Poland.
authors.forename: Maria
authors.initials: M
authors.lastname: Koziołkiewicz
authors.affiliation: Institute of Technical Biochemistry, Faculty of Biotechnology and Food Sciences, Lodz University of Technology, Stefanowskiego 4/10, 90-924 Lodz, Poland anna.bujacz@p.lodz.pl.
authors.forename: Anna
authors.initials: A
authors.lastname: Bujacz
mesh_terms: D000818:Animals; D001665:Binding Sites; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000235:genetics; D018360:Crystallography, X-Ray; D006736:Horses; D006801:Humans; D008246:Lysophospholipids / Q000737:chemistry* / Q000378:metabolism; D008297:Male; D010712:Phosphatidic Acids / Q000737:chemistry* / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology; D011485:Protein Binding; D012709:Serum Albumin / Q000737:chemistry* / Q000378:metabolism; D013045:Species Specificity
chemical_list: C000625203:1-O-myristoylglycerol-2,3-cyclic phosphorodithioate; D008246:Lysophospholipids; D010712:Phosphatidic Acids; D012709:Serum Albumin
keywords: antiproliferative action; crystal structure; cyclic phosphatidic acid (cPA); lysophospholipid transport; modified lysophospholipids; serum albumin