Glycation alters ligand binding, enzymatic, and pharmacological properties of human albumin.
Albumin, the major circulating protein in blood plasma, can be subjected to an increased level of glycation in a diabetic context. Albumin exerts crucial pharmacological activities through its drug binding capacity, i.e., ketoprofen, and via its esterase-like activity, allowing the conversion of prodrugs into active drugs. In this study, the impact of the glucose-mediated glycation on the pharmacological and biochemical properties of human albumin was investigated. Aggregation product levels and the redox state were quantified to assess the impact of glycation-mediated changes on the structural properties of albumin. Glucose-mediated changes in ketoprofen binding properties and esterase-like activity were evaluated using fluorescence spectroscopy and p-nitrophenyl acetate hydrolysis assays, respectively. With the exception of oxidative parameters, significant dose-dependent alterations in biochemical and functional properties of in vitro glycated albumin were observed. We also found that the dose-dependent increase in levels of glycation and protein aggregation and average molecular mass changes correlated with a gradual decrease in the affinity of albumin for ketoprofen and its esterase-like property. In parallel, significant alterations in both pharmacological properties were also evidenced in albumin purified from diabetic patients. Partial least-squares regression analyses established a significant correlation between glycation-mediated changes in biochemical and pharmacological properties of albumin, highlighting the important role for glycation in the variability of the drug response in a diabetic situation.
†Inserm, UMR 1188 Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), plateforme CYROI, F-97490 Sainte-Clotilde, France.|‡Université de La Réunion, UMR 1188, F-97490 Sainte-Clotilde, France.
Jennifer
J
Baraka-Vidot
†Inserm, UMR 1188 Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), plateforme CYROI, F-97490 Sainte-Clotilde, France.|‡Université de La Réunion, UMR 1188, F-97490 Sainte-Clotilde, France.
Cynthia
C
Planesse
†Inserm, UMR 1188 Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), plateforme CYROI, F-97490 Sainte-Clotilde, France.|‡Université de La Réunion, UMR 1188, F-97490 Sainte-Clotilde, France.|§CHU de La Réunion, Centre d'Investigation Clinique, F-97400 Saint-Denis, France.
Olivier
O
Meilhac
∥Dipartimento di Fisica-Chimica, Università di Palermo, 90128 Palermo, Italy.
Valeria
V
Militello
⊥Department of Biology and Biochemistry, University of Bath, Claverton Down, Bath BA2 7AY, U.K.
Jean
J
van den Elsen
†Inserm, UMR 1188 Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), plateforme CYROI, F-97490 Sainte-Clotilde, France.|‡Université de La Réunion, UMR 1188, F-97490 Sainte-Clotilde, France.
Emmanuel
E
Bourdon
†Inserm, UMR 1188 Diabète athérothrombose Thérapies Réunion Océan Indien (DéTROI), plateforme CYROI, F-97490 Sainte-Clotilde, France.|‡Université de La Réunion, UMR 1188, F-97490 Sainte-Clotilde, France.
Philippe
P
Rondeau
D000418:Albumins / Q000737:chemistry* / Q000378:metabolism*; D002846:Chromatography, Affinity; D017127:Glycation End Products, Advanced; D006031:Glycosylation; D006801:Humans; D007660:Ketoprofen / Q000737:chemistry / Q000378:metabolism; D013058:Mass Spectrometry; D011485:Protein Binding; D017433:Protein Structure, Secondary; D012709:Serum Albumin / Q000737:chemistry / Q000378:metabolism; D013050:Spectrometry, Fluorescence; D000093423:Glycated Serum Albumin
D000418:Albumins; D017127:Glycation End Products, Advanced; D012709:Serum Albumin; D007660:Ketoprofen; D000093423:Glycated Serum Albumin