Identification and Characterization of a Single High‐Affinity Fatty Acid Binding Site in Human Serum Albumin. Issue 4 (27th December 2017)

• Record Type: Journal Article
• Authors: Wenskowsky, Lea; Schreuder, Herman; Derdau, Volker; Matter, Hans; Volkmar, Julia; Nazaré, Marc; Opatz, Till; Petry, Stefan
• Is Part Of: Angewandte Chemie international edition. Volume 57:Issue 4(2018)
• Page Start: 1044
• Page End: 1048
• Publication Date: 2017-12-27
• Subjects: binding sites -- drug interactions -- fatty acids -- human serum albumin -- NBD labels; Chemistry -- Periodicals; 540
• DOI: 10.1002/anie.201710437
• Languages: English
• ISSNs: 1433-7851

Abstract

Abstract: A single high‐affinity fatty acid binding site in the important human transport protein serum albumin (HSA) is identified and characterized using an NBD (7‐nitrobenz‐2‐oxa‐1, 3‐diazol‐4‐yl)‐C12 fatty acid. This ligand exhibits a 1:1 binding stoichiometry in its HSA complex with high site‐specificity. The complex dissociation constant is determined by titration experiments as well as radioactive equilibrium dialysis. Competition experiments with the known HSA‐binding drugs warfarin and ibuprofen confirm the new binding site to be different from Sudlow‐sites I and II. These binding studies are extended to other albumin binders and fatty acid derivatives. Furthermore an X‐ray crystal structure allows locating the binding site in HSA subdomain IIA. The knowledge about this novel HSA site will be important for drug depot development and for understanding drug‐protein interaction, which are important prerequisites for modulation of drug pharmacokinetics. Abstract : It's not a hydrophobic sponge : The identification and characterization of a single high‐affinity fatty acid binding site in human serum albumin has been achieved using a labeled fatty acid with highly specific binding. An X‐ray crystal structure locates the binding site in subdomain IIA. The identified binding site helps in the understanding of drug protein binding, modulation of pharmacokinetic profiles, and drug depot development.