title: Functional transformations of bile acid transporters induced by high-affinity macromolecules.
abstract: Apical sodium-dependent bile acid transporters (ASBT) are the intestinal transporters that form intermediate complexes with substrates and its conformational change drives the movement of substrates across the cell membrane. However, membrane-based intestinal transporters are confined to the transport of only small molecular substrates. Here, we propose a new strategy that uses high-affinity binding macromolecular substrates to functionally transform the membrane transporters so that they behave like receptors, ultimately allowing the apical-basal transport of bound macromolecules. Bile acid based macromolecular substrates were synthesized and allowed to interact with ASBT. ASBT/macromolecular substrate complexes were rapidly internalized in vesicles, localized in early endosomes, dissociated and escaped the vesicular transport while binding of cytoplasmic ileal bile acid binding proteins cause exocytosis of macromolecules and prevented entry into lysosomes. This newly found transformation process of ASBT suggests a new transport mechanism that could aid in further utilization of ASBT to mediate oral macromolecular drug delivery.
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Taslim A
authors.initials: TA
authors.lastname: Al-Hilal
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Seung Woo
authors.initials: SW
authors.lastname: Chung
authors.affiliation: Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Farzana
authors.initials: F
authors.lastname: Alam
authors.affiliation: College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Jooho
authors.initials: J
authors.lastname: Park
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, South Korea.
authors.forename: Kyung Eun
authors.initials: KE
authors.lastname: Lee
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, South Korea.
authors.forename: Hyesung
authors.initials: H
authors.lastname: Jeon
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, South Korea.
authors.forename: Kwangmeyung
authors.initials: K
authors.lastname: Kim
authors.affiliation: Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, South Korea.
authors.forename: Ick Chan
authors.initials: IC
authors.lastname: Kwon
authors.affiliation: 1] Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, South Korea [2] Department of Biochemistry and Cell Biology, School of Medicine, Kyungpook National University, Daegu 700-422, South Korea.
authors.forename: In-San
authors.initials: IS
authors.lastname: Kim
authors.affiliation: 1] Center for Theragnosis, Biomedical Research Institute, Korea Institute of Science and Technology, Seoul 136-791, South Korea [2] Department of Otolaryngology, Asan Medical Center, College of Medicine, University of Ulsan, Seoul 138-736, South Korea.
authors.forename: Sang Yoon
authors.initials: SY
authors.lastname: Kim
authors.affiliation: 1] College of Pharmacy, Seoul National University, Seoul 151-742, South Korea [2] Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, College of Pharmacy, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Youngro
authors.initials: Y
authors.lastname: Byun
mesh_terms: D000595:Amino Acid Sequence; D001692:Biological Transport; D018938:Caco-2 Cells; D002352:Carrier Proteins / Q000378:metabolism*; D016503:Drug Delivery Systems; D011992:Endosomes / Q000378:metabolism; D005089:Exocytosis / Q000235:genetics; D006801:Humans; D008562:Membrane Glycoproteins / Q000378:metabolism*; D026901:Membrane Transport Proteins / Q000378:metabolism*; D029363:Organic Anion Transporters, Sodium-Dependent / Q000737:chemistry* / Q000378:metabolism; D011485:Protein Binding; D013379:Substrate Specificity; D027981:Symporters / Q000737:chemistry* / Q000378:metabolism
chemical_list: D002352:Carrier Proteins; D008562:Membrane Glycoproteins; D026901:Membrane Transport Proteins; D029363:Organic Anion Transporters, Sodium-Dependent; D027981:Symporters; C037643:bile acid binding proteins; C071908:sodium-bile acid cotransporter