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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.

SUBMITTER: Al-Hilal TA

PROVIDER: S-EPMC3933907 | biostudies-other | 2014

REPOSITORIES: biostudies-other

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Functional transformations of bile acid transporters induced by high-affinity macromolecules.

Al-Hilal Taslim A TA Chung Seung Woo SW Alam Farzana F Park Jooho J Lee Kyung Eun KE Jeon Hyesung H Kim Kwangmeyung K Kwon Ick Chan IC Kim In-San IS Kim Sang Yoon SY Byun Youngro Y

Scientific reports 20140225

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 ...[more]

PMID: 24566561

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Project description:Transporters influence the disposition of chemicals within the body by participating in absorption, distribution, and elimination. Transporters of the solute carrier family (SLC) comprise a variety of proteins, including organic cation transporters (OCT) 1 to 3, organic cation/carnitine transporters (OCTN) 1 to 3, organic anion transporters (OAT) 1 to 7, various organic anion transporting polypeptide isoforms, sodium taurocholate cotransporting polypeptide, apical sodium-dependent bile acid transporter, peptide transporters (PEPT) 1 and 2, concentrative nucleoside transporters (CNT) 1 to 3, equilibrative nucleoside transporter (ENT) 1 to 3, and multidrug and toxin extrusion transporters (MATE) 1 and 2, which mediate the uptake (except MATEs) of organic anions and cations as well as peptides and nucleosides. Efflux transporters of the ATP-binding cassette superfamily, such as ATP-binding cassette transporter A1 (ABCA1), multidrug resistance proteins (MDR) 1 and 2, bile salt export pump, multidrug resistance-associated proteins (MRP) 1 to 9, breast cancer resistance protein, and ATP-binding cassette subfamily G members 5 and 8, are responsible for the unidirectional export of endogenous and exogenous substances. Other efflux transporters [ATPase copper-transporting beta polypeptide (ATP7B) and ATPase class I type 8B member 1 (ATP8B1) as well as organic solute transporters (OST) alpha and beta] also play major roles in the transport of some endogenous chemicals across biological membranes. This review article provides a comprehensive overview of these transporters (both rodent and human) with regard to tissue distribution, subcellular localization, and substrate preferences. Because uptake and efflux transporters are expressed in multiple cell types, the roles of transporters in a variety of tissues, including the liver, kidneys, intestine, brain, heart, placenta, mammary glands, immune cells, and testes are discussed. Attention is also placed upon a variety of regulatory factors that influence transporter expression and function, including transcriptional activation and post-translational modifications as well as subcellular trafficking. Sex differences, ontogeny, and pharmacological and toxicological regulation of transporters are also addressed. Transporters are important transmembrane proteins that mediate the cellular entry and exit of a wide range of substrates throughout the body and thereby play important roles in human physiology, pharmacology, pathology, and toxicology.

Project description:The importance of the family of high affinity ammonium transporters is demonstrated by the presence of these proteins in all domains of life, including bacteria, archaea, fungi, plants, and humans. The majority of the proteins that have been studied from this family show high affinity and selectivity for ammonium, are impermeable to alkaline cations, saturate rapidly at low millimolar concentrations and most of them, are also permeable to methylammonium. Crystallization of homologue proteins from bacteria and archaea has demonstrated that the functional entity corresponds to a trimer, with each monomer maintaining a conductive pore. Through molecular modeling, it has been demonstrated that even though the identity of the proteins between bacteria/archaea with those from plants is below 25%, the latter seem to maintain similar tertiary and quaternary structures, an observation that has helped to address the functionality of conserved residues by means of mutational analysis. Results have shown that changes in the extracellular binding site of some plant transporters may result in their inhibition or reduction in transport activity, while in Escherichia coli, dissimilar replacements like Phe/Ala or Ser/Leu that eliminate possible ?-interactions or H-bonds with ammonium, respectively, lead to more active transporters. Active mutants with changes in the pair of conserved His in the center of the transporter suggest these residues are dispensable. Additional mutations have identified other important amino acids, both in the entrance of the pore and in cytoplasmic loops. Regulation of this family of transporters can be achieved by interactions of the C-terminal with cytoplasmic loops within the same monomer, or with a neighbor in the trimer. Depending on the interacting residues, these contacts may lead to the activation or inhibition of the protein. The aim of this review is to critically evaluate the newest findings on the role of the proposed amino acids that structure the ammonium pathway, as well as highlight the importance of additional residues that have been identified through mutational analyses.

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Functional transformations of bile acid transporters induced by high-affinity macromolecules.

Publications

Functional transformations of bile acid transporters induced by high-affinity macromolecules.

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