Design of novel synthetic MTS conjugates of bile acids for site-directed sulfhydryl labeling of cysteine residues in bile acid binding and transporting proteins

Ray, Abhijit; Banerjee, Antara; Chang, Cheng; Khantwal, Chandra M.; Swaan, Peter W.

doi:10.1016/j.bmcl.2005.12.050

Cited by 6 publications

(7 citation statements)

References 11 publications

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“…This detailed model served as a guide for the subsequent mutagenesis studies. The experimental strategies included using a combination of charged, exoplasmic specific methanethiosulfonates and site-directed mutagenesis, substitute cysteine accessibility mutagenesis, different bile acid substrates, and high affinity specific inhibitors to finely map the solute binding site and translocation sites in the ASBT (Hallen et al 2000; Hallen et al 2002; Banerjee et al 2005; Hussainzada et al 2006; Ray et al 2006; Hussainzada et al 2008; Khantwal and Swaan 2008). …”

Section: The Apical Sodium-dependent Bile Acid Transporter: Asbtmentioning

confidence: 99%

Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition

Dawson

2010

Handbook of Experimental Pharmacology

188

166

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Membrane transporters expressed by the hepatocyte and enterocyte play critical roles in maintaining the enterohepatic circulation of bile acids, an effective recycling and conservation mechanism that largely restricts these potentially cytotoxic detergents to the intestinal and hepatobiliary compartments. In doing so, the hepatic and enterocyte transport systems ensure a continuous supply of bile acids to be used repeatedly during the digestion of multiple meals throughout the day. Absorption of bile acids from the intestinal lumen and export into the portal circulation is mediated by a series of transporters expressed on the enterocyte apical and basolateral membranes. The ileal apical sodium-dependent bile acid cotransporter (abbreviated ASBT; gene symbol, SLC10A2) is responsible for the initial uptake of bile acids across the enterocyte brush border membrane. The bile acids are then efficiently shuttled across the cell and exported across the basolateral membrane by the heteromeric Organic Solute Transporter, OSTα-OSTβ. This chapter briefly reviews the tissue expression, physiology, genetics, pathophysiology, and transport properties of the ASBT and OSTα-OSTα. In addition, the chapter discusses the relationship between the intestinal bile acid transporters and drug metabolism, including development of ASBT inhibitors as novel hypocholesterolemic or hepatoprotective agents, prodrug targeting of the ASBT to increase oral bioavailability, and involvement of the intestinal bile acid transporters in drug absorption and drug-drug interactions.

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Section: The Apical Sodium-dependent Bile Acid Transporter: Asbtmentioning

confidence: 99%

Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition

Dawson

2010

Handbook of Experimental Pharmacology

188

166

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“…To generate mutations on each individual residue of TM2, C270A or wild type (WT) plasmid of hASBT in pCMV5 vector was used as the template. Our previous studies demonstrated that the C270A mutant is functionally active and has resistance to thiol modification (20). The mutations were generated by QuikChange site-directed mutagenesis.…”

Section: Materials-radiolabeledmentioning

confidence: 99%

Transmembrane Domain II of the Human Bile Acid Transporter SLC10A2 Coordinates Sodium Translocation

Sabit

Mallajosyula

MacKerell

et al. 2013

Journal of Biological Chemistry

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Background: Transmembrane domains are critical to the structure and function of bile acid transporters. Results: Sodium sensitive residues follow distinct ␣-helical periodicity along TM2. Conclusion: TM2 forms part of the sodium translocation pathway, which is highly conserved in its putative remote bacterial homologue ASBT NM . Significance: The proposed sodium translocation mechanism may be universal to other SLC10A family members.

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“…Combination of photoaffinity labeling, enzymatic digestion, and epitope-specific antibodies further allowed identification of the bile acid attachment site (of position 7) to the C-terminal 56 to 67 amino acids [25,[74][75][76]. Recent studies by Banerjee, Ray, and colleagues [77,78] have aimed at preparing bile acid-containing MTS agents capable of modifying the bile acid binding site of ASBT. Use of these conjugates provides information about the protein-ligand interactions of ASBT, and the prepared bile acid-MTS conjugates may find use in characterizing other bile acid transporters, such as NTCP and BSEP as well [77,78].…”

Section: Bile Acid Transport Proteinsmentioning

confidence: 99%

“…Recent studies by Banerjee, Ray, and colleagues [77,78] have aimed at preparing bile acid-containing MTS agents capable of modifying the bile acid binding site of ASBT. Use of these conjugates provides information about the protein-ligand interactions of ASBT, and the prepared bile acid-MTS conjugates may find use in characterizing other bile acid transporters, such as NTCP and BSEP as well [77,78]. Kramer and co-workers [79] have widely studied the substrate specificity of ASBT and NTCP.…”

Section: Bile Acid Transport Proteinsmentioning

confidence: 99%

Exploitation of Bile Acid Transport Systems in Prodrug Design

Sievänen

2007

Molecules

101

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Abstract:The enterohepatic circulation of bile acids is one of the most efficient recycling routes in the human body. It is a complex process involving numerous transport proteins, which serve to transport bile acids from the small intestine into portal circulation, from the portal circulation into the hepatocyte, from the hepatocyte into the bile, and from the gall bladder to the small intestine. The tremendous transport capacity and organ specificity of enterohepatic circulation combined with versatile derivatization possibilities, rigid steroidal backbone, enantiomeric purity, availability, and low cost have made bile acids attractive tools in designing pharmacological hybrid molecules and prodrugs with the view of improving intestinal absorption, increasing the metabolic stability of pharmaceuticals, specifically targeting drugs to organs involved in enterohepatic circulation, as well as sustaining therapeutically reasonable systemic concentrations of active agents. This article briefly describes bile acid transport proteins involved in enterohepatic circulation, summarizes the key factors affecting on the transport by these proteins, and reviews the use of bile acids and their derivatives in designing prodrugs capable of exploiting the bile acid transport system.

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Design of novel synthetic MTS conjugates of bile acids for site-directed sulfhydryl labeling of cysteine residues in bile acid binding and transporting proteins

Cited by 6 publications

References 11 publications

Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition

Role of the Intestinal Bile Acid Transporters in Bile Acid and Drug Disposition

Transmembrane Domain II of the Human Bile Acid Transporter SLC10A2 Coordinates Sodium Translocation

Exploitation of Bile Acid Transport Systems in Prodrug Design

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