ArticleThe international journal of biochemistry & cell biology2009
The transmembrane tyrosines Y56, Y91 and Y167 play important roles in determining the affinity and transport rate of the rabbit proton-coupled peptide transporter PepT1.
Article in The international journal of biochemistry & cell biology, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 16 papers.
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16 citing papers in PubMed, 27 citations in OpenAlex.
- Functional characterization of Atlantic salmon (Salmo salar L.) PepT2 transporters.The Journal of physiology · 2022Article
- Recent advances in understanding prodrug transport through the SLC15 family of proton-coupled transporters.Biochemical Society transactions · 2020Review
- Structural basis for prodrug recognition by the SLC15 family of proton-coupled peptide transporters.Proceedings of the National Academy of Sciences of the United States of America · 2019Article
- Multispecific Substrate Recognition in a Proton-Dependent Oligopeptide Transporter.Structure (London, England : 1993) · 2018Article
- Chemical Modulation of the Human Oligopeptide Transporter 1, hPepT1.Molecular pharmaceutics · 2017Article
- Salt Bridge Swapping in the EXXERFXYY Motif of Proton-coupled Oligopeptide Transporters.The Journal of biological chemistry · 2015Article
- Crystal Structures of the Extracellular Domain from PepT1 and PepT2 Provide Novel Insights into Mammalian Peptide Transport.Structure (London, England : 1993) · 2015Article
- Molecular insights into proton coupled peptide transport in the PTR family of oligopeptide transporters.Biochimica et biophysica acta · 2015Review
- Gating topology of the proton-coupled oligopeptide symporters.Structure (London, England : 1993) · 2015Article
- Article
- Alternating access mechanism in the POT family of oligopeptide transporters.The EMBO journal · 2012Article
- Probing the putative active site of YjdL: an unusual proton-coupled oligopeptide transporter from E. coli.PloS one · 2012Article
- Residues R282 and D341 act as electrostatic gates in the proton-dependent oligopeptide transporter PepT1.The Journal of physiology · 2011Article
- Crystal structure of a prokaryotic homologue of the mammalian oligopeptide-proton symporters, PepT1 and PepT2.The EMBO journal · 2011Article
- Bioavailability through PepT1: the role of computer modelling in intelligent drug design.Current computer-aided drug design · 2010Review
- Proton-coupled oligopeptide transporter family SLC15: physiological, pharmacological and pathological implications.Molecular aspects of medicineReview
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4 authors at 3 institutions in 1 country.
Funding
Abstract
The mammalian proton-coupled peptide transporter PepT1 is widely accepted as the major route of uptake for dietary nitrogen, as well as being responsible for the oral absorption of a number of classes of drugs, including beta-lactam antibiotics and angiotensin-converting enzyme (ACE) inhibitors. Using site-directed mutagenesis and zero-trans transport assays, we investigated the role of conserved tyrosines in the transmembrane domains (TMDs) of rabbit PepT1 as predicted by hydropathy plots. All the individual TMD tyrosines were substituted with phenylalanine and shown to retain the ability to traffic to the plasma membrane of Xenopus laevis oocytes. These single substitutions of TMD tyrosines by phenylalanine residues did not affect the proton dependence of peptide uptake, with all retaining wild-type PepT1-like pH dependence. Individual mutations of four of the nine TMD residue tyrosines (Y64, Y287, Y345 and Y587) were without measurable effect on PepT1 function, whereas the other five (Y12, Y56, Y91, Y167 and Y345) were shown to result in altered transport function compared to the wild-type PepT1. Intriguingly, the affinity of Y56F-PepT1 was found to be dramatically increased (approximately 100-fold) in comparison to that of the wild-type rabbit PepT1. Y91 mutations also affected the substrate affinity of the transporter, which increased in line with the hydrophilicity of the substituted amino acid (F>Y>Q>R). Y167 was demonstrated to play a pivotal role in rabbit PepT1 function since Y167F, Y167R and Y167Q demonstrated very little transport function. These results are discussed with regard to a proposed mechanism for PepT1 substrate binding.
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