Proton/peptide cotransporter (PEPT 2) from human kidney: Functional characterization and chromosomal localization

Ramamoorthy, Sammanda; Liu, Wei; Ma, Yen-Ying; Yang‐Feng, Teresa L.; Ganapathy, Vadivel; Leibach, Frederick H.

doi:10.1016/0005-2736(95)00178-7

Cited by 71 publications

(38 citation statements)

References 17 publications

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“…Vaccinia Virus Expression of PEPT 1 and PEPT 2-This was done using the procedure described earlier (11)(12)(13). Subconfluent HeLa cells in 24-well culture plates were first infected with a recombinant vaccinia virus VTF 7-3 which carries the gene for T7 RNA polymerase as a part of its genome.…”

Section: Methodsmentioning

confidence: 99%

Differential Recognition of β-Lactam Antibiotics by Intestinal and Renal Peptide Transporters, PEPT 1 and PEPT 2

Ganapathy

Brandsch

Prasad

et al. 1995

Journal of Biological Chemistry

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This study was initiated to determine if there are differences in the recognition of ␤-lactam antibiotics as substrates between intestinal and renal peptide transporters, PEPT 1 and PEPT 2. Reverse transcription-coupled polymerase chain reaction and/or Northern blot analysis have established that the human intestinal cell line Caco-2 expresses PEPT 1 but not PEPT 2, whereas the rat proximal tubule cell line SKPT expresses PEPT 2 but not PEPT 1. Detailed kinetic analysis has provided unequivocal evidence for participation of PEPT 2 in SKPT cells in the transport of the dipeptide glycylsarcosine and the aminocephalosporin cephalexin. The substrate recognition pattern of PEPT 1 and PEPT 2 was studied with cefadroxil (a cephalosporin) and cyclacillin (a penicillin) as model substrates for the peptide transporters constitutively expressed in Caco-2 cells (PEPT 1) and SKPT cells (PEPT 2). Cyclacillin was 9-fold more potent than cefadroxil in competing with glycylsarcosine for uptake via PEPT 1. In contrast, cefadroxil was 13-fold more potent than cyclacillin in competing with the dipeptide for uptake via PEPT 2. The substrate recognition pattern of PEPT 1 and PEPT 2 was also investigated using cloned human peptide transporters functionally expressed in HeLa cells. Expression of PEPT 1 or PEPT 2 in HeLa cells was found to induce H ؉ -coupled cephalexin uptake in these cells. As was the case with Caco-2 cells and SKPT cells, the uptake of glycylsarcosine induced in HeLa cells by PEPT 1 cDNA and PEPT 2 cDNA was inhibitable by cyclacillin and cefadroxil. Again, the PEPT 1 cDNA-induced dipeptide uptake was inhibited more potently by cyclacillin than by cefadroxil, and the PEPT 2 cDNA-induced dipeptide uptake was inhibited more potently by cefadroxil than by cyclacillin. It is concluded that there are marked differences between the intestinal and renal peptide transporters in the recognition of ␤-lactam antibiotics as substrates.

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Section: Methodsmentioning

confidence: 99%

Differential Recognition of β-Lactam Antibiotics by Intestinal and Renal Peptide Transporters, PEPT 1 and PEPT 2

Ganapathy

Brandsch

Prasad

et al. 1995

Journal of Biological Chemistry

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251

164

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“…The murine Pept2 gene is 34 kb long, consists of 22 exons and 21 introns (52), and also carries a TATA-less promoter. The human Pept1 and Pept2 genes have been mapped to chromosomes 13q33-34 and 3q13.3-q21, respectively (39,51). The murine Pept2 gene was localized in a syntenic region with human chromosome 3q13.3-q21, on central mouse chromosome 16 close to D16Mit4 and D16Mit59 (52).…”

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confidence: 99%

An update on renal peptide transporters

Daniel

Rubio‐Aliaga

2003

American Journal of Physiology-Renal Physiology

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Daniel, Hannelore, and Isabel Rubio-Aliaga. An update on renal peptide transporters. Am J Physiol Renal Physiol 284: F885-F892, 2003; 10.1152/ajprenal.00123.2002The brush-border membrane of renal epithelial cells contains PEPT1 and PEPT2 proteins that are rheogenic carriers for short-chain peptides. The carrier proteins display a distinct surface expression pattern along the proximal tubule, suggesting that initially di-and tripeptides, either filtered or released by surface-bound hydrolases from larger oligopeptides, are taken up by the low-affinity but high-capacity PEPT1 transporter and then by PEPT2, which possesses a higher affinity but lower transport capacity. Both carriers transport essentially all possible di-and tripeptides and numerous structurally related drugs. A unique feature of the mammalian peptide transporters is the capability of proton-dependent electrogenic cotransport of all substrates, regardless of their charge, that is achieved by variable coupling in proton movement along with the substrate down the transmembrane potential difference. This review focuses on the postcloning research efforts to understand the molecular physiology of peptide transport processes in renal tubules and summarizes available data on the underlying genes, protein structures, and transporter function as derived from studies in heterologous expression systems. PEPT1; PEPT2; renal physiology; localization; functional analysis RENAL TUBULAR PEPTIDE TRANSPORT activity was originally discovered after intravenous infusion of the resistant dipeptide Gly-Sar in rats that resulted in a high accumulation of the intact dipeptide in renal tissue (1, 3). Studies with renal brush-border membrane vesicles established that renal apical peptide uptake was an electrogenic, proton-dependent uphill transport process for di-and tripeptides and related drugs mediated by two kinetically different systems (for a review, see Ref. 38). The underlying proteins, differing in transport characteristics, now designated as PEPT1 (SLC15A1) and PEPT2 (SLC15A2), have been identified, and the corresponding genes have been cloned from a variety of species (10,24,25,39,41,(52)(53)(54). The transporters have been expressed in various cellular models, and information on structure, transport function, and regulation has been gathered by flux studies and electrophysiological techniques. Expression analysis of transporter mRNA and protein by in situ hybridization and immunohistochemistry has extended our knowledge of tissue distribution, particularly the renal zonation of PEPT1 and PEPT2 surface expression. THE MOLECULAR ENTITIES OF APICAL PEPTIDE TRANSPORTPEPT1 and PEPT2 are polytopic integral membrane proteins with 12 predicted membrane-spanning domains and NH 2 -and COOH-terminal ends facing the cytosol. Transporter architecture and membrane topology have not been studied systematically, and therefore structural information is still mainly based on hydropathic analysis of amino acid sequences. The mammalian PEPT1 proteins comprise 701-710 amino acids, ...

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“…PEPT1 is expressed in the early part of the proximal tubule (pars convolute), whereas PEPT2 is expressed further along the proximal tubule (pars recta). 32 These transporters may play roles in the reabsorption of di-and tri-peptides and peptide-mimetics, such as β-lactam antibiotics, from urine into tubular epithelial cells. 32 The affinities of β-lactam antibiotics are higher for PEPT2 and lower for PEPT1.…”

Section: ) Elimination From the Kidneymentioning

confidence: 99%

“…32 These transporters may play roles in the reabsorption of di-and tri-peptides and peptide-mimetics, such as β-lactam antibiotics, from urine into tubular epithelial cells. 32 The affinities of β-lactam antibiotics are higher for PEPT2 and lower for PEPT1. 33 Orally effective β-lactam antibiotics, such as cefaclor, cefadroxil, cephalexin, cephradine, ceftibuten, amoxicillin and cyclacillin have affinity constants of 0.003 -0.4 mM for PEPT2 and 0.3 -25 mM for PEPT1.…”

Section: ) Elimination From the Kidneymentioning

confidence: 99%

Impact of transporter-mediated drug absorption, distribution, elimination and drug interactions in antimicrobial chemotherapy

Tsuji¹

2006

Journal of Infection and Chemotherapy

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Proton/peptide cotransporter (PEPT 2) from human kidney: Functional characterization and chromosomal localization

Cited by 71 publications

References 17 publications

Differential Recognition of β-Lactam Antibiotics by Intestinal and Renal Peptide Transporters, PEPT 1 and PEPT 2

Differential Recognition of β-Lactam Antibiotics by Intestinal and Renal Peptide Transporters, PEPT 1 and PEPT 2

An update on renal peptide transporters

Impact of transporter-mediated drug absorption, distribution, elimination and drug interactions in antimicrobial chemotherapy

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