Peptide transporter 1 (PepT1) and Peptide transporter 2 (PepT2) (PepT1 (SLC15A1), PepT2 (SLC15A2))

Peptide transporters are secondary active membrane transport proteins belonging to the Major Facilitator Superfamily (MFS), primarily represented in mammals by Peptide transporter 1 (PepT1, SLC15A1) and Peptide transporter 2 (PepT2, SLC15A2). These transporters use the inward proton gradient across epithelial cell membranes, especially in the intestine (PepT1) and kidney (PepT2), to drive the efficient uptake of dipeptides, tripeptides, and a wide range of peptide-mimetic drugs[1][2][3][4][5][6]. PepT1 is crucial for protein-derived nutrient absorption in the small intestine, while PepT2 is responsible for peptide reabsorption and conservation in the renal tubule[1][6]. Both exhibit broad substrate specificity, recognizing thousands of di/tripeptides and many peptide-like drugs, such as certain beta-lactam antibiotics and ACE inhibitors, which has made them important for pharmaceutical design to enhance oral drug bioavailability[1][2][3]. The mechanism is proton-coupled symport, providing concentrative substrate uptake determined by the proton electrochemical gradient[2][3][5]. The substrate promiscuity and drug interactions pose challenges relating to drug-drug interactions and pharmacokinetics. Structurally, PepT1 and PepT2 each possess 12 transmembrane domains forming a large substrate-binding cavity and have been structurally resolved in multiple conformational states[3][4][6][7]. These features make peptide transporters important therapeutic targets and facilitators for drug absorption, as well as potential biomarkers for predicting pharmacokinetics of peptide-like therapeutics.

Other names

H⁺/peptide cotransporterProton-coupled oligopeptide transporterSLC15A1 (PepT1)SLC15A2 (PepT2)POT family transporterProton-coupled peptide transporter

Proton-coupled symport: drug/peptide import is driven by the proton electrochemical gradient; Carrier-mediated uptake