Peptide transporters

ALAN TALEVI; CAROLINA L. BELLERA

The ADME Encyclopedia. A Comprehensive Guide on Biopharmacy and Pharmacokinetics

Springer Nature

Lugar: Basignstoke; Año: 2022; p. 767 - 773

The proton-coupled oligopeptide transporters from the SLC15 family are integral membrane proteins that mediate the cellular uptake of dipeptides, tripeptides and peptide-like (peptidomimetic) drugs (e.g., antiviral prodrugs and β-lactam antibiotics). Substrate movement across the membrane is coupled with proton movement down and inward electrochemical gradient, which (eventually) allows the transfer of small peptides against a substrate gradient. Whereas it is commonly stated that this type of transporters move their substrates uphill, note that very frequently they are also involved in the movement of the substrate down a concentration gradient, e.g. when dietary peptides or oral drugs initiate their absorption from the intestinal lumen (due to unfavorable physicochemical properties, such as high polarity and flexibility, some of the physiological substrates of these transporters would hardly be efficiently absorbed by free diffusion). The peptide transporters are responsible for the absorption and conservation of the nitrogen from dietary protein, and the absorption and disposition of peptide-related drugs. The symport or co-transport of substrate molecules and protons is generally classified as secondary active transport, though it has also been referred as tertiary active transport [1] (See Active and facilitated transport in drug absorption). In tertiary active transport, three transporter systems function serially [2]: a first transporter is directly coupled (primary active transport) to ATP utilization and creates a favorable electrochemical gradient for a molecular species A; the second transporter uses the electrochemical gradient of species A to establish an electrochemical gradient for species B (secondary active transport); in turn, the third transporter dissipates the electrochemical gradient of B to transport species C. In the particular case of the peptide transporters, the activity of the Na+-H+ exchanger couples the influx of Na+ into the cell with the efflux of H+, being primarily responsible for the presence of the H+ gradient. The driving force for such exchange, the transmembrane Na+ gradient, is generated at the expense of ATP by the (Na+-K+) ATPase [1] .