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The intestinal H+/peptide symporter PEPT1: structure-affinity relationships
Matthias Brandsch1, Ilka Knütter, Frederick H Leibach
1Membrane Transport Group, Biozentrum of Martin-Luther-University Halle-Wittenberg, Weinbergweg 22, D-06120 Halle, Germany. brandsch@biozentrum.uni-halle.de
Summary
Peptide transporter 1 (PEPT1) is crucial for nutrient and drug absorption. Understanding substrate affinities helps identify new PEPT1 substrates and their interactions.
Area of Science:
- Pharmacology
- Biochemistry
- Molecular Biology
Background:
- Mammalian enterocyte peptide transporter 1 (PEPT1) plays a vital role in absorbing dietary peptides and is a key uptake route for many drugs.
- Current understanding of PEPT1's substrate binding site is limited, hindering the identification of novel substrates.
Purpose of the Study:
- To review and discuss the affinities of various substrates for PEPT1.
- To explore structural determinants influencing substrate affinity to PEPT1.
Main Methods:
- Literature review of reported affinity constants for PEPT1 substrates and inhibitors.
- Classification of affinity constants into high (<0.5 mM), medium (0.5–5.0 mM), and low (>5 mM) categories.
Main Results:
- Reported affinity constants for PEPT1 substrates range widely from 2 microM to 30 mM.
- A significant number of drugs and prodrugs utilize PEPT1 for systemic circulation entry.
- Affinity values above 15 mM are viewed with caution due to potential variability.
Conclusions:
- Affinity determination remains a critical method for assessing potential PEPT1 substrates in the absence of crystallographic data.
- Understanding substrate affinity and structural determinants is essential for optimizing drug delivery and nutritional absorption via PEPT1.