MAMMALIAN OLIGOPEPTIDE TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 110

Luminal Cytoplasm Abluminal

Signal transduction
• Gene Transcription
• Intracellular pool release,
e.g. Unfolded Protein
response

Proteins/
Oligopeptides

Proteases/
Peptidases

Amino Acid
transporters?

Amino acids

Proteolysis

PHT-1

Free Drug/
Peptides?

Peptide
Transporter?

PT-1

Peptide - based
agents, Di- &
Tripeptides

Free
peptide-
based drug

Peptide-based
agents, Di- &
Tripeptides

Metabolism/Protein
synthesis
• Membrane proteins
• Intracellular proteins
• Energy
• Other

PepT1

PHT-2

Dissolution

Passive
Transcellular
Diffusion

Passive
Transcellular
Diffusion Intracellular accumulation

Peptide - based agent
in formulation

Passive
Paracellular
Diffusion

FIGURE 6.1. Potential parallel or competing pathways available for oligopeptide and peptide-
based drug permeation and their potential intracellular fates across cellular barriers. Depicted
are PepT1, PHT1, PHT2, and PT1 as the concentrative oligopeptide transporters. PepT2 is not
expressed in intestinal epithelial cells and is therefore not illustrated here.

third consensus sequence has been proposed by Fei et al., (GTGGIKPXV). 25 Based
on their phylogenetic analysis, Saier et al. have also proposed three different signature
sequences associated with the POT superfamily. 26 Despite these identified consensus
sequences, there is little identity between the PepT and PHT members of this
superfamily. For instance, while the human PepT1 (hPepT1) shares 83.5% identity
with its rat homolog, its identity with the human PHT1 (hPHT1) is just 20.4%. 13
Interestingly, hPepT1 shares just 26.0% identity with the intracellularly localized
hPHT2. 13
As mentioned previously, PepT1 is arguably the most widely studied member of
the POT superfamily of transporters. However, relatively little information is known
concerning its tissue and cellular localizations as well as species variations. The cloned
human PepT1 cDNA sequence encodes a 708-amino acid protein with an estimated
molecular weight of 79 kDa and an isoelectrical point of 8.6. 27 PepT1 expression has
been demonstrated in several animal species, 15 , 30 - 33 with each isoform exhibiting high
homology with other species. Although hPepT1 shows high homology with its various
orthologs, studies have demonstrated different tissue expressions of PepT1 among
different species. 34 These expressional differences have not been limited to PepT1,
as rPHT1 was not expressed in the gastrointestinal tract, in contrast to its human