phenomenon in single-cell and complex
organisms. The study of peptide-bound
amino acid absorption was initiated with
the proposal by Fisher in 1954 that
‘peptides, rather than amino acids, may be
the protein currency of the body’ (as
reviewed by Matthews, 1991). Thanks in
large part to the pioneering work of David
Matthews (Matthews, 1991) and Siamak
Adibi (Adibi, 1997), it is now understood
that dietary and plasma proteins do not
need to be completely hydrolysed to their
constituent amino acids for absorption to
occur across the apical membranes of
intestinal and kidney tubule epithelia.Data
collected from many studies designed to
understand the quantitative importance of
free versus peptide-bound amino acids
indicate that peptide-bound amino acids
can account for the majority of amino acids
absorbed by enterocytes from the intestinal
lumen (Matthews, 1991; Seal and Parker,
1991; Webb and Matthews, 1998). A repre-
sentative list of peptide transport sub-
strates and affinity constants as measured
in the tissues, cells and membranes of vari-
ous species is presented in Table 1.2. The
use of hydrolysis-resistant peptides (-
alanylhistidine; carnosine; and glycylsarco-
sine, Gly-Sar) in whole tissue and brush
border membrane (BBM) vesicle experi-
ments has shown that the transport of
intact peptides is independent of pepti-
dase or amino acid transport activities
and that concentrative peptide uptake is
coupled to co-transport of a proton(s)
(Ganapathy et al., 1994; Adibi, 1997). In
apical (brush border) membrane transport
systems, such as enterocytes and kidney
tubule epithelia, an extracellular-to-intra-
cellular H+gradient energizes the transport
of di-, tri and/or tetra-peptide substrates.
In isolated intestinal loops, the pH of the
transport environment additionally is
reported to affect the affinity of the low-
affinity, high capacity transport system
(Lister et al., 1997).
Three generalized peptide transport
systems have been characterized biochemic-
ally in mammals: (i) a low-affinity trans-
port system highly expressed in the apical
membranes of differentiated enterocytes,
which also is weakly expressed in the
microvillus membrane of kidney tubule
epithelia; (ii) a high-affinity transport
capacity expressed primarily in the apical
membranes of kidney proximal tubules
epithelia; and (iii) a low-affinity system on
the basolateral membranes of polarized cell
types that displays a more limited range
of binding capacity than the low-affinity
apical transporters. Consequently, the
generalized model that has resulted for the
transport of small peptides across mam-
malian polarized epithelia involves: (i) the
recognition and absorption of peptides by
the low-affinity, high-capacity transporter;
(ii) transport across the apical membrane
into the cell cytosol, and hydrolysis to free
amino acids; and/or (iii) the passage of
intact peptides into the blood by a high-
affinity, low-capacity basolateral membrane
transporter (Ganapathy et al., 1994; Adibi,
1997; Steel et al., 1997). In fish, a similar
model has been proposed, except for the
presence of both high- and low-affinity
transport systems in the apical membranes
and the presence of a low-affinity, high-
capacity basolateral transport system that
displays a broader range of substrate
recognition than that of the apical trans-
porters (Thamotharan et al., 1998).
Consistent with the relatively few
transport systems that have been identified
for peptide transport, recognition by these
‘promiscuous’ transporters has been pro-
posed to be achieved with an oligopeptide
of four or less amino acids that contains at
least one peptide bond, a C-terminal L
conformer amino acid, and an overall net
positive charge of <2 (Boyd, 1995).
Accordingly, -lactam and cephalosporin
antibiotics are substrates for peptide trans-
port systems. A recent report suggests that
the peptide bond may not be required for
substrate binding by either the low- or
high-affinity peptide transport systems
(Ganapathy et al., 1998). Although any of
the three characterized peptide transport
systems recognize many more substrates
than does any given amino acid trans-
porter, not all small peptides are recog-
nized, substantial differences do exist in
the relative affinities for substrates among8 J.C. Matthews