MONOCARBOXYLATE TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 163

MCT1-4 prefer monocarboxylates containing two to four unbranched, aliphatic car-
bon atoms, with the highest affinity for compounds containing three carbons. Single
carbon atoms containing monocarboxylates, such as formate and bicarbonate, are
poor substrates. 1 Substitutions in the C2 and C3 positions are tolerated (excluding
amino and amido groups), with carbonyl or hydroxyl substitutions at C2 generally
being preferred (pyruvate and lactate). MCTs are stereoselective for L-lactate but not
for 2-chloropropionate and

-hydroxybutyrate. 14
Monocarboxylate compounds containing long-branched aliphatic or aromatic side
chains are also acceptable substrates for MCTs. Some of these compounds can bind
to the transporter with high affinity but are not easily translocated and thus function
as inhibitors. The monocarboxylate group does not appear to be essential because
compounds such as the PPD derivatives, quercetin, phloretin, and 6-MP also serve as
substrates for MCTs. Additionally, the PPD derivatives may serve as good templates
for drug design because they are isoform specific.
X-ray crystallography provides a means by which the structures of the translocation
pore of membrane transporters may be deduced. 111 , 112 Thus far no MCT protein has
succumbed to any such structural analysis. However, a hypothetical three-dimensional
structure of MCT proteins can be obtained by threading the amino acid sequence onto
the previously determined three-dimensional structures of similar 12-transmembrane-
domain-containing proteins (lactose permease, glycerol-3-phosphate transporter)
(Figure 7. 1). In the near future it may be possible to apply software to describe
the dimensions, electronic configuration, and putative amino acids that define the
substrate binding and translocation features of MCTs.
Few studies have been conducted concerning the substrates and inhibitors of SM-
CTs, therefore, it is difficult to determine its overall substrate preference. It can be
assumed, however, that because MCT1-4 and SMCTs transport similar natural sub-
strates, they are both likely to be involved in transport of the same clinically relevant
substrates. From the available kinetic studies it appears that both SMCT1 and SMCT2
have a higher affinity for unsubstituted monocarboxylates (butyrate). Additionally,
as the chain length increases from two to four carbons, the affinity increases. Fur-
thermore, the ability of SMCTs to transport both L- and D-lactate with high affinity
may provide a means by which synthetic compounds can be targeted specifically for
SMCT-mediated transport.

Acknowledgments

This work was supported in part by the University of Minnesota-Duluth Department
of Biology and grants from the American Heart Association and National Institutes
of Health (NS37764).

REFERENCES

1. Halestrap AP, Meredith D. 2004. The SLC16 gene family: from monocarboxylate
transporters (MCTs) to aromatic amino acid transporters and beyond. Pflugers Arch
447(5):619-628.