MONOCARBOXYLATE TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 150

Outside

D302

E369

F360

R143

R306

G153

Inside

G153

E369

F360

R306

R143

D302

Inside Outside

(a) (b)

Substrate binding
Transport activity

TMD1 TMD12

FIGURE 7.2. ( a) A side view of the hypothetical structure of MCT1 embedded in the plasma
membrane is depicted with solid lines indicating the edge of the lipid bilayer . (b) MCT1 is
shown as in (a) , but viewed from the exofacial membrane surface. Each transmembrane domain
(TMD) is color coded from the N- (red) to the c-terminus (purple). The positions predicted for
the critical amino acids necessary for substrate binding (red) and transport activity (black) are
highlighted and numbered according to their position in the protein sequence. This structure
was deduced by threading the MCT1 protein sequence onto the crystal structure of the E. coli
lactose permease A chain using the Cn3D software available from NCBI . (See insert for color
representation of figure.)

comprise two of 12 identified members of the solute carrier 5 gene family and are
denoted SLC5A8 and SLC5A12. This family, also known as the sodium/glucose
cotransporter gene family , contains carriers whose substrates include glucose, my-
oinositol, iodide, choline, and B-complex vitamins. 13 Hydropathy analysis of SMCT
protein sequences predicts the presence of 13 transmembrane domains with extracel-
lular N- and intracellular C-termini. The link between colon cancer and SMCT1 gene
suppression make this protein particularly important from a pharmacological per-
spective for clinical and therapeutic purposes. Unlike many MCTs, which generally
have relatively broad tissue expression patterns, the protein expression of SMCTs is
highly tissue specific. This leads to the supposition that these transporters may have
evolved as a mechanism to cope with the unique metabolic requirements associated
with specific tissues. Aside from tissue distribution, there are many other properties
of SMCTs that differ from those of MCTs. As the name implies, the transport mech-
anism for SMCTs involves the transport of monocarboxylates along with sodium
ions in an electrogenic fashion. That is, the symporter cotransports multiple (between
two and four) sodium ions along with a monocarboxylate anion down a concentra-
tion gradient. 10 Finally, the substrate affinity of SMCTs for monocarboxylates differs
greatly from that reported for MCTs (Table 7. 1).