ORGANIC ANION TRANSPORTERS - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 60

FIGURE 4.6. Mechanisms of proximal tubular uptake and efflux of organic ions mediated by
organic anion and cation transporters (OATs, OCTs, OCTNs). Transporters whose encoding
genes are chromosomally paired are enclosed in ovals. (From ref. 82.) ( See insert for color
representation of figure. )

in an adenosine triphosphate (ATP)-independent mechanism. As a requisite, the high
concentration gradient of dicarboxylates is maintained by the sodium-dicarboxylate
cotransporter, which in turn is driven by the inwardly directed sodium gradient across
the basolateral membrane generated by Na + /K + -ATPase (Figure 4.6). Basolateral en-
try of anions is followed by apical efflux through the brush border membrane, probably
through a sodium-independent system whose exact mechanism remains unclear.
Even though the structure of the OATs has not been elucidated, the crystal structure
has been determined recently for three related MFS proteins: the glycerol 3-phosphate
(G3P) transporter from the Escherichia coli inner membrane (a G3P/P i antiporter,
GlpT), the E. coli lactose permease (a lactose/H + symporter, LacY), and the oxalate
transporter from Oxalobacter formigenes (an oxalate-formate antiporter, OxlT). 47 − 54
These transporters have similar topology, suggesting similar structural design for
other MFS proteins, including the OATs. Therefore, the resolved structure of these
bacterial transporters, with substrate-binding sites located at the interface between the
N- and C-terminal halves of the protein, may prove useful as a template for structural
modeling of the OATs and other SLC22 transporters.

4.4.1. Substrate Translocation

Using MFS transporter mechanisms as models for OATs, one might postulate a
single-binding-site alternating access mechanism such as that suggested for the
MFS transporters 55 , 56 and elaborated in more detail in thermodynamic and kinetic