to the other, releasing the ion on the other side. A channel former simply provides a polar
tunnel that allows the migration of a polar ion across an otherwise impenetrable lipid
layer.
An example of an ionophore that is a cage carrier is valinomycin (9.56). This cyclic
peptide lactone consists of three molecules each of L-valine,D-α-hydroxyisovaleric
acid, and L-lactate. The six highly polarized lactone carbonyl oxygens line the inside of
the ring, whereas the nonpolar alkyl groups point to the outside of the molecule. Thus
the polar interior can accommodate a nonhydrated potassium ion and surround it with
an apolar bracelet. This complex can then be transported through a membrane in an
energy-dependent K+–H+exchange. The selectivity of valinomycin for K+over Na+is
very high, the ratio being about 10^4 :1. In this way, valinomycin will increase the K+con-
ductivity of lipid membranes at concentrations as low as 10−^9 M. The high K+selectiv-
ity is due to the relative ease of dehydration of this ion: with its larger diameter, the
potassium ion holds hydrate water less firmly than does sodium; consequently, whereas
the hydrated sodium ion does not fit the valinomycin “doughnut,” the dehydrated K+
does bind easily, with the bonding energy providing a further energy advantage for the
selective reaction. A hydrated sodium ion is larger than a potassium ion with or with-
out a hydrate envelope.
An example of a channel- or pore-forming antibiotic is gramicidin A (9.57), a peptide
consisting of 15 amino acids. It induces the transmembrane transport of protons, alkali-
metal ions, and thallium ions at concentrations as low as 10−^10 M, even though it is unable
to complex these ions in solution. Gramicidin also forms several dimers with itself.
570 MEDICINAL CHEMISTRY