Na⁺/L⁺ selectivity in transport systemA: Effects of substrate structure

Summary

The effect of amino acid structure on the selectivity between Na and Li as co-substrates for transport SystemA in the Ehrlich cell has been explored to localize relative binding positions. By various tests the relative effectiveness of the two cations varies over fivefold. Changes in structure of the amino acid that lower its response to Na tend to decrease its selectivity for Na over Li, but with many exceptions. The higher the Li level required to half-maximize amino acid entry, the slower tends to be the entry attainable for both Li and amino acid. Our attention fell on strong departures from these trends. An atypically fast uptake is produced by Li in the presence of a second amino group pK′₂<8.5, in exceptional association with the known fast uptake in Na. The hydroxyl group of serine yields exceptionally strong uptake, whereas hydroxyl groups in restrained orientation (as in threonine and hydroxyprolines) sharply limit co-substrate interaction. Despite the absence of a sidechain, glycine shows unexceptional relative co-substrate responses. A sidechain in the α₂ position, as ind-alanine, lowers tolerance for both ions, an aberration largely corrected by the insertion of a second (α₂) methyl group, and surprisingly, even by an N-methyl group. Forl-alanine, an N-methyl group has in contrast unfavorable effects on co-substrate interaction. These factors point to disturbance by the α₂ methyl group of the position taken by the amino acid at the site, largely rectifiable by balancing effects of a second methyl group. They also point to a position of the alkali ion quite close to the α-carbon and far from the position taken in SystemASC. Addition of an ethylene bridge between the α-methyl groups of α(methylamino)-isobutyric acid leads to the strongest discrimination seen against Li⁺ relative to Na⁺, suggesting through crowding of the area that the alkali ion adjoins the three methyl groups of this analog.