Substrate specificity of the intestinal brush-border proline/sodium (IMINO) transporter

Summary l-proline uptake via the intestinal brush-borderIMINO carrier was tested for inhibition by 41 compounds which included sugars, N-methylated, -,-, - and -amino and imino acids, and heterocyclic analogs of pyrrolidine, piperidine and pyridine. Based on competitive inhibitor constants (apparentK/'s) we find that theIMINO carrier binding site interacts with molecules which possess a well-defined set of structural prerequisites. The ideal inhibitor must 1) be a heterocyclic nitrogen ring, 2) have a hydrophobic region, 3) be thel-stereoisomer of 4) an electronegative carbonyl group which is 5) separated by a one-carbon atom spacer from 6) an electropositive tetrahedral imino nitrogen with two H atoms. Finally, 7) the inhibitor conformation determined by dynamic ring puckering must position all these features within a critical domain. The two best inhibitors arel-pipecolate (apparentK/0.2mm) andl-proline (apparentK/0.3mm).