[A19-Phenylalanine] Insulin: A New Synthetic Analogue

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Abstract
An analogue of porcine insulin which differs from the native molecule in that the tyrosine residue in position A19 is replaced by phenylalanine was synthesized. The [PheA19]A chain was synthesized by the fragment condensation and purified as tetra-S-sulfonate by ion-exchange chromatography on DEAE-cellulose at pH 3.5. Conversion of the latter into the sulfhydryl form and combination with native sulfhydryl B chain yielded the [PheA19]insulin, which was purified by ion-exchange chromatography on CM[carboxymethyl]-cellulose at pH 4.0 with a linear NaCl gradient. The biological activity of this analog was 22.6% as measured by the rat epididymal adipocytes. In the insulin molecule the hydroxyl function of A19-tyrosine participates in a H-bond with the carbonyl function of A1-glycine. That H bond formation is critical for the stability of the insulin monomer and for the stability of the hormone-receptor complex. The low biological activity supports this hypothesis. The circular dichroism data in far UV suggest that the introduction of phenylalanine leaves the molecule structure essentially undisturbed; however, the change observed in near UV could account for the exchange.