Nature of the B10 amino acid residue. Requirements for high biological activity of insulin.

Human [10-asparagine-B] insulin ([ Asn10 -B] insulin), an analogue which differs from the parent molecule in that the histidine residue at position 10 of the B chain (B10) is replaced by asparagine, has been synthesized and isolated in purified form. In vitro biological assays indicated a potency of ca. 35% compared to insulin. We have previously shown that the replacement of histidine at position B10 by lysine resulted in an analogue displaying ca. 15% of the biological activity of natural hormone, while the substitution of leucine in this position produced a molecule exhibiting ca. 45% potency in in vivo assays. The data indicate that molecular size of the amino acid residue at position B10 may be important in the maintenance of a structure commensurate with high biological activity. Polarity at this position appears to be rather unimportant while a strongly basic group appears to be deleterious.