title: Contribution of the B16 and B26 tyrosine residues to the biological activity of insulin.
abstract: We report the synthesis and biological evaluation of five insulin analogues in which one or both of the B-chain tyrosine residues have been substituted. [B16 Phe]insulin and [B16 Trp]insulin display a very modest reduction in potency (c. 65%) relative to porcine insulin; [B26 Phe]insulin is less active (30-50%), and the doubly substituted [B16 Phe, B26 Phe]insulin displays still lower potency (c. 35%). The further substitution of Asp for B10 His in [B16 Phe, B26 Phe]insulin raises its activity to approximately twofold greater than natural insulin, an increase of approximately fivefold over the parent compound. We conclude that the bulk and/or aromaticity of the amino acid residue at position B16, but not its hydrogen-bonding capacity, contributes to the biological activity of the hormone. We further conclude that hydrogen-bonding capacity or special side-chain packing characteristics are required at the B26 position for insulin to display high biological activity.
authors.affiliation: Department of Biochemistry, Mount Sinai School of Medicine of the City University of New York, New York 10029-6574.
authors.forename: S Q
authors.initials: SQ
authors.lastname: Hu
authors.forename: G T
authors.initials: GT
authors.lastname: Burke
authors.forename: P G
authors.initials: PG
authors.lastname: Katsoyannis
mesh_terms: D000595:Amino Acid Sequence; D001681:Biological Assay; D006801:Humans; D007328:Insulin / Q000031:analogs & derivatives* / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology; D011487:Protein Conformation; D014443:Tyrosine
chemical_list: D007328:Insulin; D014443:Tyrosine