Contribution of the B16 and B26 tyrosine residues to the biological activity of insulin |
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Authors: | Shi-quan Hu G Thompson Burke and Panayotis G Katsoyannis |
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Institution: | (1) Department of Biochemistry, Mount Sinai School of Medicine of the City University of New York, 10029-6574 New York, New York |
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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. |
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Keywords: | Synthetic analogues structure-activity B-chain peptide synthesis |
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