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Isosteric Replacement of A3 Val of Porcine Insulin by allo‐Thr
Author(s) -
Li Moyi,
Cui Dafu,
Zhang Youshang
Publication year - 2002
Publication title -
iubmb life
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.132
H-Index - 113
eISSN - 1521-6551
pISSN - 1521-6543
DOI - 10.1080/15216540210808
Subject(s) - insulin , insulin receptor , chemistry , receptor , medicine , in vivo , endocrinology , insulin receptor substrate , stereochemistry , biochemistry , biology , insulin resistance , microbiology and biotechnology
A3 Val is important for insulin activity. It is invariant in insulins from different species studied thus far. Based on the three dimensional structure of insulin, it was thought to be involved in receptor binding. Its replacement by Leu resulted in remarkable lowering of insulin activity, indicating the crucial requirement of the side chain geometry at this position. When A3 Val was replaced by Thr, which is hydrophilic but isosteric with Val, substantial insulin activity was retained. Therefore, the isosteric requirement for receptor binding at this site is more stringent than the hydrophobic requirement. Here we report the replacement of A3 Val of porcine insulin by the unnatural allo‐Thr. The in vivo biological activity of A3 allo‐Thr insulin is similar to that of A3 Thr insulin or native insulin, but its receptor binding activity is 7.6% instead of 50% for A3 Thr insulin, indicating that at the A3 position the hydrophilic OH group of Thr could be more tolerated in receptor binding than the OH group of allo‐Thr. The retention of insulin activity by substituting A3 Val with the unnatural isosteric allo‐Thr demonstrates again the importance of isosteric interaction in the binding of insulin with its receptor.