Lin M C, Nicosia S, Rodbell M
Biochemistry. 1976 Oct 5;15(20):4537-40. doi: 10.1021/bi00665a031.
The binding and action of glucagon at its receptor in hepatic plasma membranes have been compared, as a function of pH, with that of glucagon containing iodotyrosyl residues. Iodinated glucagon, at pH 7.0 and below, binds to the receptor and activates adenylate cyclase with an affinity about threefold higher than that of native glucagon. At pH 8.5, the affinity of the receptor for native glucagon is the same as that seen at pH 7.0. However, iodinated glucagon binds with a lowered affinity with increasing pH. The decreased affinity of the iodinated hormone correlates with ionization of the iodotyrosyl phenoxy groups, which has a pKa of 8.2. It is suggested that the decreased affinity is actually due to the inability of the ionized iodoglucagon to bind to the receptor. The relative potency of native and iodoglucagon will depend, therefore, on the concentrations of ionized and un-ionized species of iodoglucagon, which in turn depend on the pH of the medium. We conclude that incorporation of iodine atoms in the tyrosyl residues of glucagon has two major effects: (i) the iodine atom increases hydrophobic interaction of the hormone with the receptor and (ii) ionization of the phenoxy groups results in the loss of biological activity possibly as the result of loss of hydrogen bonding capability. Thus, the tyrosyl residues in glucagon are critically involved in the function of the hormone.
已将胰高血糖素在肝细胞膜中与其受体的结合及作用，作为pH的函数，与含碘酪氨酸残基的胰高血糖素进行了比较。在pH 7.0及以下时，碘化胰高血糖素与受体结合并激活腺苷酸环化酶，其亲和力比天然胰高血糖素高约三倍。在pH 8.5时，受体对天然胰高血糖素的亲和力与在pH 7.0时相同。然而，碘化胰高血糖素的结合亲和力随pH升高而降低。碘化激素亲和力的降低与碘酪氨酸苯氧基的电离有关，其pKa为8.2。提示亲和力降低实际上是由于离子化的碘胰高血糖素无法与受体结合。因此，天然胰高血糖素和碘胰高血糖素的相对效力将取决于碘胰高血糖素离子化和非离子化形式的浓度，而这又取决于介质的pH。我们得出结论，在胰高血糖素的酪氨酸残基中引入碘原子有两个主要影响：（i）碘原子增加了激素与受体的疏水相互作用；（ii）苯氧基的电离可能导致氢键结合能力丧失，从而导致生物活性丧失。因此，胰高血糖素中的酪氨酸残基对激素的功能至关重要。
