Cockram C S, Jones R H, Sönksen P H
Diabet Med. 1985 Jul;2(4):241-4.
The tyrosine residues at positions 14 and 19 of the insulin A chain are of both theoretical and practical interest. In order to clarify their roles in insulin function we have studied the biological properties of the two chemically modified insulins in which phenylalanine replaces tyrosine at these sites. In comparison to native bovine insulin the lipogenesis potency (in rat adipocytes) of pheA19-insulin was 33% and of pheA14-insulin was 84%. Metabolic clearance rates (MCR) over a range of plasma concentrations were also reduced compared to native insulin both with pheA19-insulin and pheA14-insulin. Plasma half-disappearance times were 4.6 min for insulin, 5.1 min for pheA14-insulin and 7.3 min for pheA19-insulin. However, as a result of these differences in metabolism, the in vivo hypoglycaemic activity of the modified insulins was not reduced. Both modified insulins conform to the general relationship between lipogenesis potency and MCR. These results confirm the importance of the A19 tyrosine to the activity of insulin and show that manipulation at the A14 position can also influence activity even though this residue is not thought to be directly involved in receptor binding.
胰岛素A链第14和19位的酪氨酸残基具有理论和实际意义。为了阐明它们在胰岛素功能中的作用，我们研究了两种化学修饰胰岛素的生物学特性，这两种胰岛素在这些位点上苯丙氨酸取代了酪氨酸。与天然牛胰岛素相比，pheA19 -胰岛素（在大鼠脂肪细胞中的）脂肪生成能力为33%，pheA14 -胰岛素为84%。与天然胰岛素相比，在一系列血浆浓度范围内，pheA19 -胰岛素和pheA14 -胰岛素的代谢清除率（MCR）也降低了。胰岛素的血浆半衰期为4.6分钟，pheA14 -胰岛素为5.1分钟，pheA19 -胰岛素为7.3分钟。然而，由于这些代谢差异，修饰胰岛素的体内降血糖活性并未降低。两种修饰胰岛素均符合脂肪生成能力与MCR之间的一般关系。这些结果证实了A19位酪氨酸对胰岛素活性的重要性，并表明在A14位进行操作也能影响活性，尽管该残基被认为不直接参与受体结合。
