Shabanpoor Fazel, Separovic Frances, Wade John D
Howard Florey Institute, University of Melbourne, Victoria 3010, Australia.
Vitam Horm. 2009;80:1-31. doi: 10.1016/S0083-6729(08)00601-8.
The identification in the 1950s of insulin, an essential carbohydrate regulatory hormone, as consisting of not one but two peptide chains linked by three disulfide bonds in a distinctive pattern was a milestone in peptide chemistry. When it was later found that relaxin also possessed a similar overall structure, the term 'insulin superfamily' was coined. Use of methods of conventional protein chemistry followed by recombinant DNA and more recently bioinformatics has led to the recognition that insulin is the precursor to a large protein superfamily that extends beyond the human. Insulin-like peptides are found not only in vertebrates such as mammals, birds, reptiles, amphibians but also in the invertebrates such as chordates, molluscs and insects. All superfamily members share the distinctive insulin structural motif. In the human, there exists ten members of the superfamily, each of which are expressed on the ribosome as a single-chain pre-prohormone that undergoes proteolytic processing to produce eight double-chain mature proteins and two single-chain forms. The six cysteine residues that form the three insulin disulfide cross-links - one intramolecular within the A-chain and two intermolecular between that A- and B-chains - are absolutely conserved across all members of the superfamily. They are responsible for imparting a similar overall tertiary structure. The human insulin superfamily members have each evolved to assume remarkably distinctive biological functions ranging from glucose homeostasis to neuroendocrine actions. That such diversity is contained within a modestly sized superfamily is testament to efficiency of the insulin structural motif as an evolutionary template.
20世纪50年代，人们发现胰岛素这种重要的碳水化合物调节激素并非由一条而是由两条肽链组成，这两条肽链通过三个二硫键以独特的方式相连，这是肽化学领域的一个里程碑。后来发现松弛素也具有类似的整体结构，于是创造了“胰岛素超家族”这个术语。运用传统蛋白质化学方法，随后结合重组DNA技术以及最近的生物信息学方法，人们逐渐认识到胰岛素是一个大型蛋白质超家族的前体，这个超家族的范围不仅限于人类。胰岛素样肽不仅存在于哺乳动物、鸟类、爬行动物、两栖动物等脊椎动物中，也存在于脊索动物、软体动物和昆虫等无脊椎动物中。所有超家族成员都具有独特的胰岛素结构基序。在人类中，该超家族有十个成员，每个成员在核糖体上最初表达为单链前激素原，经过蛋白水解加工后产生八种双链成熟蛋白和两种单链形式。形成胰岛素三个二硫键交联的六个半胱氨酸残基——一个在A链内分子内，两个在A链和B链之间分子间——在超家族的所有成员中绝对保守。它们赋予了相似的整体三级结构。人类胰岛素超家族成员各自进化以承担从葡萄糖稳态到神经内分泌作用等显著不同的生物学功能。如此多样的功能包含在一个规模适中的超家族中，这证明了胰岛素结构基序作为进化模板的高效性。
