Genetically Introducing Biochemically Reactive Amino Acids Dehydroalanine and Dehydrobutyrine in Proteins,Journal of the American Chemical Society

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Genetically Introducing Biochemically Reactive Amino Acids Dehydroalanine and Dehydrobutyrine in Proteins
Journal of the American Chemical Society ( IF 14.4 ) Pub Date : 2019-04-30 , DOI: 10.1021/jacs.9b02611
Bing Yang , Nanxi Wang , Paul D Schnier , Feng Zheng ₁ , He Zhu ₂ , Nicholas F Polizzi , Avinash Ittuveetil ₂ , Varma Saikam ₂ , William F DeGrado , Qian Wang ₁ , Peng G Wang ₂ , Lei Wang

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Expansion of the genetic code with unnatural amino acids (Uaas) has significantly increased the chemical space available to proteins for exploitation. Due to the inherent limitation of translational machinery and the required compatibility with biological settings, function groups introduced via Uaas to date are restricted to chemically inert, bioorthogonal, or latent bioreactive groups. To break this barrier, here we report a new strategy enabling the specific incorporation of biochemically reactive amino acids into proteins. A latent bioreactive amino acid is genetically encoded at a position proximal to the target natural amino acid; they react via proximity-enabled reactivity, selectively converting the latter into a reactive residue in situ. Using this Genetically Encoded Chemical COnversion (GECCO) strategy and harnessing the sulfur-fluoride exchange (SuFEx) reaction between fluorosulfate-l-tyrosine and serine or threonine, we site-specifically generated the reactive dehydroalanine and dehydrobutyrine into proteins. GECCO works both inter- and intramolecularly, and is compatible with various proteins. We further labeled the resultant dehydroalanine-containing protein with thiol-saccharide to generate glycoprotein mimetics. GECCO represents a new solution for selectively introducing biochemically reactive amino acids into proteins and is expected to open new avenues for exploiting chemistry in live systems for biological research and engineering.

中文翻译：

在蛋白质中遗传引入具有生化反应活性的氨基酸脱氢丙氨酸和脱氢丁氨酸

使用非天然氨基酸 (Uaas) 扩展遗传密码已显着增加了蛋白质可用于开发的化学空间。由于翻译机制的固有限制和与生物环境所需的兼容性，迄今为止通过 Uaas 引入的功能组仅限于化学惰性、生物正交或潜在的生物反应性基团。为了打破这一障碍，我们在此报告了一种新策略，能够将生化反应性氨基酸特异性结合到蛋白质中。潜在的生物反应性氨基酸在接近目标天然氨基酸的位置被遗传编码；它们通过邻近反应性进行反应，选择性地将后者原位转化为反应性残基。使用这种基因编码化学转化 (GECCO) 策略并利用氟硫酸盐-l-酪氨酸和丝氨酸或苏氨酸之间的硫-氟化物交换 (SuFEx) 反应，我们将反应性脱氢丙氨酸和脱氢丁氨酸定点生成为蛋白质。GECCO 在分子间和分子内起作用，并且与各种蛋白质相容。我们进一步用硫醇糖标记所得的含脱氢丙氨酸的蛋白质以产生糖蛋白模拟物。GECCO 代表了一种将生化反应性氨基酸选择性引入蛋白质的新解决方案，有望为在生物研究和工程的活系统中利用化学开辟新途径。我们定点地将反应性脱氢丙氨酸和脱氢丁氨酸生成为蛋白质。GECCO 在分子间和分子内起作用，并且与各种蛋白质相容。我们进一步用硫醇糖标记所得的含脱氢丙氨酸的蛋白质以产生糖蛋白模拟物。GECCO 代表了一种将生化反应性氨基酸选择性引入蛋白质的新解决方案，有望为在生物研究和工程的活系统中利用化学开辟新途径。我们定点地将反应性脱氢丙氨酸和脱氢丁氨酸生成为蛋白质。GECCO 在分子间和分子内起作用，并且与各种蛋白质相容。我们进一步用硫醇糖标记所得的含脱氢丙氨酸的蛋白质以产生糖蛋白模拟物。GECCO 代表了一种将生化反应性氨基酸选择性引入蛋白质的新解决方案，有望为在生物研究和工程的活系统中利用化学开辟新途径。

更新日期：2019-04-30

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