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Synthetic biology: Progressing from protein design toward de novo genomes.

机译：合成生物学：从蛋白质设计向新的基因组发展。

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摘要

Many research endeavors that push the limits of "what is possible" fall under the umbrella of synthetic biology. While some efforts in synthetic biology are directed at recombining biological components from nature into novel systems, others aim to reproduce emergent behaviors from nature by using novel components created 'from scratch'. Such components would not parrot existing biological information, but would instead be constructed de novo. This thesis describes the isolation and characterization of de novo proteins encoded by synthetic genes that provide biologically essential activities to enable the growth of living cells.;I have constructed a collection of de novo proteins (encoded by a designed library of synthetic genes) and challenged this artificial minimalist 'proteome' to enable the growth of single-gene knockout auxotrophs of Escherichia coli. Remarkably, several E. coli auxotrophs achieve cell growth under selective conditions due to the biologically essential activities of these de novo proteins. Sequence analysis confirmed that these proteins are dissimilar to all of the known amino acid sequences that nature has provided. Elaborating on these findings, a quadruple-gene knockout E. coli auxotroph was created, and the growth of this multiple auxotroph is rescued by the co-expression of combinations of these de novo proteins, demonstrating that the activities of combinations of novel macromolecules are sufficient to provide partial genome replacement.;Moreover, two new libraries of de novo proteins were designed and constructed in order to enable the exploration of additional amino acid sequence space. In sum, this work demonstrates that novel macromolecules are indeed capable of sustaining biological systems and that the de novo design of functional biological components is possible. It may one day also be possible to design an entire genome de novo.
机译：推动“一切皆有可能”的极限的许多研究努力都属于合成生物学的范畴。虽然合成生物学的一些努力旨在将自然界的生物成分重组为新系统，但其他目标则是通过使用“从头开始”创造的新颖成分来再现自然界的新兴行为。这样的组件不会模仿现有的生物学信息，而是从头构造。本论文描述了由合成基因编码的从头蛋白的分离和表征，这些合成基因提供了使活细胞生长的生物学必不可少的活性。我已经构建了从头蛋白的集合（由合成基因的设计库编码）并提出了挑战。这种人为的极简主义“蛋白质组”，可以使大肠杆菌的单基因敲除营养缺陷型细菌生长。显着地，由于这些从头蛋白质的生物学上必不可少的活性，几种大肠杆菌营养缺陷型在选择条件下实现了细胞生长。序列分析证实，这些蛋白质与自然界提供的所有已知氨基酸序列都不相同。详细说明这些发现，创建了四基因敲除大肠杆菌营养缺陷型，并且通过从头合成这些蛋白质的组合来挽救了这种多种营养缺陷型的生长，这表明新型大分子组合具有足够的活性。此外，还设计并构建了两个新的从头蛋白新文库，以便能够探索其他氨基酸序列空间。总而言之，这项工作表明新型大分子确实能够维持生物系统，并且从头设计功能性生物组分是可能的。从头开始设计整个基因组也许有一天是可能的。

著录项

  • 作者

    Fisher, Michael A.;

  • 作者单位

    Princeton University.;

  • 授予单位 Princeton University.;
  • 学科 Biology Molecular.;Engineering Civil.;Biology Bioinformatics.;Biology Genetics.
  • 学位 Ph.D.
  • 年度 2009
  • 页码 175 p.
  • 总页数 175
  • 原文格式 PDF
  • 正文语种 eng
  • 中图分类
  • 关键词

  • 入库时间 2022-08-17 11:38:30

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