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Rational design of a bacterial import system for new-to-nature molecules
Metabolic Engineering ( IF 6.8 ) Pub Date : 2024-05-25 , DOI: 10.1016/j.ymben.2024.05.005 Emilio Rodríguez-Robles 1 , David Müller 1 , Tilmann Künzl 1 , Suren J Nemat 2 , Martin Peter Edelmann 1 , Puneet Srivastava 3 , Dominique Louis 4 , Elisabetta Groaz 3 , Konrad Tiefenbacher 2 , Tania Michelle Roberts 1 , Piet Herdewijn 3 , Philippe Marlière 5 , Sven Panke 1
Metabolic Engineering ( IF 6.8 ) Pub Date : 2024-05-25 , DOI: 10.1016/j.ymben.2024.05.005 Emilio Rodríguez-Robles 1 , David Müller 1 , Tilmann Künzl 1 , Suren J Nemat 2 , Martin Peter Edelmann 1 , Puneet Srivastava 3 , Dominique Louis 4 , Elisabetta Groaz 3 , Konrad Tiefenbacher 2 , Tania Michelle Roberts 1 , Piet Herdewijn 3 , Philippe Marlière 5 , Sven Panke 1
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Integration of novel compounds into biological processes holds significant potential for modifying or expanding existing cellular functions. However, the cellular uptake of these compounds is often hindered by selectively permeable membranes. We present a novel bacterial transport system that has been rationally designed to address this challenge. Our approach utilizes a highly promiscuous sulfonate membrane transporter, which allows the passage of cargo molecules attached as amides to a sulfobutanoate transport vector molecule into the cytoplasm of the cell. These cargoes can then be unloaded from the sulfobutanoyl amides using an engineered variant of the enzyme γ-glutamyl transferase, which hydrolyzes the amide bond and releases the cargo molecule within the cell. Here, we provide evidence for the broad substrate specificity of both components of the system by evaluating a panel of structurally diverse sulfobutanoyl amides. Furthermore, we successfully implement the synthetic uptake system in vivo and showcase its functionality by importing an impermeant non-canonical amino acid.
中文翻译：
为自然新分子的细菌导入系统进行合理设计
将新型化合物整合到生物过程中具有修饰或扩展现有细胞功能的巨大潜力。然而，这些化合物的细胞摄取经常受到选择性渗透膜的阻碍。我们提出了一种新型的细菌运输系统，该系统经过合理设计以应对这一挑战。我们的方法利用高度混杂的磺酸盐膜转运蛋白，它允许作为酰胺附着在磺基丁酸转运载体分子上的货物分子进入细胞的细胞质。然后，可以使用 γ-谷氨酰转移酶的工程变体从磺基丁酰酰胺中卸载这些货物，该酶水解酰胺键并在细胞内释放货物分子。在这里，我们通过评估一组结构不同的磺基丁酰酰胺，为系统两种组分的广泛底物特异性提供了证据。此外，我们成功地在体内实施了合成摄取系统，并通过导入不可渗透的非经典氨基酸来展示其功能。
更新日期：2024-05-25
中文翻译：
为自然新分子的细菌导入系统进行合理设计
将新型化合物整合到生物过程中具有修饰或扩展现有细胞功能的巨大潜力。然而，这些化合物的细胞摄取经常受到选择性渗透膜的阻碍。我们提出了一种新型的细菌运输系统，该系统经过合理设计以应对这一挑战。我们的方法利用高度混杂的磺酸盐膜转运蛋白，它允许作为酰胺附着在磺基丁酸转运载体分子上的货物分子进入细胞的细胞质。然后，可以使用 γ-谷氨酰转移酶的工程变体从磺基丁酰酰胺中卸载这些货物，该酶水解酰胺键并在细胞内释放货物分子。在这里，我们通过评估一组结构不同的磺基丁酰酰胺，为系统两种组分的广泛底物特异性提供了证据。此外，我们成功地在体内实施了合成摄取系统，并通过导入不可渗透的非经典氨基酸来展示其功能。
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