Siderophores as anchors in artificial metalloenzymes

铁载体作为人工金属酶的锚

• 批准号: EP/L024829/1
• 负责人: Anne-Kathrin Duhme-Klair
• 金额: $ 80.01万
• 依托单位: University of York
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2014
• 资助国家: 英国
• 起止时间: 2014 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=EP%2FL024829%2F1
• 关键词: Siderophores; anchors; artificial; metalloenzymes

The project involves the development of artificial metalloenzymes that consist of a synthetic catalytic centre that is linked via an anchor group to a protein that acts as a scaffold. This design allows the combination of the chemical reactivity of organometallic catalysts with the selectivity and biocompatibility of proteins. Such artificial enzymes would allow existing catalytic processes to run under mild conditions and make new biotechnological transformations possible. In addition, such artificial enzymes could be used to activate antibiotics.The anchor groups to be investigated in this project are based on siderophores, which are ligands that are produced by bacteria for the uptake of essential iron. The iron(III)-siderophore complexes formed are extremely stable and actively transported into the bacterial cell. In Gram-negative bacteria, transport involves recognition and uptake via a specific outer membrane receptor, followed by capture by a periplasmic binding protein and delivery to an inner membrane transporter for translocation into the cytoplasm. It is the periplasmic siderophore binding proteins that will be explored as novel protein scaffolds in artificial enzymes. The advantage of this approach is the active transport of the synthetic catalysts into the bacterial cell via the siderophore uptake system. Once the catalysts are taken-up along with the iron siderophore complexes, they are captured by their respective binding proteins. Hence the target artificial enzymes self-assemble and accumulate in the periplasm of the bacterial cell, where they may be used for catalytic transformations or the activation of antimicrobial prodrugs. In this way, by taking advantage of the bacterial iron-uptake pathway that is mediated by siderophores, the metabolism of the bacterial cell is exploited to support chemical transformations in vivo.

该项目涉及人工金属酶的开发，该酶由一个合成催化中心组成，该催化中心通过一个锚基团与一个充当支架的蛋白质相连。这种设计允许有机金属催化剂的化学反应性与蛋白质的选择性和生物相容性相结合。这种人造酶将使现有的催化过程在温和的条件下运行，并使新的生物技术转化成为可能。此外，这种人工酶可用于激活抗生素。本项目中研究的锚基团基于铁载体，铁载体是由细菌产生的用于吸收必需铁的配体。形成的铁（III）-铁载体复合物非常稳定，并被主动转运到细菌细胞中。在革兰氏阴性细菌中，转运涉及通过特异性外膜受体识别和摄取，随后被周质结合蛋白捕获并递送至内膜转运蛋白以易位至细胞质中。这是周质铁载体结合蛋白，将探索作为新的蛋白质支架在人工酶。这种方法的优点是通过铁载体摄取系统将合成催化剂主动转运到细菌细胞中。一旦催化剂与铁载体复合物一起被沿着吸收，它们就被各自的结合蛋白捕获。因此，目标人工酶自组装并积累在细菌细胞的周质中，在那里它们可用于催化转化或活化抗微生物前药。以这种方式，通过利用由铁载体介导的细菌铁摄取途径，利用细菌细胞的代谢来支持体内化学转化。

项目成果

Artificial imine reductases: developments and future directions.

• DOI: 10.1039/d0cb00113a
• 发表时间: 2020-12-01
• 期刊: RSC chemical biology
• 影响因子: 4.1
• 作者: Booth RL;Grogan G;Wilson KS;Duhme-Klair AK
• 通讯作者: Duhme-Klair AK

Electrochemical and Solution Structural Characterization of Fe(III) Azotochelin Complexes: Examining the Coordination Behavior of a Tetradentate Siderophore.

• DOI: 10.1021/acs.inorgchem.2c02777
• 发表时间: 2022-12-05
• 期刊: INORGANIC CHEMISTRY
• 影响因子: 4.6
• 作者: Baranska, Natalia G.;Parkin, Alison;Duhme-Klair, Anne -K.
• 通讯作者: Duhme-Klair, Anne -K.