Suppr超能文献

对β-葡萄糖基转移酶IroB的重新评估揭示了其对非天然三儿茶酚肠杆菌素模拟物进行β-葡萄糖基化的能力。

Re-evaluation of the -Glucosyltransferase IroB Illuminates Its Ability to -Glucosylate Non-native Triscatecholate Enterobactin Mimics.

作者信息

Motz Rachel N, Anderson Jaden K, Nolan Elizabeth M

机构信息

Department of Chemistry, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, United States.

出版信息

Biochemistry. 2025 Jan 7;64(1):224-237. doi: 10.1021/acs.biochem.4c00581. Epub 2024 Dec 24.

Abstract

The pathogen-associated -glucosyltransferase IroB is involved in the biosynthesis of salmochelins, -glucosylated derivatives of enterobactin (Ent), which is a triscatecholate siderophore of enteric bacteria including and . Here, we reassess the ability of IroB to -glucosylate non-native triscatecholate mimics of Ent, which may have utility in the design and development of siderophore-based therapeutics and diagnostics. We establish TRENCAM (TC) and MECAM (MC), synthetic Ent analogs with tris(2-aminoethyl)amine- or mesitylene-derived backbones replacing the trilactone core of Ent, respectively, and their monoglucosylated congeners as substrates of IroB. Time course analyses and steady-state kinetic studies, which were performed under conditions that provide enhanced activity relative to prior studies, inform the substrate selectivity and catalytic efficiencies of this enzyme. We extend these findings to the preparation of a siderophore-antibiotic conjugate composed of monoglucosylated TC and ampicillin (MGT-Amp). Examination of its antibacterial activity and receptor specificity demonstrates that MGT-Amp targets pathogenicity because it shows specificty for the pathogen-associated outer membrane receptor IroN. Overall, our findings extend the biochemical characterization of IroB and its substrate scope and illustrate the ability to leverage a bacterial -glucosyltransferase for non-native chemoenzymatic transformations along with potential applications of salmochelin mimics.

摘要

病原体相关的β-葡萄糖基转移酶IroB参与了沙门菌素的生物合成,沙门菌素是肠杆菌素(Ent)的β-葡萄糖基化衍生物,肠杆菌素是包括大肠杆菌和沙门氏菌在内的肠道细菌的三儿茶酚铁载体。在此,我们重新评估IroB对Ent的非天然三儿茶酚类似物进行β-葡萄糖基化的能力,这可能在基于铁载体的治疗和诊断的设计与开发中具有实用性。我们分别建立了TRENCAM(TC)和MECAM(MC),这两种合成的Ent类似物,其具有分别用三(2-氨基乙基)胺或均三甲苯衍生的主链取代Ent的三内酯核心,以及它们的单葡萄糖基化同系物作为IroB的底物。在相对于先前研究能提高活性的条件下进行的时间进程分析和稳态动力学研究,为该酶的底物选择性和催化效率提供了信息。我们将这些发现扩展到了由单葡萄糖基化的TC和氨苄青霉素(MGT-Amp)组成的铁载体-抗生素缀合物的制备。对其抗菌活性和受体特异性的研究表明MGT-Amp靶向致病性,因为它对病原体相关的外膜受体IroN具有特异性。总体而言,我们的发现扩展了IroB的生化特性及其底物范围,并说明了利用细菌β-葡萄糖基转移酶进行非天然化学酶转化的能力以及沙门菌素类似物的潜在应用。

相似文献

1
Re-evaluation of the -Glucosyltransferase IroB Illuminates Its Ability to -Glucosylate Non-native Triscatecholate Enterobactin Mimics.
Biochemistry. 2025 Jan 7;64(1):224-237. doi: 10.1021/acs.biochem.4c00581. Epub 2024 Dec 24.
2
Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis.
Cochrane Database Syst Rev. 2021 Apr 19;4(4):CD011535. doi: 10.1002/14651858.CD011535.pub4.
3
Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis.
Cochrane Database Syst Rev. 2020 Jan 9;1(1):CD011535. doi: 10.1002/14651858.CD011535.pub3.
5
Signs and symptoms to determine if a patient presenting in primary care or hospital outpatient settings has COVID-19.
Cochrane Database Syst Rev. 2022 May 20;5(5):CD013665. doi: 10.1002/14651858.CD013665.pub3.
8
The C-glycosyltransferase IroB from pathogenic Escherichia coli: identification of residues required for efficient catalysis.
Biochim Biophys Acta. 2014 Sep;1844(9):1619-30. doi: 10.1016/j.bbapap.2014.06.010. Epub 2014 Jun 21.
9
Systemic pharmacological treatments for chronic plaque psoriasis: a network meta-analysis.
Cochrane Database Syst Rev. 2017 Dec 22;12(12):CD011535. doi: 10.1002/14651858.CD011535.pub2.
10
Interventions to improve antibiotic prescribing practices for hospital inpatients.
Cochrane Database Syst Rev. 2017 Feb 9;2(2):CD003543. doi: 10.1002/14651858.CD003543.pub4.

引用本文的文献

1
Structural basis of iron piracy by human gut .
bioRxiv. 2025 Aug 24:2024.04.15.589501. doi: 10.1101/2024.04.15.589501.

本文引用的文献

2
"Off-Label Use" of the Siderophore Enterobactin Enables Targeted Imaging of Cancer with Radioactive Ti.
Angew Chem Int Ed Engl. 2024 Apr 24;63(18):e202319578. doi: 10.1002/anie.202319578. Epub 2024 Mar 25.
4
Forming coumarin C-glycosides via biocatalysis: Characterization of a C-glycosyltransferase from Angelica decursiva.
Biochem Biophys Res Commun. 2022 Jul 23;614:85-91. doi: 10.1016/j.bbrc.2022.05.008. Epub 2022 May 6.
5
The Advances and Challenges in Enzymatic -glycosylation of Flavonoids in Plants.
Curr Pharm Des. 2022;28(18):1466-1479. doi: 10.2174/1381612828666220422085128.
6
9
A Salmochelin S4-Inspired Ciprofloxacin Trojan Horse Conjugate.
ACS Infect Dis. 2020 Sep 11;6(9):2532-2541. doi: 10.1021/acsinfecdis.0c00568. Epub 2020 Aug 25.
10
Leloir glycosyltransferases of natural product C-glycosylation: structure, mechanism and specificity.
Biochem Soc Trans. 2020 Aug 28;48(4):1583-1598. doi: 10.1042/BST20191140.

文献AI研究员

20分钟写一篇综述,助力文献阅读效率提升50倍。

立即体验

用中文搜PubMed

大模型驱动的PubMed中文搜索引擎

马上搜索

文档翻译

学术文献翻译模型,支持多种主流文档格式。

立即体验