Synthesis of Gramicidin S and Its Analogues via an On-Resin Macrolactamization Assisted by a Predisposed Conformation of the Linear Precursors

Bu, Xianzhang; Wu, Xiaoming; Ng, Na Lee; Mak, Gannon C.K.; Qin, Chuanguang; Guo, Zhihong

doi:10.1021/jo035712x

Cited by 30 publications

(28 citation statements)

References 19 publications

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“…Previously, Wadhwani and Bu investigated the pre-fold of the linear native gramicidin S decapeptide substrate [25,26]. They were able to show that even the linear substrate adopts a similar b sheet structure to gramicidin S itself.…”

Section: Chemistry and Biologymentioning

confidence: 99%

The Iterative Gramicidin S Thioesterase Catalyzes Peptide Ligation and Cyclization

Hoyer

Mahlert

Marahiel

2007

Chemistry & Biology

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Here, we present a comprehensive in vitro characterization of the excised iterative, bimodular PCP-TE of the gramicidin S synthetase GrsB, which is able to act both as a ligation and a cyclization catalyst. Using the native pentapeptidyl-thioester substrates, GrsB PCP-TE catalyzes the dimerization and subsequent formation of the decapeptide lactam gramicidin S. Interestingly, the detection of linear decapeptidyl-SNAC as an enzyme-dependent intermediate supports the iterative mechanism in vivo, in which two pentapeptides, one bound as an ester to the active site serine of the TE domain and the second bound as a thioester to the adjacent pan-PCP, are ligated to a decapeptidyl-pan-PCP that subsequently transferred to the adjacent TE domain and cyclized. Moreover, GrsB PCP-TE can handle different substrates length, leading not only to dimerization, but also to trimerization and the formation of different ring sizes.

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Section: Chemistry and Biologymentioning

confidence: 99%

The Iterative Gramicidin S Thioesterase Catalyzes Peptide Ligation and Cyclization

Hoyer

Mahlert

Marahiel

2007

Chemistry & Biology

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“…化学基元组学研究的目的之一就是用化学合成技术仿真自然界的生物合成规律, 以相对较低的成本、快速地合成大量的类天然产物, 为药物筛选提供可持续发展的物质资源. 然而, 通过厘清它的合成机理, 化学家采用简单的 1-乙酰氨基, 2-巯基乙烷代替肽携带蛋白, 用氨水做催化剂即可高效率地合成 [26] . 实际上, 没有绝对单靶标作用的药物, 只有尚未知晓更多作用靶标的药物.…”

Section: 化学基元组装的基本规律unclassified

化学基元组学与药物创新

刘¹,

黄²,

顾³

et al. 2013

Sci. Sin.-Chim

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Chemomics is an interdisciplinary study using approaches from chemoinformatics, bioinformatics, synthetic chemistry, and other related disciplines. Biological systems make natural products from endogenous small molecules (natural product building blocks) through a sequence of enzyme catalytic reactions. For each reaction, the natural product building blocks may contribute a group of atoms to the target natural product. We describe this group of atoms as a chemoyl. A chemome is the complete set of chemoyls in an organism. Chemomics studies chemomes and the principles of natural product syntheses and evolutions. Driven by survival and reproductive demands, biological systems have developed effective protocols to synthesize natural products in order to respond to environmental changes; this results in biological and chemical diversity. In recent years, it has been realized that one of the bottlenecks in drug discovery is the lack of chemical resources for drug screening. Chemomics may solve this problem by revealing the rules governing the creation of chemical diversity in biological systems, and by developing biomimetic synthesis approaches to make quasi natural product libraries for drug screening. This treatise introduces chemomics and outlines its contents and potential applications in the fields of drug innovation.

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“…Alanine scanning of the cyclic peptide showed that the Pro-2 residue is crucial for maintaining the -sheet structure while Pro-7 is substitutable [8] while more recent reports show ring sizes less than 10 amino acid residues still showed some moderate antibacterial activity [9]. GS interacts with lipid membranes and expresses its antibacterial activity via interaction with membrane phospholipids, disrupting the permeability barrier of the outer Gram negative membrane, allowing molecular translocation, while the inner cytoplasmic membrane shows increased potassium (K+) efflux [10].…”

Section: Gramicidinsmentioning

confidence: 99%

Polyfunctional Antibiotics Affecting Bacterial Membrane Dynamics

Nelson¹,

Grier²,

Barbaro³

et al. 2009

AIAMC

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The -lactam family of antibiotics, the penicillins and cephalosporins, act primarily at the level of the bacterial membrane by inhibiting membrane proteins associated with cell wall synthesis. As a family they represent some of the most clinically relevant antibiotics known, although antibiotic resistance has limited the use of older generation -lactams, novel compounds are currently emerging from research efforts worldwide. Fortuitously, there are other families of antibiotics of peptide-derived origin and possessing polyfunctional chemical groups-compounds with complex and multiple pharmacophores with biological function-that also act at the level of the bacterial membrane. Polyfunctional antibiotics interfere with bacterial growth by direct interaction with the cell membrane lipid bilayer and its constitutive array of metabolically active enzymes and structural proteins. and received his doctorate at Temple University in medicinal chemistry and molecular pharmacology. Post-doctoral studies were with Stuart. B. Levy, M. D., leading to the formation of Paratek and the discovery of PTK-0796, a novel third-generation tetracycline. Currently, his efforts are focused on semi-synthetic modifications of antibiotics and natural products and mechanisms of antibiotic drug efflux and their inhibition.

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Synthesis of Gramicidin S and Its Analogues via an On-Resin Macrolactamization Assisted by a Predisposed Conformation of the Linear Precursors

Cited by 30 publications

References 19 publications

The Iterative Gramicidin S Thioesterase Catalyzes Peptide Ligation and Cyclization

The Iterative Gramicidin S Thioesterase Catalyzes Peptide Ligation and Cyclization

化学基元组学与药物创新

Polyfunctional Antibiotics Affecting Bacterial Membrane Dynamics

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