Biosynthesis and Chemical Applications of Thioamides

Mahanta, Nilkamal; Szantai‐Kis, D. Miklos; Petersson, E. James; Mitchell, Douglas A.

doi:10.1021/acschembio.8b01022

Cited by 147 publications

(117 citation statements)

References 218 publications

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“…High resolution cryo-EM maps are now on the cusp of matching or exceeding the quality of those generated by X-ray crystallography, opening the door to deeper understanding of the The remarkable finding of a thioamide modification in protein uL16, only the second such example in a protein (Mahanta et al 2019), is a perfect example of the power of working at <2 Å resolution. The difference in bond length of a thiocarbonyl compared to a typical peptide carbonyl is ~0.4 Å, with otherwise unchanged geometry, and is too subtle to identify at lower resolution.…”

Section: Discussionmentioning

confidence: 99%

Structure of the Bacterial Ribosome at 2 Å Resolution

Watson

Ward

Méheust

et al. 2020

Preprint

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Continuing advances in cryo-electron microscopy (cryo-EM) demonstrate the promise it holds for revealing biological structures at chemical resolution, in which noncovalent interactions, RNA and protein modifications, and solvation can be modeled accurately. At present, the best cryo-EM-derived models of the bacterial ribosome are of the large (50S) ribosomal subunit with effective global resolutions of 2.4-2.5 Å, based on map-to-model Fourier shell correlation (FSC). Here we present a model of the E. coli 70S ribosome with an effective global resolution of 2.0 Å, based on maps showcasing unambiguous positioning of residues, their detailed chemical interactions, and chemical modifications. These modifications include the first examples of isopeptide and thioamide backbone substitutions in ribosomal proteins, the former of which is likely conserved in all domains of life. The model also defines extensive solvation of the small (30S) ribosomal subunit for the first time, as well as interactions with A-site and P-site tRNAs, mRNA, and the antibiotic paromomycin. The high quality of the maps now allows a deeper phylogenetic analysis of ribosomal components, and identification of structural conservation to the level of solvation. The maps and models of the bacterial ribosome presented here should enable future structural analysis of the chemical basis for translation, and the development of robust tools for cryo-EM structure modeling and refinement.

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Section: Discussionmentioning

confidence: 99%

Structure of the Bacterial Ribosome at 2 Å Resolution

Watson

Ward

Méheust

et al. 2020

Preprint

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“…The desire to mimic the biological properties of peptides and proteins by synthetic analogs with improved pharmacokinetic properties has led to the development of several peptide bond mimetics 1–4 . A thioamide (─CSNH─) represents a peptide bond (─CONH─) mimetic with a single‐atom (O to S) substitution 5,6 . Although a near‐isosteric modification, sulfur has a larger van der Waals radius (1.85 Å) 7 and lower electronegativity (2.58) than oxygen (1.40 Å; 3.44).…”

Section: Introductionmentioning

confidence: 99%

“…[1][2][3][4] A thioamide (─CSNH─) represents a peptide bond (─CONH─) mimetic with a single-atom (O to S) substitution. 5,6 Although a near-isosteric modification, sulfur has a larger van der Waals radius (1.85 Å) 7 and lower electronegativity (2.58) than oxygen (1.40 Å; 3.44). This ultimately results in longer C═S bond length (1.71 Å) than the corresponding amide (1.23 Å), 8 weakened hydrogen bond accepting property, 7 and enhanced nucleophilicity of the thioamide sulfur (>C═S) than the carbonyl oxygen (>C═O).…”

Section: Introductionmentioning

confidence: 99%

Convenient synthesis of thioamidated peptides and proteins

Khatri

Bhat

Chatterjee

2020

Journal of Peptide Science

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The unique physicochemical properties of a thioamide bond, which is an ideal isostere of an amide bond, have not been fully exploited because of the tedious synthesis of thionated amino acid building blocks. Here, we report a purification‐free and highly efficient synthesis of thiobenzotriazolides of Fmoc‐protected and orthogonally protected 20 naturally occurring amino acids including asparagine, glutamine, and histidine. The near‐quantitative conversion to the respective thioamidated peptides on solid support demonstrates the robustness of the synthetic route. Furthermore, the unaltered incorporation efficiency of thiobenzotriazolides from their stock solution till 48 h suggests their compatibility toward automated peptide synthesis. Finally, utilizing an optimized cocktail of 2% DBU + 5% piperazine for fast Fmoc‐deprotection, we report the synthesis of a thioamidated Pin1 WW domain and thioamidated GB1 directly on solid support.

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“…Thioamides mimic the shape and structure of peptide bonds but present different electronic and hydrogen-bonding properties-making thioamides important biophysical probes of peptide structure and function. 1,2 For example, thioamides have been employed to interrogate hydrogen-bonding in α-helices and β-turn structures, [3][4][5] as well as n→π* interactions between peptides bonds across amino acids (i → i + 1). [6][7][8] Further, thioamides have been applied in photochemical isomerization schemes, 9,10 and can serve as quenchers of fluorescent probes to study peptide folding.…”

Section: Introductionmentioning

confidence: 99%

Deprotection Strategies for Thioimidates During Fmoc Solid-Phase Peptide Synthesis: A Safe Route to Thioamides

Camacho¹,

Nguyen²,

Turner³

et al. 2019

Preprint

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Thioamides are important biophysical probes of peptide folding, but are prone to α-C epimerization during Fmoc solid-phase peptide synthesis. The stereochemical integrity of thioamide-containing peptides can be dramatically improved by protecting the thioamide as a thioimidate during synthesis. A drawback of this approach, however, is that once synthesis of the peptide is complete, regeneration of the thioamide requires the toxic, corrosive, and flammable gas H2S. This work examines several approaches to supplant H2S as a deprotection reagent in favor of a safer and more convenient alternative. Ultimately, a new application of the 4-azidobenzyl protecting group to thioamides was found to provide the most suitable means of both protection of α-C stereochemistry and conversion back to thioamide.

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Biosynthesis and Chemical Applications of Thioamides

Cited by 147 publications

References 218 publications

Structure of the Bacterial Ribosome at 2 Å Resolution

Structure of the Bacterial Ribosome at 2 Å Resolution

Convenient synthesis of thioamidated peptides and proteins

Deprotection Strategies for Thioimidates During Fmoc Solid-Phase Peptide Synthesis: A Safe Route to Thioamides

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