scholarly journals Copper-mediated selenazolidine deprotection enables one-pot chemical synthesis of challenging proteins

2019 ◽  
Author(s):  
Zhenguang Zhao ◽  
Norman Metanis
Keyword(s):  
Protein Synthesis ◽  
Catalytic Activity ◽  
Chemical Synthesis ◽  
Total Synthesis ◽  
Active Site ◽  
Synthetic Approach ◽  
One Pot ◽  
Chemical Protein Synthesis ◽  
Key Technologies ◽  
The One

<p>While chemical protein synthesis (CPS) has granted access to challenging proteins, synthesis of longer proteins is often limited by low abundance or non-strategic placement of cysteine (Cys) residues, essential for native chemical ligations (NCL), as well as multiple purification and isolation steps. Selective deselenization and one-pot CPS serve as key technologies to circumvent these issues. Herein, we describe the one-pot total synthesis of human thiosulfate: glutathione sulfurtransferase (TSTD1), a 115-residue protein with a single Cys residue at its active site, and its seleno-analogue. WT-TSTD1 was synthesized in a C-to-N synthetic approach employing multiple NCL reactions, Cu(II)-mediated deprotection of selenazolidine (Sez), and chemoselective deselenization, all in one-pot. In addition, the protein’s seleno analogue (Se-TSTD1), in which the active site Cys is replaced with selenocysteine, was synthesized with a kinetically controlled ligation in a one-pot, N-to-C synthetic approach. TSTD1’s one-pot synthesis was made possible by the newly reported, rapid, and facile copper-mediated selenazolidine deprotection that can be accomplished in one minute. Finally, catalytic activity of the two proteins indicated that Se-TSTD1 possessed only four-fold lower activity than WT-TSTD1 as a thiosulfate: glutathione sulfurtransferase, suggesting that selenoproteins can have physiologically comparable sulfutransferase activity as their cysteine counterparts. </p>

scholarly journals Copper-mediated selenazolidine deprotection enables one-pot chemical synthesis of challenging proteins

2019 ◽  
Author(s):  
Zhenguang Zhao ◽  
Norman Metanis
Keyword(s):  
Protein Synthesis ◽  
Catalytic Activity ◽  
Chemical Synthesis ◽  
Total Synthesis ◽  
Active Site ◽  
Synthetic Approach ◽  
One Pot ◽  
Chemical Protein Synthesis ◽  
Key Technologies ◽  
The One

<p>While chemical protein synthesis (CPS) has granted access to challenging proteins, synthesis of longer proteins is often limited by low abundance or non-strategic placement of cysteine (Cys) residues, essential for native chemical ligations (NCL), as well as multiple purification and isolation steps. Selective deselenization and one-pot CPS serve as key technologies to circumvent these issues. Herein, we describe the one-pot total synthesis of human thiosulfate: glutathione sulfurtransferase (TSTD1), a 115-residue protein with a single Cys residue at its active site, and its seleno-analogue. WT-TSTD1 was synthesized in a C-to-N synthetic approach employing multiple NCL reactions, Cu(II)-mediated deprotection of selenazolidine (Sez), and chemoselective deselenization, all in one-pot. In addition, the protein’s seleno analogue (Se-TSTD1), in which the active site Cys is replaced with selenocysteine, was synthesized with a kinetically controlled ligation in a one-pot, N-to-C synthetic approach. TSTD1’s one-pot synthesis was made possible by the newly reported, rapid, and facile copper-mediated selenazolidine deprotection that can be accomplished in one minute. Finally, catalytic activity of the two proteins indicated that Se-TSTD1 possessed only four-fold lower activity than WT-TSTD1 as a thiosulfate: glutathione sulfurtransferase, suggesting that selenoproteins can have physiologically comparable sulfutransferase activity as their cysteine counterparts. </p>

Synthetic Approach to Fused Azasultams with 1,2,4-Thiadiazepine Framework

Synthesis ◽  
2020 ◽  
Vol 52 (19) ◽  
pp. 2857-2869
Author(s):  
Demyd S. Milokhov ◽  
Vasyl Y. Hys ◽  
Olesya B. Volovenko ◽  
Irina S. Konovalova ◽  
Svitlana V. Shishkina ◽  
...  
Keyword(s):  
Building Blocks ◽  
Synthetic Approach ◽  
Chemical Behavior ◽  
One Pot ◽  
Enamino Ketone ◽  
The One

Synthetic approach to fused azasultams with 1,2,4-thiadi­azepine framework via base promoted protocols has been developed. 1H-Azole-2-carboxylates and N-(chloromethyl)-N-methylmethanesulfonamide were used as ambiphilic building blocks in the one-pot and two-step reaction sequences. Chemical behavior of the obtained azasultams in reactions with amines, hydrazine, DMFDMA, and NaBH4 was investigated. An enamino ketone derived from an azasultam was exploited in the synthesis of new pyrazole and pyrimidine heterocycles.

scholarly journals Insights into the Mechanism and Catalysis of Peptide Thioester Synthesis by Alkylselenols Provide a New Tool for Chemical Protein Synthesis

Molecules ◽  
2021 ◽  
Vol 26 (5) ◽  
pp. 1386
Author(s):  
Florent Kerdraon ◽  
Gemma Bogard ◽  
Benoît Snella ◽  
Hervé Drobecq ◽  
Muriel Pichavant ◽  
...  
Keyword(s):  
Protein Synthesis ◽  
Total Synthesis ◽  
Adaptive Immunity ◽  
Biologically Active ◽  
Acidic Ph ◽  
Innate And Adaptive Immunity ◽  
Chemotactic Protein ◽  
Chemical Protein Synthesis ◽  
Peptide Thioester ◽  
Peptide Thioesters

While thiol-based catalysts are widely employed for chemical protein synthesis relying on peptide thioester chemistry, this is less true for selenol-based catalysts whose development is in its infancy. In this study, we compared different selenols derived from the selenocysteamine scaffold for their capacity to promote thiol–thioester exchanges in water at mildly acidic pH and the production of peptide thioesters from bis(2-sulfanylethyl)amido (SEA) peptides. The usefulness of a selected selenol compound is illustrated by the total synthesis of a biologically active human chemotactic protein, which plays an important role in innate and adaptive immunity.

One-pot total synthesis of streptindole, arsindoline B and their congeners through tandem decarboxylative deaminative dual-coupling reaction of amino acids with indoles

2015 ◽  
Vol 13 (14) ◽  
pp. 4240-4247 ◽  
Author(s):  
Jiachen Xiang ◽  
Jungang Wang ◽  
Miao Wang ◽  
Xianggao Meng ◽  
Anxin Wu
Keyword(s):  
Amino Acids ◽  
Natural Products ◽  
Total Synthesis ◽  
Coupling Reaction ◽  
One Pot ◽  
The One

This paper described a decarboxylative deaminative dual-coupling reaction of amino acids with indoles to afford BIM scaffolds and its further application to the one-pot total synthesis of natural products.

scholarly journals Ru Catalyst Facilitates Total Chemical Protein Synthesis to Investigate the Effect of Epigenetic Modifications Decorated on Linker Histone H1.2 and Heterochromatin Protein 1α (HP1α)

2020 ◽  
Author(s):  
Naoki Kamo ◽  
Tomoya Kujirai ◽  
Hitoshi Kurumizaka ◽  
Hitoshi Murakami ◽  
Gosuke Hayashi ◽  
...  
Keyword(s):  
Amino Acids ◽  
Protein Synthesis ◽  
Metal Complexes ◽  
Palladium Complexes ◽  
Protecting Groups ◽  
One Pot ◽  
Heterochromatin Protein ◽  
Site Specific ◽  
Ru Catalyst ◽  
Chemical Protein Synthesis

For epigenetics research, preparing homogeneous proteins bearing site-specific posttranslational modifications (PTMs) is essential to understand the behavior of chromatin. Total chemical protein synthesis is a very powerful method to obtain target proteins with various modifications at site-specific positions. To produce large proteins efficiently, one-pot ligation of multiple peptide fragments was previously reported through repetitive deprotection of protecting groups for N-terminal Cys with palladium complexes. However, this method demanded more than a catalytic amount of metal complexes, and, in general, it had been challenging to achieve catalytic cycles of metal complexes especially for reactions on proteins. Here, we report an efficient and facile method of chemical protein synthesis using Ru catalyst. The use of 10–20 mol% of Ru complexes enabled us to remove the protecting groups on peptides or proteins under peptide ligation conditions, and this complex showed more than 50-fold activity compared to the previous palladium complexes due to the great stability toward thiol moieties. By using this Ru catalyst, we accomplished total chemical synthesis of linker histone H1.2 (212 amino acids) and heterochromatin protein 1a (HP1a) (191 amino acids), which are important components of heterochromatin, through one-pot multiple peptide ligation. This method prompted the preparation of H1.2 and HP1a bearing various patterns of PTMs. Moreover, we found that R53Cit at H1.2 reduced its binding affinity toward nucleosomes and four consecutive phosphorylations at N-terminus HP1a controlled its binding ability against DNA. We envisage that homogeneously modified proteins prepared by our method would facilitate epigenetics research and be applied for the elucidation of various biological phenomena.

scholarly journals Cu-metal organic frameworks (Cu-MOF) as an environment-friendly and economical catalyst for one pot synthesis of tacrine derivatives

RSC Advances ◽  
2020 ◽  
Vol 10 (4) ◽  
pp. 1995-2003 ◽  
Author(s):  
Hoda Mollabagher ◽  
Salman Taheri ◽  
Mohammad majid Mojtahedi ◽  
SeyedAmirhossein Seyedmousavi
Keyword(s):  
Catalytic Activity ◽  
Metal Organic Frameworks ◽  
One Pot ◽  
Environment Friendly ◽  
One Pot Synthesis ◽  
Metal Organic ◽  
The One

The present work describes the catalytic activity of Cu-MOF for the one-pot synthesis of tacrine derivatives via a four-component reaction of 2-hydroxynaphthalene-1,4-dione, aldehydes, malononitrile and cycloketones in the presence of AlCl3.

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