ChemInform Abstract: Shifting Native Chemical Ligation into Reverse Through N- versus S-Acyl Transfer

ChemInform ◽  
2012 ◽  
Vol 43 (9) ◽  
pp. no-no
Author(s):  
Derek Macmillan ◽  
Anna Adams ◽  
Bhavesh Premdjee
Keyword(s):  
Acyl Transfer ◽  
Native Chemical Ligation ◽  
Chemical Ligation

Access to phosphoproteins and glycoproteins through semi-synthesis, Native Chemical Ligation and N→S acyl transfer

2010 ◽  
Vol 8 (22) ◽  
pp. 5113 ◽  
Author(s):  
Jinit Masania ◽  
Jiejin Li ◽  
Stephen J. Smerdon ◽  
Derek Macmillan
Keyword(s):  
Acyl Transfer ◽  
Native Chemical Ligation ◽  
Chemical Ligation

Exploring neoglycoprotein assembly through native chemical ligation using neoglycopeptide thioesters prepared via N→S acyl transfer

2010 ◽  
Vol 8 (6) ◽  
pp. 1351 ◽  
Author(s):  
Jonathan P. Richardson ◽  
Chung-Hei Chan ◽  
Javier Blanc ◽  
Mona Saadi ◽  
Derek Macmillan
Keyword(s):  
Acyl Transfer ◽  
Native Chemical Ligation ◽  
Chemical Ligation

scholarly journals Investigation of Cysteine as an Activator of Side-Chain N→S Acyl Transfer and Tail-to-Side-Chain Cyclization

Synlett ◽  
2017 ◽  
Vol 28 (15) ◽  
pp. 1923-1928 ◽  
Author(s):  
Derek Macmillan ◽  
Durbis Castillo-Pazos
Keyword(s):  
Glutamic Acid ◽  
Chain Length ◽  
Cyclic Peptides ◽  
Fine Tuning ◽  
Acyl Transfer ◽  
Native Chemical Ligation ◽  
Side Chain ◽  
Chemical Ligation ◽  
Popular Method ◽  
Slow Reaction

N→S Acyl transfer is a popular method for the postsynthesis production of peptide C α-thioesters for use in native chemical ligation and for the synthesis of head-to-tail cyclic peptides. Meanwhile thioester formation at the side chain of aspartic or glutamic acids, leading to tail-to-side-chain-cyclized species, is less common. Herein we explore the potential for cysteine to function as a latent thioester when appended to the side chain of glutamic acid. Initial insights gained through study of C-terminal β-alanine as a model for the increased chain length were ultimately applied to peptide macrocyclization. Our results emphasize the increased barrier to acyl transfer at the glutamic acid side chain and indicate how a slow reaction, facilitated by cysteine itself, may be accelerated by fine-tuning of the stereoelectronic environment.

scholarly journals Shifting Native Chemical Ligation into Reverse through N→S Acyl Transfer

2011 ◽  
Vol 51 (8-9) ◽  
pp. 885-899 ◽  
Author(s):  
Derek Macmillan ◽  
Anna Adams ◽  
Bhavesh Premdjee
Keyword(s):  
Acyl Transfer ◽  
Native Chemical Ligation ◽  
Chemical Ligation

Acceleration of thiol additive-free native chemical ligation by intramolecular S → S acyl transfer

2015 ◽  
Vol 51 (35) ◽  
pp. 7554-7557 ◽  
Author(s):  
J. Schmalisch ◽  
O. Seitz
Keyword(s):  
Sh3 Domain ◽  
High Reactivity ◽  
Acyl Transfer ◽  
Native Chemical Ligation ◽  
One Pot ◽  
Chemical Ligation ◽  
Synthetic Utility ◽  
Peptide Thioesters

The old dog and a new trick; mercaptopropionylcysteine (MPA–Cys) peptide thioesters show a surprisingly high reactivity in native chemical ligation (NCL) and allow thiol-additive free reactions. This facilitates sequential NCL reactions and ligation–desulfurization reactions in one-pot formats. The synthetic utility is demonstrated by the synthesis of a SH3 domain.

scholarly journals Peptide Bond Synthesis by a Mechanism Involving an Enzymatic Reaction and a Subsequent Chemical Reaction

2015 ◽  
Vol 291 (4) ◽  
pp. 1735-1750 ◽  
Author(s):  
Tomoko Abe ◽  
Yoshiteru Hashimoto ◽  
Ye Zhuang ◽  
Yin Ge ◽  
Takuto Kumano ◽  
...  
Keyword(s):  
Peptide Synthesis ◽  
Chemical Reaction ◽  
Enzymatic Reaction ◽  
Amide Bond ◽  
Acyl Transfer ◽  
Native Chemical Ligation ◽  
Specific Substrate ◽  
Chemical Ligation ◽  
Subsequent Chemical Reaction ◽  
Subsequent Chemical

We recently reported that an amide bond is unexpectedly formed by an acyl-CoA synthetase (which catalyzes the formation of a carbon-sulfur bond) when a suitable acid and l-cysteine are used as substrates. DltA, which is homologous to the adenylation domain of nonribosomal peptide synthetase, belongs to the same superfamily of adenylate-forming enzymes, which includes many kinds of enzymes, including the acyl-CoA synthetases. Here, we demonstrate that DltA synthesizes not only N-(d-alanyl)-l-cysteine (a dipeptide) but also various oligopeptides. We propose that this enzyme catalyzes peptide synthesis by the following unprecedented mechanism: (i) the formation of S-acyl-l-cysteine as an intermediate via its “enzymatic activity” and (ii) subsequent “chemical” S → N acyl transfer in the intermediate, resulting in peptide formation. Step ii is identical to the corresponding reaction in native chemical ligation, a method of chemical peptide synthesis, whereas step i is not. To the best of our knowledge, our discovery of this peptide synthesis mechanism involving an enzymatic reaction and a subsequent chemical reaction is the first such one to be reported. This new process yields peptides without the use of a thioesterified fragment, which is required in native chemical ligation. Together with these findings, the same mechanism-dependent formation of N-acyl compounds by other members of the above-mentioned superfamily demonstrated that all members most likely form peptide/amide compounds by using this novel mechanism. Each member enzyme acts on a specific substrate; thus, not only the corresponding peptides but also new types of amide compounds can be formed.

Nucleobase-involved native chemical ligation: a novel reaction between an oxanine nucleobase and N-terminal cysteine for oligonucleotide–peptide conjugation

2020 ◽  
Vol 56 (41) ◽  
pp. 5508-5511
Author(s):  
Eui Kyoung Jang ◽  
Yohei Koike ◽  
Yuko Ide ◽  
Kunihiko Tajima ◽  
Kenji Kanaori ◽  
...  
Keyword(s):  
Transfer Reaction ◽  
Acyl Transfer ◽  
Native Chemical Ligation ◽  
Chemical Ligation ◽  
Site Specific ◽  
Peptide Conjugation ◽  
Acyl Transfer Reaction ◽  
A Site

A novel nucleobase-involved native chemical ligation (NbCL) that allows a site–specific oligonucleotide–peptide conjugation via a new S–N acyl transfer reaction between an oxanine nucleobase and N-terminal cysteine.

scholarly journals Going Round in Circles with N→S Acyl Transfer

Synlett ◽  
2017 ◽  
Vol 28 (13) ◽  
pp. 1517-1529 ◽  
Author(s):  
Derek Macmillan
Keyword(s):  
Transfer Reaction ◽  
Peptide Sequence ◽  
Acyl Transfer ◽  
Native Chemical Ligation ◽  
Full Potential ◽  
Chemical Ligation ◽  
Peptide Engineering ◽  
Naturally Occurring ◽  
Native Peptide ◽  
Peptide Thioesters

It is not highly sophisticated, yet the N→S acyl transfer reaction of a native peptide sequence potentially fills an important technology gap. While several routes to synthetic peptide thioesters exist, only one is routinely applicable for biologically derived samples. Using the naturally occurring amino acid cysteine as the sole activator for N→S acyl transfer we have demonstrated transformation of synthetic and biologically derived precursors into thioesters for use in Native Chemical Ligation, providing a viable alternative for biological samples. Further refinement will be key to realising the full potential of this intriguing process, and increase the number of applications in peptide engineering and therapeutics.1 Introduction2 N→S acyl transfer in ‘normal’ peptide sequences3 Reduced reactivity of internal Xaa-Cys motifs as an advantage in head-to-tail peptide cyclisation4 Reduced reactivity of internal Xaa-Cys motifs as an advantage in modification and cyclisation of biologically produced precursors5 Hydrazinolysis of Xaa-Cys motifs and the acyl hydrazide as a stable thioester equivalent6 Rapid thioester formation via an N→Se acyl shift7 Outlook and conclusions

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