Sequential α‐Ketoacid‐Hydroxylamine (KAHA) Ligations: Synthesis of C‐Terminal Variants of the Modifier Protein UFM1

Ogunkoya, Ayodele O.; Pattabiraman, Vijaya R.; Bode, Jeffrey W.

doi:10.1002/anie.201204144

Cited by 67 publications

(43 citation statements)

References 44 publications

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“…Bode et al., in 2012, reported the incorporation of 5‐oxaproline into their ketoacid–hydroxylamine (KAHA) ligation method to yield an O ‐acyl‐Hse (Hse: homeserine) isopeptide, which possessed similar biophysical properties to those of O ‐acyl‐Ser/Thr isopeptides (see Section 3.3) and could be readily converted into the native amide bonds under mildly basic conditions (Scheme D) …”

Section: Application Of Isoacyl Structural Motifs In Synthetic Peptidmentioning

confidence: 99%

The Application of Isoacyl Structural Motifs in Prodrug Design and Peptide Chemistry

Mailig

Liu

2019

ChemBioChem

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Intramolecular N‐to‐O and O‐to‐N acyl migrations have been known for a century. Recent decades have witnessed a considerable number of applications of such chemical transformations in the fields of medicinal chemistry and peptide chemistry. The former has been focused on employing the isoacyl‐mediated prodrug approach to improve the physicochemical properties of insoluble drug candidates. The latter involves multiple directions, including establishing new peptide segment ligation methods; facilitating sterically hindered amide‐bond coupling; and enabling the synthesis, handling and investigation of difficult sequences. Notably, most of these cases can be achieved in a traceless manner. These successes are mainly attributed to the unique chemical and biophysical properties of the isoacyl structural motif. This review will summarize the historical achievements and highlight the recent advances in this topic.

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Section: Application Of Isoacyl Structural Motifs In Synthetic Peptidmentioning

confidence: 99%

The Application of Isoacyl Structural Motifs in Prodrug Design and Peptide Chemistry

Mailig

Liu

2019

ChemBioChem

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“…The protein (semi)-synthesis community is moving rapidly to catch up with this phenomenon and semi-synthetic strategies for obtaining ubiquitinated SUMO-2 [24] and ubiquitinated Rub1, the yeast NEDD8 homolog, have already been reported [78 ]. Synthetic strategies for obtaining full length UbL proteins such as Nedd8 [61], SUMO-1 [79,80 ] and Ufm1 [81] are also starting to emerge. It is not hard to imagine the existence of other PTMs on ubiquitin such as methylation or glycosylation, both of which could be incorporated through (semi-)synthetic approaches.…”

Section: Crosstalk With Other Post-translational Modificationsmentioning

confidence: 99%

Synthetic and semi-synthetic strategies to study ubiquitin signaling

Tilburg

Elhebieshy

Ovaa

2016

Current Opinion in Structural Biology

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The post-translational modification ubiquitin can be attached to the ɛ-amino group of lysine residues or to a protein's N-terminus as a mono ubiquitin moiety. Via its seven intrinsic lysine residues and its N-terminus, it can also form ubiquitin chains on substrates in many possible ways. To study ubiquitin signals, many synthetic and semi-synthetic routes have been developed for generation of ubiquitin-derived tools and conjugates. The strength of these methods lies in their ability to introduce chemo-selective ligation handles at sites that currently cannot be enzymatically modified. Here, we review the different synthetic and semi-synthetic methods available for ubiquitin conjugate synthesis and their contribution to how they have helped investigating conformational diversity of diubiquitin signals. Next, we discuss how these methods help understanding the ubiquitin conjugation-deconjugation system by recent advances in ubiquitin ligase probes and diubiquitin-based DUB probes. Lastly, we discuss how these methods help studying post-translational modification of ubiquitin itself.

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“…One of the first examples of a multi-segment KAHA ligation is the synthesis of the important modifier protein UFM1 [54,55]. In this three-segment, two-ligation strategy (Scheme 30), the N-terminal 5-oxaproline residue of the bifunctional internal segment 2 UFM1 (29-61) is protected by an Fmoc group to avoid side reactions.…”

Section: Ufm-1mentioning

confidence: 99%

Chemical Protein Synthesis with the KAHA Ligation

Rohrbacher

Wucherpfennig

Bode

2014

Topics in Current Chemistry

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Since the first report of the chemoselective amide bond forming reaction between α-ketoacids and hydroxylamines in 2006, the KAHA (α-ketoacid-hydroxylamine) ligation has advanced to a useful tool for the routine synthesis of small to medium sized proteins and cyclic peptides. In this chapter we introduce the concept of KAHA ligation starting with the synthesis and properties of hydroxylamines and α-ketoacids, methods for their incorporation into peptides, and give an insight into the mechanism of the KAHA ligation. We cover important improvements including sequential ligations with 5-oxaproline, traceless synthesis of peptide α-ketoacids and show their application in chemical protein synthesis and cyclic peptide synthesis. Recent developments of the KAT (potassium acyl trifluoroborate) ligation and its application as fast and chemoselective bioconjugation method are described and an outlook on ongoing work and possible future developments is given at the end of the chapter.

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Sequential α‐Ketoacid‐Hydroxylamine (KAHA) Ligations: Synthesis of C‐Terminal Variants of the Modifier Protein UFM1

Cited by 67 publications

References 44 publications

The Application of Isoacyl Structural Motifs in Prodrug Design and Peptide Chemistry

The Application of Isoacyl Structural Motifs in Prodrug Design and Peptide Chemistry

Synthetic and semi-synthetic strategies to study ubiquitin signaling

Chemical Protein Synthesis with the KAHA Ligation

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