Chemical Synthesis of Ubiquitin, Ubiquitin‐Based Probes, and Diubiquitin

Oualid, Farid El; Merkx, Remco; Ekkebus, Reggy; Hameed, Dharjath S.; Smit, Judith J.; Jong, Annemieke de; Hilkmann, Henk; Sixma, Titia K.; Ovaa, Huib

doi:10.1002/ange.201005995

Cited by 86 publications

(63 citation statements)

References 45 publications

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“…Beginning with the preparation of b-thiol phenylalanine (Phe) [16,17] and the application of this Phe derivative in peptide ligation followed by a post-ligation reductive desulfurization with nickel boride [17], a number of additional thiol-derived amino acids have been added to the ligation-desulfurization toolbox. These additions include access to post-desulfurization Xaa-Yaa ligation junctions where Yaa can be valine (Val) [15,18], lysine (Lys) [19][20][21], threonine (Thr) [22], leucine (Leu) [23,24], proline (Pro) [25,26], glutamine (Gln) [27], arginine (Arg) [28], aspartic acid (Asp) [29 ,30], glutamic acid (Glu) [31] or tryptophan (Trp) [32] using suitable thiol-derived amino acid building blocks (Figure 2Ia-c). Importantly, thiolated amino acids tend to exhibit increased rates of reactivity and improved reaction scope relative to Nlinked and side-chain appended auxiliaries, owing in part to the decreased steric bulk at the ligation junction (relative to N-linked auxiliaries) and the ability to proceed primarily through 5-membered (for b-thiol derivatives, Figure 2Ia) or 6-membered (for g-thiol derivatives, Figure 2Ib) ring intermediates in the S-to-N acyl transfer step.…”

Section: Development Of New N-terminal Cys Surrogatesmentioning

confidence: 99%

Recent extensions to native chemical ligation for the chemical synthesis of peptides and proteins

Malins

Payne

2014

Current Opinion in Chemical Biology

126

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Native chemical ligation continues to play a pivotal role in the synthesis of increasingly complex peptide and protein targets twenty years after its initial report. This opinion article will highlight a number of recent, powerful extensions of the technology that have expanded the scope of the reaction, accelerated ligation rates, enabled chemoselective post-ligation modifications, and streamlined the ligation of multiple peptide fragments. These advances have facilitated the synthesis of a number of impressive protein targets to date and hold great promise for the continued application of native chemical ligation for the detailed study of protein structure and function.

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Section: Development Of New N-terminal Cys Surrogatesmentioning

confidence: 99%

Recent extensions to native chemical ligation for the chemical synthesis of peptides and proteins

Malins

Payne

2014

Current Opinion in Chemical Biology

126

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“…81 This method has proven extremely effective, as yields approaching 80% have been observed for the 2-mercaptoethanesulfonate (MESNa) thioester. 82 An additional benefit to using the E1 approach is the ability to label a single monomer in a polyUb chain with a chemical tag.…”

Section: Native Chemical Ligation (Ncl)mentioning

confidence: 99%

“…As mentioned by the authors, further improvements could be made by exploiting recent developments in SPPS. 82 Upon implementing these approaches, this methodology may lend itself to the construction other types of homopolymers ( e.g. , K6, K27, K29, and K33) as well as linear heteropolymers (monomers linked through different lysine residues), both of which are unattainable by enzymatic means in a well-defined manner.…”

Section: Native Chemical Ligation (Ncl)mentioning

confidence: 99%

Unraveling the Complexity of Ubiquitin Signaling

Strieter

Korasick

2012

ACS Chem. Biol.

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Protein ubiquitination, the covalent attachment of ubiquitin to target proteins, has emerged as one of the most prevalent posttranslational modifications (PTMs), regulating nearly every cellular pathway. The diversity of signaling associated with this particular PTM stems from the myriad ways in which a target protein can be modified by ubiquitin, e.g., monoubiquitin, multi-monoubiquitin, and polyubiquitin linkages. In this Review, we focus on developments in both enzymatic and chemical methods that engender ubiquitin with new chemical and physical properties. Moreover, we highlight how these methods have enabled studies directed toward (i) characterizing enzymes responsible for reversing the ubiquitin modification, (ii) understanding the influence of ubiquitin on protein function and crosstalk with other PTMs, and (iii) uncovering the impact of polyubiquitin chain linkage and length on downstream signaling events.

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“…[133] Unter den Bedingungen der PyBOP/DIEA-Kupplung konnten verschiedenste Ub-Fusionen erzeugt werden, beispielsweise N-und C-terminale Modifikationen wie HA-Epitope und AMC. [133] Unter den Bedingungen der PyBOP/DIEA-Kupplung konnten verschiedenste Ub-Fusionen erzeugt werden, beispielsweise N-und C-terminale Modifikationen wie HA-Epitope und AMC.…”

Section: Chemische Synthese Und Semisynthese Des Ub-monomers Von Ub-dunclassified

Die Chemie und Biologie des Ubiquitin‐Signals

Spasser

Brik

2012

Angewandte Chemie

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Die Ubiquitinierung ist eine der häufigsten posttranslationalen Modifikationen in Eukaryoten und spielt bei einer Vielzahl zellulärer Prozesse eine Rolle, die zumeist als Signal für den proteasomalen Abbau bekannt sind. Vor kurzem stellte sich heraus, dass das Ubiquitin‐Signal wesentlich komplexer ist und durch die Ubiquitin‐Komponente und das Substrat bestimmt wird. Die bemerkenswerte Mannigfaltigkeit des Ubiquitin‐Signalprozesses hat enorme Bemühungen zur Erforschung der Rolle der Ubiqitinierung in biologischen Prozessen ausgelöst. Trotz der seit mehr als drei Jahrzehnten andauernden Untersuchungen sind aber noch mehrere wichtige Fragestellungen offen. Eine große Hürde ist das Unvermögen, homogene Ubiquitin‐Biokonjugate durch Isolierung aus Zellen oder durch enzymatische Mechanismen zugänglich zu machen. Jüngste Erfolge bei chemischen und semisynthetischen Strategien bieten zunehmend Lösungen für diese Herausforderungen, indem sie die Produktion großer Mengen homogener Ubiquitinkonjugate ermöglichen. In diesem Aufsatz diskutierten wir die fundamentalen biologischen Aspekte des Ubiquitin‐Signals und stellen neuartige nichtenzymatische Ansätze vor, die diese Hindernisse umgehen.

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Chemical Synthesis of Ubiquitin, Ubiquitin‐Based Probes, and Diubiquitin

Cited by 86 publications

References 45 publications

Recent extensions to native chemical ligation for the chemical synthesis of peptides and proteins

Recent extensions to native chemical ligation for the chemical synthesis of peptides and proteins

Unraveling the Complexity of Ubiquitin Signaling

Die Chemie und Biologie des Ubiquitin‐Signals

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