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Review
. 2019 May 22;141(20):8005-8013.
doi: 10.1021/jacs.8b13187. Epub 2019 Apr 25.

Concepts of Catalysis in Site-Selective Protein Modifications

Patrick G Isenegger  1 , Benjamin G Davis  1
Affiliations
Review

Concepts of Catalysis in Site-Selective Protein Modifications

Patrick G Isenegger et al. J Am Chem Soc. .

Abstract

The manipulation and modulation of biomolecules has the potential to herald new modes of Biology and Medicine through chemical "editing". Key to the success of such processes will be the selectivities, reactivities and efficiencies that may be brought to bear in bond-formation and bond-cleavage in a benign manner. In this Perspective, we use select examples, primarily from our own research, to examine the current opportunities, limitations and the particular potential of metal-mediated processes as exemplars of possible alternative catalytic modes and manifolds to those already found in nature.

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Conflict of interest statement

The authors declare no competing financial interest.

Figures

Figure 1
Figure 1
Protein modification strategies to make or mimic natural post-translational modifications (PTMs). Tag examples chosen here focus on use of metal-mediated catalysis (see also Figure 2).
Figure 2
Figure 2
Protein modifications using metal-mediated catalysis. Tag orientation determines cycle and hence reactivity and selectivity.
Figure 3
Figure 3
CuAAC combined with other modifications allows either (a) dual display of different PTM mimics, or (c) nested selectivity in sequential catalysis. (b) Such mimics function even in vivo allowing a PSGL1-mimic to visualize CD62P as a marker of inflammation. [Adapted from reference (14) with permission from SpringerNature.]
Figure 4
Figure 4
(a) RuOCM is enabled by various modes of chemical (for Sac, Seac),, or genetic (for Ahc) allylchalcogen tag installation as privileged motifs. (b) RuOCM may be embedded in mimics of write–read–erase cycles.
Figure 5
Figure 5
(a) Benign PdCC allows attachment of various groups using pyrimidine- or guanidine-based ligands including (b) use at low concentrations of 18F-prosthetic reagent and (c) self-liganding PEG-ylation reagents.
Figure 6
Figure 6
Use of PdCC-mediated “shunting” allows access to mimics of intermediate states found in the initiation of glycogen.
Figure 7
Figure 7
(a) S-Arylation of native Cys is enabled either by use of prepalladated oxidative-addition complexes, or metal-binding-site directed methods. (b) Active site directed S-arylation allows effective covalent inhibition in enzymes.
See this image and copyright information in PMC

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