Abstract
Post-translational modifications (PTMs) are used by organisms to control protein structure and function after protein translation, but their study is complicated and their roles are not often well understood as PTMs are difficult to introduce onto proteins selectively. Designing reagents that are both good mimics of PTMs, but also only modify select amino acid residues in proteins is challenging. Frequently, both a chemical warhead and linker are used, creating a product that is a misrepresentation of the natural modification. We have previously shown that biotin-chloromethyl-triazole is an effective reagent for cysteine modification to give S-Lys derivatives where the triazole is a good mimic of natural lysine acylation. Here, we demonstrate both how the reactivity of the alkylating reagents can be increased and how the range of triazole PTM mimics can be expanded. These new iodomethyl-triazole reagents are able to modify a cysteine residue on a histone protein with excellent selectivity in 30 min to give PTM mimics of acylated lysine side-chains. Studies on the more complicated, folded protein SCP-2L showed promising reactivity, but also suggested the halomethyl-triazoles are potent alkylators of methionine residues.
Highlights
EaStCHEM School of Chemistry, University of Edinburgh, Joseph Black Building, David Brewster Road, Abstract: Post-translational modifications (PTMs) are used by organisms to control protein structure and function after protein translation, but their study is complicated and their roles are not often well understood as PTMs are difficult to introduce onto proteins selectively
Significant advances in mass spectrometry and proteomics have led to an exponential rise in the number of reported PTMs but there is still only limited understanding of the role and significance that many of these modifications play in cellular processes and disease [2]
The reactivity of the reagents could be further of lysine residues, changing protein properties
Summary
PTMs sired hydrolysis and is the competing elimination reaction.form of PTM found on more. It is known to play an important role at both protein and cellular level and has been linked with autoimmune diseases and cancer. Methods to produce synthetic glycoproteins typically rely on lengthy chemical ligation strategies [27], α-halocarbonyls have been used to create glycoprotein mimics through Cys alkylation [28,29]. The reactivity of sulfhydryl-based reagents has been exploited through both the chemical [30] and genetic [31] introduction of dehydroalanine (Dha) to proteins and subsequent thia-Michael addition of glycosyl sulfhydryl reagents to give site-specific incorporation of mimics of glycosyl PTMs. To investigate further expansion of Molecules 2021, 26, x FOR PEER REVIEW the straightforward Cys-alkylation approach using our triazole based alkylating reagents, we targeted the synthesis of a glucosamine halomethyl-triazole reagent.
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