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Methionine sulfoxide- and sulfone-containing peptide synthesis: management of a relevant post-translational modification in proteins


* Corresponding author
1. French-Italian Interdepartmental Laboratory of Peptide and Protein Chemistry & Biology – PeptLab
2. PeptLab@UCP Platform & Laboratory of Chemical Biology EA4505, University of Cergy-Pontoise, 5 mail Gay-Lussac, F-95031 Cergy-Pontoise CEDEX, France
3. Department of Chemistry “Ugo Schiff”, University of Florence, Via della Lastruccia 13, I-50019 Sesto Fiorentino, Italy
4. Department of Neurosciences, Psychology, Drug Research and Child Health – Section of Pharmaceutical Sciences and Nutraceutics, University of Florence, Via Ugo Schiff 6, I-50019 Sesto Fiorentino, Italy


Methionine (Met) is with Cysteine one of the most easily oxidized amino acids. Sulfoxide and sulfone forms can both be formed, only the latter being irreversible in biological systems, with important consequences on protein interactions and structuration. In this paper we discuss the conditions for Met oxidation in solid-phase peptide synthesis (SPPS). As case studies we selected the following peptide sequences: the biologically relevant β-amyloid (1-40) in which Met oxidation could decrease the aggregation and toxicity in Alzheimer’s disease and an irrelevant tetradecapeptide GHSVFLAPYGWMVK. In particular we investigated manual and classical in batch or microwave-assisted automatic SPPS (MW-SPPS) to evaluate the synthetic conditions to obtain Met oxidation and we highlighted the experimental parameters for automated MW-SPPS. Moreover, we reported specific conditions to deal with sulfoxide formation just in case non-oxidized Met-containing peptides have to be obtained.


Met, one of the eight essential amino acids (1), is characterized by a thioether function on the side chain that is particularly sensitive to oxidation. Indeed, low oxidation potential of Met makes it fairly easily oxidized.
The biological relevance of Met oxidation is a relatively new topic (2,3). So far, Met was considered as a generic hydrophobic amino acid, interchangeable with others such as Leu or Val. But in the last decade, scientific consideration has risen for Met, which is now considered as a biologically relevant residue, especially in regards to its redox properties possibly influencing protein function, structuration, and protein-protein interaction (4).
Exposed Met residues can be modified by a large number of oxidants both in vivo and in vitro, producing Met(O). In vivo, Met is oxidized by Reactive Oxygen Species (ROS) such as hydrogen peroxide (H2O2) and hydroxyl radicals (HO.).
Oxidized Met is more hydrophilic than the native amino acid. Therefore this post-translational modification in protein structures can occur and it is believed to be responsible of inactivation, inhibiti ...