DehydroalanylGly, a new post translational modification resulting from the breakdown of glutathione

Publication date: Available online 6 January 2018
Source:Biochimica et Biophysica Acta (BBA) - General Subjects
Author(s): Michael G. Friedrich, Zhen Wang, Kevin L. Schey, Roger J.W. Truscott
BackgroundThe human body contains numerous long-lived proteins which deteriorate with age, typically by racemisation, deamidation, crosslinking and truncation. Previously we elucidated one reaction responsible for age-related crosslinking, the spontaneous formation of dehydroalanine (DHA) intermediates from phosphoserine and cysteine. This resulted in non-disulphide covalent crosslinks. The current paper outlines a novel posttranslational modification (PTM) in human proteins, which involves the addition of dehydroalanylglycine (DHAGly) to Lys residues.MethodsHuman lens digests were examined by mass spectrometry for the presence of (DHA)Gly (+144.0535Da) adducts to Lys residues. Peptide model studies were undertaken to elucidate the mechanism of formation.ResultsIn the lens, this PTM was detected at 18 lysine sites in 7 proteins. Using model peptides, a pathway for its formation was found to involve initial formation of the glutathione degradation product, γ-Glu(DHA)Gly from oxidised glutathione (GSSG). Once the Lys adduct formed, the Glu residue was lost in a hydrolytic mechanism apparently catalysed by the ε-amino group of the Lys.ConclusionsThis discovery suggests that within cells, the functional groups of amino acids in proteins may be susceptible to modification by reactive metabolites derived from GSSG.General Significance: Our finding demonstrates a novel +144.0535Da PTM arising from the breakdown of oxidised glutathione.



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