DehydroalanylGly, a new post translational modification resulting from the breakdown of glutathione
RIS ID
121637
Abstract
Background: The 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.
Methods: Human lens digests were examined by mass spectrometry for the presence of (DHA)Gly (+144.0535 Da) adducts to Lys residues. Peptide model studies were undertaken to elucidate the mechanism of formation.
Results: In 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.
Conclusions: This 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 +144.0535 Da PTM arising from the breakdown of oxidised glutathione.
Publication Details
Friedrich, M. G., Wang, Z., Schey, K. L. & Truscott, R. J. W. (2018). DehydroalanylGly, a new post translational modification resulting from the breakdown of glutathione. Biochimica et Biophysica Acta - General Subjects, 1862 (4), 907-913.