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

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, ?-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 ?-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.

SUBMITTER: Friedrich MG 

PROVIDER: S-EPMC7020663 | biostudies-literature | 2018 Apr

REPOSITORIES: biostudies-literature