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

Friedrich MG, Wang Z, Schey KL, Truscott RJW
Biochim Biophys Acta Gen Subj. 2018 1862 (4): 907-913

PMID: 29309825 · DOI:10.1016/j.bbagen.2018.01.003

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.

Copyright © 2018. Published by Elsevier B.V.

MeSH Terms (17)

Alanine Amino Acid Sequence Crystallins Dipeptides Glutathione Glutathione Disulfide Humans Lens, Crystalline Lysine Middle Aged Molecular Structure Peptides Protein Conformation Protein Processing, Post-Translational Proteins Tandem Mass Spectrometry Young Adult

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