The acetaminophen metabolite N-acetyl-p-benzoquinone imine (NAPQI) inhibits glutathione synthetase in vitro; a clue to the mechanism of 5-oxoprolinuric acidosis?
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2. Peptide mapping of co-incubated NAPQI and GS using mass spectrometry demonstrated binding of NAPQI with cysteine-422 of GS, which is known to be essential for GS activity. Computational docking shows that NAPQI is properly positioned for covalent bonding with cysteine-422 via Michael addition and hence supports adduct formation.
3. Co-incubation of 0.77 μM of GS with NAPQI (25–400 μM) decreased enzyme activity by 16–89%. Inhibition correlated strongly with the concentration of NAPQI and was irreversible.
4. NAPQI binds covalently to GS causing irreversible enzyme inhibition in vitro. This is an important novel biochemical observation. It is the first indication that NAPQI may inhibit glutathione synthesis, which is pivotal in NAPQI detoxification. Further studies are required to investigate its biological significance and its role in 5-oxoprolinuric acidosis.
|Early online date||18 Apr 2016|
|Publication status||Published - Feb 2017|
- The acetaminophen metabolite
Rights statement: This is an Accepted Manuscript of an article published by Taylor & Francis in Xenobiotica on 18/04/2016, available online: http://www.tandfonline.com/10.3109/00498254.2016.1166533
Accepted author manuscript (Post-print), 1.04 MB, PDF document