Elsevier

Redox Biology

Volume 30, February 2020, 101421
Redox Biology

Research Paper
Methylglyoxal interaction with superoxide dismutase 1

https://doi.org/10.1016/j.redox.2019.101421Get rights and content
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Highlights

  • MG forms stable adducts with the immature forms of SOD1.

  • MG causes the unfolding of the apo-SOD1SH form.

  • MG causes the monomerization of the E,Zn-SOD1SH form.

  • In both forms, arginine 143 is more prone to interact with MG.

  • The structural modifications caused by MG impair the correct maturation of SOD1.

Abstract

Methylglyoxal (MG) is a highly reactive aldehyde spontaneously formed in human cells mainly as a by-product of glycolysis. Such endogenous metabolite reacts with proteins, nucleotides and lipids forming advanced glycation end-products (AGEs). MG binds to arginine, lysine and cysteine residues of proteins causing the formation of stable adducts that can interfere with protein function. Among the proteins affected by glycation, MG has been found to react with superoxide dismutase 1 (SOD1), a fundamental anti-oxidant enzyme that is abundantly expressed in neurons. Considering the high neuronal susceptibility to MG-induced oxidative stress, we sought to investigate by mass spectrometry and NMR spectroscopy which are the structural modifications induced on SOD1 by the reaction with MG. We show that MG reacts preferentially with the disulfide-reduced, demetallated form of SOD1, gradually causing its unfolding, and to a lesser extent, with the intermediate state of maturation – the reduced, zinc-bound homodimer – causing its gradual monomerization. These results suggest that MG could impair the correct maturation of SOD1 in vivo, thus both increasing cellular oxidative stress and promoting the cytotoxic misfolding and aggregation process of SOD1.

Keywords

Methylglyoxal
Superoxide dismutase 1
Glycation
AGEs
Oxidative stress

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