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. 1996 Dec 24;93(26):15036-40.
doi: 10.1073/pnas.93.26.15036.

Methionine residues as endogenous antioxidants in proteins

R L Levine  1 , L Mosoni, B S Berlett, E R Stadtman
Affiliations

Methionine residues as endogenous antioxidants in proteins

R L Levine et al. Proc Natl Acad Sci U S A. .

Abstract

Cysteine and methionine are the two sulfur-containing residues normally found in proteins. Cysteine residues function in the catalytic cycle of many enzymes, and they can form disulfide bonds that contribute to protein structure. In contrast, the specific functions of methionine residues are not known. We propose that methionine residues constitute an important antioxidant defense mechanism. A variety of oxidants react readily with methionine to form methionine sulfoxide, and surface exposed methionine residues create an extremely high concentration of reactant, available as an efficient oxidant scavenger. Reduction back to methionine by methionine sulfoxide reductases would allow the antioxidant system to function catalytically. The effect of hydrogen peroxide exposure upon glutamine synthetase from Escherichia coli was studied as an in vitro model system. Eight of the 16 methionine residues could be oxidized with little effect on catalytic activity of the enzyme. The oxidizable methionine residues were found to be relatively surface exposed, whereas the intact residues were generally buried within the core of the protein. Furthermore, the susceptible residues were physically arranged in an array that guarded the entrance to the active site.

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Figures

Figure 1
Figure 1
Oxidation of methionine residues in glutamine synthetase by hydrogen peroxide, determined by amino acid analysis. A double reciprocal plot of the same data is shown (Inset), demonstrating that extrapolation to infinite peroxide concentration would cause oxidation of 10 of the 16 methionine residues in each subunit.
Figure 2
Figure 2
The susceptibility of oxidatively modified glutamine synthetases to proteolysis by the proteosome (♦) correlated with increased surface hydrophobicity (•).
Figure 3
Figure 3
Examples of results from simultaneous sequence analysis of CNBr peptide collections of glutamine synthetases exposed to hydrogen peroxide. (♦—-♦), aparagine in cycle 2, which monitors Met-8; (•- - - -•), lysine in cycle 4, which monitors Met-272.
Figure 4
Figure 4
Location of oxidized and intact methionine residues in glutamine synthetase. This stereo figure was created by the program rasmol (19) using the coordinates determined by Almassy et al. (18), deposited in the Brookhaven Data Base (reference 2GLS). For clarity, only one of the two hexamers is shown, and subunits are alternately colored blue and white. The sulfur groups of methionine residues are shown as balls, with intact residues in green and the oxidized residues in red. The active sites are formed by two adjacent subunits, and the Mn2+ in the core of the active sites is shown in yellow. The oxidizable methionine residues appear to form an array about the entrance to the active site bay.
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