Methionine sulfoxide reductases A and B are deactivated by hydrogen peroxide (H2O2) in the epidermis of patients with vitiligo.
Patients with the depigmentation disorder vitiligo have low catalase expression/activities and constantly accumulate 10(-3) M hydrogen peroxide (H(2)O(2)) in their skin. Such high concentrations of H(2)O(2) oxidize L-methionine residues in proteins and peptides to (R and S)-methionine sulfoxide diasteriomers. In vivo FT-Raman Spectroscopy revealed the presence of methionine sulfoxide in the depigmented skin of patients with active vitiligo. In normal healthy human skin, methionine sulfoxide reductases A and B specifically reduce methionine sulfoxides (S) and (R), respectively, back to L-methionine consequently repairing oxidatively damaged proteins and peptides. In this report, we show that the expression/activities of MSRA and MSRB are significantly decreased in the epidermis of patients with vitiligo compared to healthy controls. Also, we used recombinant human MSRA and MSRB1 to show that both enzymes are deactivated by 10(-3) M H(2)O(2) by 85 and 40%, respectively. Structural modelling based on the crystal structure of human MSRA revealed that the active site of this enzyme is significantly altered after H(2)O(2)-mediated oxidation of L-methionine, L-tryptophan, and L-cysteine residues in its active site. Taken together, our results confirm that very important anti-oxidant enzymes are seriously affected in acute vitiligo.
Schallreuter
Karin U
KU
Clinical and Experimental Dermatology, Department of Biomedical Sciences, University of Bradford, Bradford, UK. K.Schallreuter@bradford.ac.uk
Rübsam
Katharina
K
Gibbons
Nicholas C J
NC
Maitland
Derek J
DJ
Chavan
Bhaven
B
Zothner
Carsten
C
Rokos
Hartmut
H
Wood
John M
JM
D001665:Binding Sites; D018360:Crystallography, X-Ray; D004817:Epidermis / Q000201:enzymology; D005260:Female; D006801:Humans; D006861:Hydrogen Peroxide / Q000378:metabolism* / Q000633:toxicity; D008297:Male; D008715:Methionine / Q000031:analogs & derivatives / Q000032:analysis / Q000378:metabolism*; D051150:Methionine Sulfoxide Reductases; D008840:Microfilament Proteins; D008958:Models, Molecular; D018384:Oxidative Stress; D010088:Oxidoreductases / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*; D011994:Recombinant Proteins / Q000187:drug effects; D013059:Spectrum Analysis, Raman; D013237:Stereoisomerism; D014157:Transcription Factors / Q000032:analysis / Q000187:drug effects / Q000378:metabolism*; D014820:Vitiligo / Q000201:enzymology*
D008840:Microfilament Proteins; D011994:Recombinant Proteins; D014157:Transcription Factors; D008715:Methionine; D006861:Hydrogen Peroxide; D010088:Oxidoreductases; C120376:MSRB2 protein, human; D051150:Methionine Sulfoxide Reductases; C027219:methionine sulfoxide reductase; C013111:methionine sulfoxide