TY - JOUR
T1 - Neuroglobin modification by reactive quinone species
AU - Nicolis, Stefania
AU - Monzani, Enrico
AU - Pezzella, Alessandro
AU - Ascenzi, Paolo
AU - Sbardella, Diego
AU - Casella, Luigi
PY - 2013/12/16
Y1 - 2013/12/16
N2 - The physiological functions of neuroglobin (Ngb), the heme protein of the globin family expressed in the nervous tissue, have not yet been clarified. Besides O2 storage and homeostasis, Ngb is thought to play a role in neuroprotection as a scavenger of toxic reactive species generated in vivo under conditions of oxidative stress. Herein, the interaction of Ngb with the quinones generated by oxidation of catecholamines (dopamine, norepinephrine) and catechol estrogens (2-hydroxyestradiol and 4-hydroxyestradiol), which have been implicated in neurodegenerative pathologies like Parkinson's and Alzheimer's diseases, has been investigated. The cytotoxicity of quinones has been ascribed to the derivatization of amino acid residues (mainly cysteine) in proteins through the formation of covalent bonds with the aromatic rings. Combined studies of tandem mass spectrometry and protein unfolding indicate the presence of quinone-promoted modifications in all of the Ngb derivatives analyzed (i.e., obtained employing either catecholamines or catechol estrogens as the source of the reactive species). Among protein residues, the highest reactivity of cysteines (Cys46, Cys55, and Cys120 in human Ngb) toward quinone species has been confirmed, and the dependence of the extent of protein modification on the method employed for catechol oxidation has been observed. When the oxidation reaction proceeds by one-electron steps, the involvement of semiquinone reactivity has been observed. The whole analysis of the data of Ngb modification suggests that the catecholamine-oxidation products can extensively modify proteins (likely by catecholamine oligomers, the compounds initially formed during the transformation of catecholamine to melanin). The modification mediated by catechol estrogens is less pronounced but strongly affects the interactions with the solvent as well as the protein stability.
AB - The physiological functions of neuroglobin (Ngb), the heme protein of the globin family expressed in the nervous tissue, have not yet been clarified. Besides O2 storage and homeostasis, Ngb is thought to play a role in neuroprotection as a scavenger of toxic reactive species generated in vivo under conditions of oxidative stress. Herein, the interaction of Ngb with the quinones generated by oxidation of catecholamines (dopamine, norepinephrine) and catechol estrogens (2-hydroxyestradiol and 4-hydroxyestradiol), which have been implicated in neurodegenerative pathologies like Parkinson's and Alzheimer's diseases, has been investigated. The cytotoxicity of quinones has been ascribed to the derivatization of amino acid residues (mainly cysteine) in proteins through the formation of covalent bonds with the aromatic rings. Combined studies of tandem mass spectrometry and protein unfolding indicate the presence of quinone-promoted modifications in all of the Ngb derivatives analyzed (i.e., obtained employing either catecholamines or catechol estrogens as the source of the reactive species). Among protein residues, the highest reactivity of cysteines (Cys46, Cys55, and Cys120 in human Ngb) toward quinone species has been confirmed, and the dependence of the extent of protein modification on the method employed for catechol oxidation has been observed. When the oxidation reaction proceeds by one-electron steps, the involvement of semiquinone reactivity has been observed. The whole analysis of the data of Ngb modification suggests that the catecholamine-oxidation products can extensively modify proteins (likely by catecholamine oligomers, the compounds initially formed during the transformation of catecholamine to melanin). The modification mediated by catechol estrogens is less pronounced but strongly affects the interactions with the solvent as well as the protein stability.
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U2 - 10.1021/tx4001896
DO - 10.1021/tx4001896
M3 - Article
C2 - 24144187
AN - SCOPUS:84890497616
VL - 26
SP - 1821
EP - 1831
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
SN - 0893-228X
IS - 12
ER -