beta-Scission of C-3 (beta-carbon) alkoxyl radicals on peptides and proteins: a novel pathway which results in the formation of alpha-carbon radicals and the loss of amino acid side chains
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beta-Scission of C-3 (beta-carbon) alkoxyl radicals on peptides and proteins : a novel pathway which results in the formation of alpha-carbon radicals and the loss of amino acid side chains. / Headlam, H A; Mortimer, A; Easton, C J; Davies, Michael Jonathan.
In: Chemical Research in Toxicology, Vol. 13, No. 11, 11.2000, p. 1087-95.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - beta-Scission of C-3 (beta-carbon) alkoxyl radicals on peptides and proteins
T2 - a novel pathway which results in the formation of alpha-carbon radicals and the loss of amino acid side chains
AU - Headlam, H A
AU - Mortimer, A
AU - Easton, C J
AU - Davies, Michael Jonathan
PY - 2000/11
Y1 - 2000/11
N2 - Exposure of proteins to radicals in the presence of O(2) brings about multiple changes in the target molecules. These alterations include oxidation of side chains, fragmentation, cross-linking, changes in hydrophobicity and conformation, altered susceptibility to proteolytic enzymes, and formation of new reactive groups, including hydroperoxides. These processes can result in the loss of structural or enzymatic activity. Backbone fragmentation is known to occur via a number of mechanisms, most of which involve hydrogen abstraction from the alpha-carbon site on the backbone. In this study, we demonstrate that initial attack at a side chain site, the beta-position (C-3), can give rise to formation of alpha-carbon radicals, and hence backbone cleavage, via the formation and subsequent beta-scission of C-3 alkoxyl radicals. This beta-scission reaction is rapid (k estimated to be >10(7) s(-)(1)) even with primary alkoxyl radicals derived from Ala residues, and occurs when the alkoxyl radicals are generated from a variety of precursors, including hydroperoxides and nitrate esters. These reactions release the former side chain as a reactive aldehyde or ketone; thus, Ala peptides release high yields of methanal (formaldehyde). This product has been quantified with a number of oxidized peptides and proteins, and can account for up to 64% of the initial attacking radicals with some Ala peptides. When quantified together with the hydroperoxide precursors, these species account for up to 80% of the initial radicals, confirming that this is a major process. Methanal causes cell toxicity and DNA damage and is an animal carcinogen and a genotoxic agent in human cells. Thus, the formation and subsequent reaction of alkoxyl radicals formed at the C-3 position on aliphatic amino acid side chains on peptides and proteins can give rise to both backbone fragmentation and the release of further reactive species which can cause cell toxicity and mutagenicity.
AB - Exposure of proteins to radicals in the presence of O(2) brings about multiple changes in the target molecules. These alterations include oxidation of side chains, fragmentation, cross-linking, changes in hydrophobicity and conformation, altered susceptibility to proteolytic enzymes, and formation of new reactive groups, including hydroperoxides. These processes can result in the loss of structural or enzymatic activity. Backbone fragmentation is known to occur via a number of mechanisms, most of which involve hydrogen abstraction from the alpha-carbon site on the backbone. In this study, we demonstrate that initial attack at a side chain site, the beta-position (C-3), can give rise to formation of alpha-carbon radicals, and hence backbone cleavage, via the formation and subsequent beta-scission of C-3 alkoxyl radicals. This beta-scission reaction is rapid (k estimated to be >10(7) s(-)(1)) even with primary alkoxyl radicals derived from Ala residues, and occurs when the alkoxyl radicals are generated from a variety of precursors, including hydroperoxides and nitrate esters. These reactions release the former side chain as a reactive aldehyde or ketone; thus, Ala peptides release high yields of methanal (formaldehyde). This product has been quantified with a number of oxidized peptides and proteins, and can account for up to 64% of the initial attacking radicals with some Ala peptides. When quantified together with the hydroperoxide precursors, these species account for up to 80% of the initial radicals, confirming that this is a major process. Methanal causes cell toxicity and DNA damage and is an animal carcinogen and a genotoxic agent in human cells. Thus, the formation and subsequent reaction of alkoxyl radicals formed at the C-3 position on aliphatic amino acid side chains on peptides and proteins can give rise to both backbone fragmentation and the release of further reactive species which can cause cell toxicity and mutagenicity.
KW - Alcohols
KW - Amino Acids
KW - Electron Spin Resonance Spectroscopy
KW - Formaldehyde
KW - Free Radicals
KW - Gamma Rays
KW - Nitrates
KW - Oxygen
KW - Peptides
KW - Peroxides
KW - Proteins
M3 - Journal article
C2 - 11087430
VL - 13
SP - 1087
EP - 1095
JO - Chemical Research in Toxicology
JF - Chemical Research in Toxicology
SN - 0893-228X
IS - 11
ER -
ID: 138280918