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from that expected on the basis of the greater stability of tertiary
primary carbon-centered radicals arising from the increased number of
electron-releasing (stabilizing) alkyl groups.
The selectivity of an attack on side chains is also markedly affected by the
presence of a functional group which can stabilize the resulting radicals. Thus,
hydrogen atom abstraction occurs preferentially at positions adjacent to
electron-stabilizing groups such as hydroxy groups (in Ser and Thr), carboxyl
and amide functions (in Asp, Glu, Asn, Gln), and the guanidine residue in Arg
(46). In contrast, the protonated amine function on the Lys side chain has a
similar effect as the protonated amine group on the
-carbon. This results in
hydrogen abstraction at sites remote from both groups, and hence products
arising mainly from the C4 and C5 positions on Lys (50, 51). Addition reactions
are usually faster than hydrogen atom abstraction reactions, as there is no
bond breaking involved in the transition state. Hence, addition to the aromatic
rings of Phe, Tyr, Trp, and His, and the sulfur atoms of Met and Cys predomi-
nates over abstraction from the methylene (-CH2-) groups. The adduct species
formed with the aromatic rings are stabilized by delocalization on to neighbor-
ing double bonds. The only major exception occurs with Cys, where hydrogen
abstraction from the thiol (-SH) group is particularly fast (52).
The conversion of the deactivating amine group on the
-carbon into an
(electron delocalizing) amide function through the formation of a peptide
bond increases both the extent and rate constant for attack of radicals such as
HO at the
-carbon, thereby resulting in significant levels of backbone oxida-
tion (49, 53). The range of rate constants for HO attack on amino acid deriva-
tives (e.g., N-acetylated species) or simple two amino acid peptides (e.g., the
Gly-X series) is much smaller than that observed with the free amino acids
-carbon radical formed as a result of hydrogen atom abstraction from
the backbone is particularly stable as a result of electron delocalization on
both the neighboring amide group (on the N-terminal side) and the carbonyl
function (on the C-terminal side) (54). This has important consequences for
radical transfer reactions. Not all
-carbon radicals are of equal stability,
however, and there is evidence for preferential formation at Gly residues in
peptides (55). This has been postulated to arise because of steric interactions
between the side chain and backbone groups, which prevents the
radical from achieving planarity (and hence effective electron delocalization)
for those residues with bulky side chains (56). This results in the secondary
-carbon radical formed from Gly being more stable than the tertiary
carbon radical formed from other amino acids in peptides.
Secondary and tertiary structures may play a significant role in blocking
access of radicals present to backbone sites as a result of the outward protu-
berance of the side chains. This would suggest that side chain reactions
may play a more important role in the chemistry of intact globular or sheet
proteins than in the chemistry of disordered structures or small random coil
peptides (57).
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