Intracellular oxidation of dipeptides. Base-promoted elimination from N-halodipeptides to 2-[N-alkyl-N-(2-N-alkylimino-2-alkyl-ethanoyl)amino]-2,2-dialkylethanoic acids.
One of the possible ways of intracellular oxidation of peptides is via the formation of the corresponding (N-X)-dipeptides, that then undergo base-promoted elimination to yield intermediate 2-[N-alkyl-N-(2-N-alkylimino-2-alkylethanoyl)amino]-2,2-dialkylethanoic acids, which subsequently hydrolyze. Such an elimination process is general-base catalyzed, with Brønsted beta values ranging from 0.26 to 0.31, which suggests an essentially constant degree of proton transfer at the TS. For (N-X)-dipeptides, the ratio k(N-Br)/k(N-Cl) ranges from 2.5 to 15, suggesting a structural dependence of the degree of N-X bond breaking at the TS. The values of beta and k(N-Br)/k(N-Cl) support a concerted asynchronous A(xh)D(H)D(N) mechanism, its TS changing from reactant-like to slightly nitrenium-like depending on the structure of the starting dipeptide. As a consequence of the antiperiplanarity requirements of the reaction, the steric interaction between the leaving group and the substituent on the C bearing the H to be eliminated controls the reaction rate. Such steric interaction is rather important, as indicated by the steric crossed-interaction coefficient (p(ssy') = 0.33). Semiempirical calculations show that bulky substituents in the vicinity of the reaction center imply additional energy requirements for the system to achieve the antiperiplanarity needed at the TS for the reaction to proceed. From the observations reported it follows that (N-X)-dipeptides lose their oxidizing power more readily than analogous (N-X)-amino acids or (N-X)-amines, opening a possible pathway to lessen intracellular halogen-based oxidative stress.
Armesto
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XL
Departamento de Química Física e Enxeñería Química I, Facultade de Ciencias, Universidade da Coruña, Rúa Alejandro de la Sota 1, E-15008 A Coruña, Galicia, Spain.
Canle L
M
M
Fernández
M I
MI
García
M V
MV
Rodríguez
S
S
Santaballa
J A
JA
D000085:Acetates / Q000737:chemistry* / Q000378:metabolism; D004151:Dipeptides / Q000737:chemistry* / Q000378:metabolism; D006997:Hypochlorous Acid / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D008958:Models, Molecular; D008968:Molecular Conformation; D010084:Oxidation-Reduction; D012972:Sodium Hydroxide / Q000737:chemistry
D000085:Acetates; D004151:Dipeptides; D012972:Sodium Hydroxide; D006997:Hypochlorous Acid