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Mechanism of Hydrolysis and Aminolysis of Homocysteine Thiolactone
Author(s) -
Garel Jonathan,
Tawfik Dan S.
Publication year - 2006
Publication title -
chemistry – a european journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.687
H-Index - 242
eISSN - 1521-3765
pISSN - 0947-6539
DOI - 10.1002/chem.200501145
Subject(s) - aminolysis , chemistry , thiolactone , amine gas treating , stereochemistry , nucleophile , hydrolysis , reactivity (psychology) , medicinal chemistry , organic chemistry , catalysis , medicine , alternative medicine , pathology
Homocysteine thiolactone (tHcy) is deemed a risk factor for cardiovascular diseases and strokes, presumably because it acylates the side chain of protein lysine residues (“N‐homocysteinylation”), thereby causing protein damage and autoimmune responses. We analysed the kinetics of hydrolysis and aminolysis of tHcy and two related thiolactones (γ‐thiobutyrolactone and N ‐trimethyl‐tHcy), and we have thereby described the first detailed mechanism of thiolactone aminolysis. As opposed to the previously studied (thio and oxo)esters and (oxo)lactones, aminolysis of thiolactones was found to be first order with respect to amine concentration. Anchimeric assistance by the α‐amino group of tHcy (through general acid/base catalysis) could not be detected, and the Brønsted plot (nucleophilicity versus p K a ) for aminolysis yielded a slope (β nuc ) value of 0.66. These data support a mechanism of aminolysis where the rate‐determining step is the formation of a zwitterionic tetrahedral intermediate. The β nuc value and steric factors dictate a regime whereby, at physiological pH values (pH 7.4), maximal reactivity of tHcy is exhibited with primary amine groups with a p K a value of 7.7; this allows the reactivity of various protein amino groups towards N‐homocysteinylation to be predicted.