Rapid hydrolysis and slow alpha,beta-dicarbonyl cleavage of an agent proposed to cleave glucose-derived protein cross-links.
The putative protein glycation cross-link cleaving agent N-phenacylthiazolium bromide (PTB) underwent hydrolysis and cyclic hemithioacetal formation under physiological conditions to form two isomeric 2,3-dihydro-4-formyl-2-hydroxy-2-phenyl-1,4-thiazines: at pH 7.4 and 37 degrees, the rate constant k(Hydrolysis) was (2.6+/-0.1) x 10(-4) sec and the chemical half-life was ca. 44 min. The alpha,beta-dicarbonyl cleavage reaction only competed effectively with the hydrolysis when the alpha,beta-dicarbonyl substrate was at nonphysiological high levels. The high concentrations of PTB (10-30 mM) used previously to demonstrate chemical and biochemical activity also lead to acidification of incubation media. The mechanism of action of PTB now requires reappraisal.
Thornalley
P J
PJ
Department of Biological Sciences, University of Essex, Colchester, UK.
Minhas
H S
HS
D003432:Cross-Linking Reagents; D017127:Glycation End Products, Advanced / Q000378:metabolism; D006031:Glycosylation; D006868:Hydrolysis; D015394:Molecular Structure; D013844:Thiazoles / Q000737:chemistry*; D013997:Time Factors
D003432:Cross-Linking Reagents; D017127:Glycation End Products, Advanced; C101705:N-phenacylthiazolium bromide; D013844:Thiazoles