Irreversible inhibition of transglutaminases by sulfonium methylketones: optimization of specificity and potency with omega-aminoacyl spacers.
Sulfonium methylketones, of structure Cbz-Phe-NH(CH2)nCOCH2S+ (CH3)2, n > 2, are specific and potent inactivators of transglutaminases. The length of the -(CH2)n-spacer moiety, n = 1-5, is a critical determinant for both the specificity and potency of the inactivator. The dipeptidyl analog Cbz-Phe-Gly-(CH2)nS+ (CH3)2, n = 1, is a more powerful inactivator of the thiol proteinase cathepsin B, k/K > 3 x 10(5) M-1 min-1, than of transglutaminases, ki(app)/Ki(app) < 1.5 x 10(4) M-1 min-1. In contrast, the gamma-aminobutyryl analog, n = 3, is a very potent transglutaminase inactivator with ki(app)/Ki(app) = 3.1 x 10(6) M-1 min-1, but does not inactivate cathepsin B. In cell studies, the gamma-aminobutyryl and epsilon-aminohexyl analogs inhibited the transglutaminase-mediated process of ionophore-induced cross-linked envelope formation by human malignant keratinocytes and the order of potency was related to that found for enzyme inhibition. The sulfonium methylketones, in equilibrium with the resonance stabilized ylides, are chemically inert towards glutathione under ambient conditions demonstrating the potential utility of this novel class of transglutaminase inhibitors for the study of enzyme inhibition in cellular environments.
Pliura
D H
DH
Syntex Research, Mississauga, Ontario, Canada.
Bonaventura
B J
BJ
Pauls
H W
HW
Killackey
J F
JF
Krantz
A
A
D000818:Animals; D002417:Cattle; D004355:Drug Stability; D004817:Epidermis / Q000201:enzymology; D007659:Ketones / Q000494:pharmacology*; D008956:Models, Chemical; D013329:Structure-Activity Relationship; D013452:Sulfonium Compounds / Q000494:pharmacology*; D011503:Transglutaminases / Q000037:antagonists & inhibitors*
D007659:Ketones; D013452:Sulfonium Compounds; D011503:Transglutaminases