Inhibition of human beta-factor XIIa by squash family serine proteinase inhibitors.
Many inhibitors of trypsin and human beta-factor XIIa have been isolated from squash and related seeds and sequenced (Wieczorek et al., Biochem. Biophys. Res. Comm. (1985) 126, 646-652). The association equilibrium constants (Ka) of several of these inhibitors have now been determined with human beta-factor XIIa using a modification of the method of Green and Work (Park et al., Fed. Proc. Fed. Am. Soc. Exp. Biol. (1984) 43, 1962). The Ka's range from 7.8 x 10(4) M-1 to 3.3 x 10(8) M-1. Two isoinhibitors from Cucurbita maxima seeds, CMTI-I and CMTI-III, differ in only a single glutamate to lysine change in the P'4 position. This results in a factor of 62 increase in the Ka of the lysine inhibitor, CMTI-III (Ka = 3.3 x 10(8) M-1). To our knowledge, this is the largest effect ever seen for a residue substitution at the P'4 position of a serine proteinase inhibitor. The result is even more surprising because beta-factor XIIa's natural substrate, Factor XI, contains Gly in the P'4 position.
Wynn
R
R
Department of Chemistry, Purdue University, West Lafayette, IN 47907-3699.
Laskowski
M
M
D000595:Amino Acid Sequence; D015956:Factor XIIa / Q000037:antagonists & inhibitors*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D010945:Plants, Edible; D011485:Protein Binding; D015842:Serine Proteinase Inhibitors / Q000302:isolation & purification / Q000494:pharmacology*
D015842:Serine Proteinase Inhibitors; D015956:Factor XIIa