Oxidation of a specific methionine in thrombomodulin by activated neutrophil products blocks cofactor activity. A potential rapid mechanism for modulation of coagulation.
Endothelial thrombomodulin (TM) plays a critical role in hemostasis as a cofactor for thrombin-dependent formation of activated protein C, a potent anticoagulant. Chloramine T, H2O2, or hypochlorous acid generated from H2O2 by myeloperoxidase rapidly destroy 75-90% of TM cofactor activity. Activated PMN, the primary in vivo source of biological oxidants, also rapidly inactivate TM. Oxidation of TM by PMN is inhibited by diphenylene iodonium, an inhibitor of NADPH oxidase. Both Met291 and Met388 in the six epidermal growth factor-like repeat domain are oxidized; however, only substitutions of Met388 lead to TM analogues that resist oxidative inactivation. We suggest that in inflamed tissues activated PMN may inactivate TM and demonstrate further evidence of the interaction between the inflammatory process and induction of thrombotic potential.
Glaser
C B
CB
Department of Protein Chemistry, Berlex Biosciences, South San Francisco, California 94080.
Morser
J
J
Clarke
J H
JH
Blasko
E
E
McLean
K
K
Kuhn
I
I
Chang
R J
RJ
Lin
J H
JH
Vilander
L
L
Andrews
W H
WH
Light
D R
DR
D000328:Adult; D000595:Amino Acid Sequence; D001777:Blood Coagulation; D002700:Chloramines / Q000737:chemistry; D004730:Endothelium, Vascular / Q000378:metabolism; D006801:Humans; D006861:Hydrogen Peroxide / Q000737:chemistry; D007700:Kinetics; D008297:Male; D008562:Membrane Glycoproteins / Q000737:chemistry; D008715:Methionine; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D009195:Peroxidase / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000737:chemistry*; D018179:Receptors, Thrombin; D011994:Recombinant Proteins / Q000737:chemistry; D013329:Structure-Activity Relationship; D013917:Thrombin / Q000378:metabolism; D014105:Tosyl Compounds
D002700:Chloramines; D008562:Membrane Glycoproteins; D011956:Receptors, Cell Surface; D018179:Receptors, Thrombin; D011994:Recombinant Proteins; D014105:Tosyl Compounds; C016300:chloramine-T; D008715:Methionine; D006861:Hydrogen Peroxide; D009195:Peroxidase; D013917:Thrombin