Dependence of the C-6 sulfate of the glucosamine moiety and 1----4 glycosidic linkage of heparin disaccharides for production of hemorrhage: reversal of the antihemostatic activity of heparin and their fragments by adenosine triphosphate and myosin.
Topical application or intraperitoneal injection of heparin and heparin oligosaccharides produces a potent inhibition of skin hemostasis. Studies conducted with disaccharides derived from heparin, heparan sulfate, and chondroitin sulfates have shown that delta-4,5-uronyl-(1----4)-glucosamine, bearing a sulfate at the C-6 position of the glucosamine residue, is the minimum structure for the antihemostatic activity. The disaccharides with this basic structure produce uncontrollable hemorrhage from small blood vessels, similar to that observed for heparin. The finding that other sulfated disaccharides, with the same sulfate to hexosamine to uronic acid ratios but with the sulfate at a different position (C-2) or with a different glycosidic linkage (1----3), were inactive as inhibitors of hemostasis indicates that a specific structure is needed to produce the effect. The inhibitory activity of the normal hemostatic process produced by heparin and its products could be reversed either by ATP or myosin. Molecular models show that part of the disaccharide inhibitors and ATP have a similar structural conformation.
Dietrich
C P
CP
Departamento de Bioquimica, Escola Paulista de Medicina, São Paulo, Brazil.
Tersariol
I L
IL
Da Silva
R G
RG
Bianchini
P
P
Nader
H B
HB
D000255:Adenosine Triphosphate / Q000494:pharmacology*; D000818:Animals; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D004187:Disaccharides / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D006470:Hemorrhage / Q000139:chemically induced*; D006487:Hemostasis / Q000187:drug effects; D006493:Heparin / Q000737:chemistry / Q000494:pharmacology*; D006494:Heparin Antagonists / Q000494:pharmacology; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009218:Myosins / Q000037:antagonists & inhibitors / Q000494:pharmacology*; D051381:Rats; D013329:Structure-Activity Relationship
D004187:Disaccharides; D006494:Heparin Antagonists; D000255:Adenosine Triphosphate; D006493:Heparin; D009218:Myosins