PubMed:26747427 / 74-80
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Comparison of biological activities of human antithrombins with high-mannose or complex- type nonfucosylated N-linked oligosaccharides.
The structure of the N-linked oligosaccharides attached to antithrombin (AT) has been shown to affect its anticoagulant activity and pharmacokinetics. Human AT has biantennary complex-type oligosaccharides with the unique feature of lacking a core fucose, which affects its biological activities by changing its heparin binding affinity. In human plasma, AT circulates as a mixture of the α-form bearing four oligosaccharides and the β-form lacking an oligosaccharide at Asn135. However, it remains unclear how the immature high-mannose-type oligosaccharides produced by mammalian cells affect biological activities of AT. Here, we succeeded in directly comparing the activities between the high-mannose and complex-types. Interestingly, although there were no substantial differences in thrombin inhibitory activity, the high-mannose-type showed higher heparin binding affinity. The anticoagulant activities were increased by heparin and correlated with the heparin binding affinity, resulting in the strongest anticoagulant activity being displayed in the β-form with the high-mannose-type. In pharmacokinetic profiling, the high-mannose-type showed a much shorter plasma half-life than the complex-type. The β-form was found to have a prolonged plasma half-life compared with the α-form for the high-mannose-type; conversely, the α-form showed a longer half-life than the β-form for the complex-type. The present study highlights that AT physiological activities are strictly controlled not only by a core fucose at the reducing end but also by the high-mannose-type structures at the nonreducing end. The β-form with the immature high-mannose-type appears to function as a more potent anticoagulant than the AT typically found in human plasma, once it emerges in the blood.
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