Abstract
The discovery, the development and the actions and uses of the coumarin-derivative anticoagulants are summarized against the simultaneously evolving understanding of the mechanism by which blood coagulates. The current understanding of the particular contribution of those plasma proteins, whose synthesis is now known to be vitamin K-dependent, to the coagulation mechanism is described. The importance of vitamin K to the post-ribosomal incorporation of the newly recognised amino acid, γ-carboxyglutamic, acid, into these proteins is identified. The mode of action of the coumarin derivative anticoagulants is revealed by recent research to be the prevention of the reduction of vitamin K epoxide to the form of the vitamin active in the biosynthetic step by which precursor protein is converted to biologically active coagulation factor. Finally, the discovery that vitamin K may function other than in relation to the coagulation of blood is summarized.
Kurzfassung
Entdeckung, Entwicklung, Wirkung und Anwendung der Kumarinderivat-Antikoagulantien werden im Zusammenhang mit den gleichzeitig erweiterten Kenntnissen der Mechanismen, die der Blutgerinnung zugrunde liegen, diskutiert. Der heutige Wissensstand um die Mitwirkung der Plasmaproteine bei der Blutgerinnung, deren Synthese Vitamin-K-abhangig ist, wird beschrieben. Die Rolle von Vitamin K beim post-ribosomalen Einbau der neu-entdeckten Aminosaure-Car-boxyglutaminsaűre in diese Proteine wird erlautert. Der Wirkungsmechanismus der Kumarinderivat-Antikoagulantien, wird aus der Sicht neuer Forschungsergebnisse als Blockierung der Reduktion von Vitamin K-Epoxid zu einer Form dargestellt, das in dem Biosyntheseschrittaktiv ist bei dem Vorstufenprotein in den biologisch aktiven Koagulationsfaktor umgewandelt wird. Schliesslich werden die Funktionen des Vitamin K zusammenfassend besprochen, die mit der Blutgerinnung nichts zu tun haben.
Resume
La découverte, le développment, les propriétés et usages des anticoagulants à structure coumarinique sont résumés par rapport aux connaissances sur la coagulation sanguine. Sont exposées ensuite les données sur les protéines plasmatiques, indispensables à la coagulation dont la synthese est dépendante de la vitamine K. L'importance de la vitamine K pourl'incorporation post-ribosomale à ces protéines d'un acide amine, 1'acide γ-carboxyglutamique, est connue depuis peu. Le mode d'action des anticoagulants derivés de la coumarine a été révélé par de récents travaux, montrant l'effet négatif de ceux-ci sur la réduction d'un epoxide de la vitamine K, biologiquement operationnel dans l'activation des protéines précurseurs des facteurs plasmatiques de la coagulation. Le rôle de la vitamine K en dehors de l'hémostase, récemment mis en évidence, est aussi exposé.
Riassunto
La scoperta, la messa a punto e le azioni ed use degli anticoagulanti derivati dalla dicumarina sono esposti in modo riassuntivo in relazione al contemporaneo evolversi delle conoscenze del meccanismo alla base della coagulazione sanguigna. Si descrivono le attuali conoscenze del ruolo particolare attraverso il quale le proteine plasmatiche, la cui sintesi e ora riconosciuta come vitamina K-dipendente, contribuiscono al meccanismo della coagulazione. Viene stabilita l'importanza della vitamina K ai fini dell'incorporazione dell'aminoacido di recente identificazione, l'acido-carbossiglutammico, nelle suddette proteine. La modalita di azione degli anticoagulanti derivati dalla dicumarina consiste, secondo recenti ricerche, nell'impedire la riduzione della vitamina K epossido nella forma della vitamina attiva nella fase di biosintesi per cui la proteina precursore viene convertita in fattore di coagulazione biologicamente attivo. Da ultimo, si descrive brevemente la scoperta che la vitamina K puo avere funzioni diverse da quelle relative alla coagulazione del sangue.
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