TY - JOUR
T1 - Mutants of human tissue-type plasminogen activator (t-PA)
T2 - Structural aspects and functional properties
AU - Pannekoek, H.
AU - de Vries, C.
AU - van Zonneveld, A. J.
N1 - Funding Information: The authors wish to express their gratitude to their colleagues Departments of Molecular Biology and Blood Coagulation institute for inspiring discussions, concerning this manuscript. of this work is supported by the Netherlands Foundation of ical Research MEDIGON (grant no. 13-30/70).
PY - 1988/7
Y1 - 1988/7
N2 - This review summarises our knowledge about the rapidly developing field of studies on the structure and function of human tissue-type plasminogen activator (t-PA). The overwhelming interest in this area is obviously related to the application of this fibrinolytic enzyme in the treatment of thrombo-embolic disorders. At present, t-PA is favoured as thrombolytic agent above other compounds, because of its preferential action at the surface of thrombi and its relatively low activity in the circulation. Currently, intravenous injections of approximately 100 mg of recombinant t-PA (rt-PA) are administered to patients, suffering from myocardial infarction, leading to transient plasma concentrations several orders of magnitude higher than the physiological concentration.1-3 The necessity to administer such a vast, effective dose of t-PA is directly related to its short half-life in humans (3-6 min4-6). Rapid clearing of t-PA from plasma is attributed mainly to interaction of t-PA with a high-affinity receptor in the liver7,8 (and reviewed in the following paper9) and, possibly to some extent, by complex formation with inhibitors. The high concentrations of t-PA, required to effectively achieve lysis of thrombi, may lead to unwanted systemic reactions that potentially can cause bleeding. Consequently, such observations have inspired many investigators to initiate extensive studies on the structure of t-PA and its function in the fibrinolytic process. Recombinant DNA techniques have been proven to be highly effective tools to construct and express variant proteins that can be structurally and functionally assessed in vitro and in vivo. Our aim is to discuss the recent scientific progress in this area and is restricted to the in vitro properties of t-PA, rt-PA and molecular variants thereof. We have also attempted to indicate some of the 'gaps' in our knowledge on the mechanism of action of t-PA in the fibrinolytic process. Finally, we have compiled a number of arguments that illustrate the problems in comparing the properties of different rt-PA preparations, due to the choice of either the expression cell line or the assay system. The data mentioned in this review have been published or are in press in scientific journals and have been subjected to the review system of those particular journals.
AB - This review summarises our knowledge about the rapidly developing field of studies on the structure and function of human tissue-type plasminogen activator (t-PA). The overwhelming interest in this area is obviously related to the application of this fibrinolytic enzyme in the treatment of thrombo-embolic disorders. At present, t-PA is favoured as thrombolytic agent above other compounds, because of its preferential action at the surface of thrombi and its relatively low activity in the circulation. Currently, intravenous injections of approximately 100 mg of recombinant t-PA (rt-PA) are administered to patients, suffering from myocardial infarction, leading to transient plasma concentrations several orders of magnitude higher than the physiological concentration.1-3 The necessity to administer such a vast, effective dose of t-PA is directly related to its short half-life in humans (3-6 min4-6). Rapid clearing of t-PA from plasma is attributed mainly to interaction of t-PA with a high-affinity receptor in the liver7,8 (and reviewed in the following paper9) and, possibly to some extent, by complex formation with inhibitors. The high concentrations of t-PA, required to effectively achieve lysis of thrombi, may lead to unwanted systemic reactions that potentially can cause bleeding. Consequently, such observations have inspired many investigators to initiate extensive studies on the structure of t-PA and its function in the fibrinolytic process. Recombinant DNA techniques have been proven to be highly effective tools to construct and express variant proteins that can be structurally and functionally assessed in vitro and in vivo. Our aim is to discuss the recent scientific progress in this area and is restricted to the in vitro properties of t-PA, rt-PA and molecular variants thereof. We have also attempted to indicate some of the 'gaps' in our knowledge on the mechanism of action of t-PA in the fibrinolytic process. Finally, we have compiled a number of arguments that illustrate the problems in comparing the properties of different rt-PA preparations, due to the choice of either the expression cell line or the assay system. The data mentioned in this review have been published or are in press in scientific journals and have been subjected to the review system of those particular journals.
KW - Function of t-PA
KW - Mutants of t-PA
KW - Structure of t-PA
KW - Tissue-type plasminogen activator
KW - Urokinase
UR - http://www.scopus.com/inward/record.url?scp=0023878126&partnerID=8YFLogxK
U2 - https://doi.org/10.1016/0268-9499(88)90025-2
DO - https://doi.org/10.1016/0268-9499(88)90025-2
M3 - Review article
SN - 0268-9499
VL - 2
SP - 123
EP - 132
JO - Fibrinolysis and Proteolysis
JF - Fibrinolysis and Proteolysis
IS - 3
ER -