Vampire bat salivary plasminogen activator exhibits a strict and fastidious requirement for polymeric fibrin as its cofactor, unlike human tissue-type plasminogen activator. A kinetic analysis.
05 Sep 1992-Journal of Biological Chemistry (American Society for Biochemistry and Molecular Biology)-Vol. 267, Iss: 25, pp 17726-17731
TL;DR: The data revealed that BatPA, unlike tPA, displayed a strict and fastidious requirement for polymeric fibrin I or II, Consequently, BatPA may preferentially promote plasmin generation during a narrow temporal window offibrin formation and dissolution.
About: This article is published in Journal of Biological Chemistry.The article was published on 1992-09-05 and is currently open access. It has received 38 citations till now. The article focuses on the topics: Plasmin & Plasminogen activator.
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TL;DR: Delayed thrombolysis amongst patients selected according to mismatch imaging is associated with increased reperfusion/recanalization, but delayed treatment, even according to mismatch selection, cannot be recommended as part of routine care.
Abstract: Background and Purpose— Clinical benefit from thrombolysis is reduced as stroke onset to treatment time increases. The use of “mismatch” imaging to identify patients for delayed treatment has face validity and has been used in case series and clinical trials. We undertook a meta-analysis of relevant trials to examine whether present evidence supports delayed thrombolysis among patients selected according to mismatch criteria. Methods— We collated outcome data for patients who were enrolled after 3 hours of stroke onset in thrombolysis trials and had mismatch on pretreatment imaging. We selected the trials on the basis of a systematic search of the Web of Knowledge. We compared favorable outcome, reperfusion and/or recanalization, mortality, and symptomatic intracerebral hemorrhage between the thrombolyzed and nonthrombolyzed groups of patients and the probability of a favorable outcome among patients with successful reperfusion and clinical findings for 3 to 6 versus 6 to 9 hours from poststroke onset. Re...
178 citations
TL;DR: Exogenously administered recombinant tPA and endogenous tPA have both turned into promising therapeutic targets for the stroke patient and their implications for further development of tPA as a stroke therapeutic are reviewed.
Abstract: Background: Ischemic stroke is a leading cause of morbidity and mortality worldwide and recombinant human tissue-type plasminogen activator (tPA) is the prominent therapeutic among very few therapeutics used in its treatment. Due to complications attributed to the drug, most notably transformation of ischemia to hemorrhage, tPA is only used in a small number of ischemic stroke cases, albeit significantly more often in specialized stroke centers. Objective: What are the mechanisms of tPA action and side effects in ischemic stroke, and can the knowledge about these mechanisms aid in making tPA a more efficacious and safe therapeutic or in developing alternative therapeutics? Methods: tPA use and alternative/combination therapies in acute ischemic stroke treatment are summarized. The review focuses on literature concerning tPA neurotoxicity and its implications for further development of tPA as a stroke therapeutic. Results/conclusion: Exogenously administered recombinant tPA and endogenous tPA have both tur...
105 citations
Cites background from "Vampire bat salivary plasminogen ac..."
...It has a much higher fibrin specificity compared to tPA [61] and does not share neurotoxic properties attributed to tPA in mice [62] ....
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TL;DR: Although this chapter does not represent a historical review, it will be clear how the biochemistry of t- PA, u-PA, PAI-1 andPAI-2 has evolved and where they stand in 1994.
Abstract: Summary Although this chapter does not represent a historical review, it will be clear how the biochemistry of t-PA, u-PA, PAI-1 and PAI-2 has evolved and where we stand in 1994. While the functional activities of the proteins were recognized at least three to four decades ago, highly purified preparations became available around 1980. In the mid-eighties the cDNAs of the proteins were cloned, representing a major breakthrough in the biochemistry of the four proteins. Amino acid sequences were derived from the nucleotide sequences, homologies with other proteins were recognized and larger amounts of (recombinant) proteins became available for research. In addition, mutant proteins were prepared by recombinant DNA technology, enabling investigation of structure-function relationships. This report is mainly based on the latter studies. Detailed information about three-dimensional structures of the proteins and the mode of interaction with other macromolecules is still lacking. To obtain this information will be the goal for biochemists in the coming years.
93 citations
TL;DR: These findings transcend the current understanding of fibrin-mediated stimulation of plasminogen activation: in addition to fibrIn binding, specific protein-protein interactions come into play, which stabilize the enzyme in its active conformation.
86 citations
TL;DR: This review surveys pharmacological approaches currently undergoing evaluation which provide the goal of establishing effective strategies for the treatment of patients with acute cerebral ischaemia.
Abstract: Stroke stands as the third leading cause of death. It makes great demands on patients, who must not only survive the complications of the acute stages, but must cope then with the great physical and economic costs of long-term disabilities. Therefore, there is urgent need to establish generally useful regimens for the acute treatment of ischaemic stroke. Three treatment approaches are based upon pathophysiologic concepts derived from experimental work with focal cerebral ischaemia. These include pharmacologic strategies for arterial recanalisation, inhibition of inflammatory processes and neural protection. Focal cerebral ischaemia secondary to occlusion of a brain-supplying artery initiates neuronal and microvascular events, and the simultaneous processes of inflammation which further injure tissue. The use of plasminogen activators to mediate thrombus and lysis in the acute setting has been shown to be clinically beneficial. Further work with arterial reperfusion strategies is under way. Early clinical studies with polymorphonuclear leukocyte-dependent endothelial adhesion receptor antagonists are being completed, but a strategy has yet to emerge. A large effort examining the potential efficacy of agents which may stabilise or protect neurons from ischaemic injury has shown promise in experimental models, and has been translated into clinical trials. Experimental work, and limited clinical experience, have indicated that: (a) the time window for intervention is important in limiting ischaemic and inflammatory injury, and for reducing the risk of haemorrhagic transformation; (b) putative neuroprotective strategies may potentially elongate the time interval for treatment; and (c) limitations from the adverse effects of plasminogen activators and of agents which beneficially affect neuronal dysfunction during ischaemia must yet be overcome. This review surveys pharmacological approaches currently undergoing evaluation which provide the goal of establishing effective strategies for the treatment of patients with acute cerebral ischaemia.
69 citations
References
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TL;DR: The kinetic analysis suggested that the activation in the presence of fibrin occurs through binding of an activator molecule to the clot surface and subsequent addition of plasminogen (sequential ordered mechanism) to form a cyclic ternary complex.
1,223 citations
TL;DR: Bacterial clones containing human tissue-type plasminogen activator cDNA sequences were identified in a cDNA library prepared using gel-fractionated mRNA from human melanoma cells and a polypeptide was produced having the fibrinolytic properties characteristic of authentic human t-PA.
Abstract: Bacterial clones containing human tissue-type plasminogen activator (t-PA) cDNA sequences were identified in a cDNA library prepared using gel-fractionated mRNA from human melanoma cells. A plasmid containing the Escherichia coli trp promoter and the cDNA sequence coding f or the 527-amino acid mature t-PA protein was constructed for expression in E. coli. A polypeptide was produced having the fibrinolytic properties characteristic of authentic human t-PA.
1,219 citations
TL;DR: Comparisons of amino acid sequences, three-dimensional structures, and enzymatic reaction mechanisms of proteases indicate that there are distinct families of these proteins.
Abstract: Proteolytic enzymes have many physiological functions, ranging from generalized protein digestion to more specific regulated processes such as the activation of zymogens, blood coagulation and the lysis of fibrin clots, the release of hormones and pharmacologically active peptides from precursor proteins, and the transport of secretory proteins across membranes. They are present in all forms of living organisms. Comparisons of amino acid sequences, three-dimensional structures, and enzymatic reaction mechanisms of proteases indicate that there are distinct families of these proteins. Changes in molecular structure and function have accompanied the evolution of proteolytic enzymes and their inhibitors, each having relatively simple roles in primitive organisms and more diverse and more complex functions in higher organisms.
618 citations
TL;DR: A lysine-binding site is involved in the interaction of the kringle-2 domain with fibrin but not in the interactions of the finger domain withFibrin, which suggests that tissue-type plasminogen activation by t-PA is mediated by two distinct interactions.
248 citations