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Prothrombin

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Official Full Name
Prothrombin
Background
Prothrombin is a vitamin K-dependent plasma protein which is synthesized in the liver. Prior to secretion into plasma, prothrombin undergoes post-translational modification by a vitamin K-dependent carboxylase which converts ten specific glutamic acid residues to γ-carboxyglutamic acid (gla). The ten gla residues are located within the first 40 amino acids of the mature protein and contribute to the ability of prothrombin to bind to negatively charged phospholipid membranes. Prothrombin contains two regions of internal homology which are referred to as "kringle" structures. These regions of conspicuous secondary structure are located between residues 40 and 270 of the mature plasma protein and replace the growth factor domains found in several other plasma serine proteases. Thus far, no function has been ascribed to these regions, but there is suspicion that they may play a role in one of several binary protein interactions involving prothrombin. The mature single chain protein circulates in plasma as a zymogen and, during coagulation, is proteolytically activated to the potent serine protease α-thrombin. This proteolysis is catalyzed by the prothrombinase enzyme complex. During activation, prothrombin is cleaved at Arg271-Thr272 (human) / Arg273-Thr274 (bovine) and at Arg320-Ser321 (human) / Arg323-Ser324 (bovine) to a "pro" fragment (fragment 1.2) and thrombin, the latter of which is composed of two chains covalently linked by a disulfide bond. In the case of human prothrombin/thrombin, there is an additional thrombin feed-back cleavage at Arg284-Thr285 resulting in an additional 13 amino acids being removed from the mature thrombin “A” chain. Human prothrombin is prepared from fresh frozen human plasma as described by Bajaj and coworkers. Bovine prothrombin is prepared from fresh bovine plasma using a modification of the procedure described by Owen and coworkers. Purified prothrombin is supplied in 50% (vol/vol) glycerol/H2O and should be stored at -20°C. Purity is determined by SDS-PAGE analysis, and activity is measured by clotting and/or chromogenic substrate assay, following conversion of prothrombin to thrombin.
Synonyms
Human Prothrombin; Prothrombin
Catalog Product Name EC No. CAS No. Source Price
CZY-026 Mouse Prothrombin Mouse Inquiry
CZY-025 Bovine Prothrombin Bovine Inquiry
CZY-024 Human Prethrombin-2 Human Inquiry
CZY-023 Human Prethrombin-1 Human Inquiry
CZY-022 Human Prothrombin Fragment 2 78768-79-3 Human Inquiry
CZY-021 Human Prothrombin Fragment 1.2 Human Inquiry
CZY-020 Human Prothrombin Fragment 1 72270-84-9 Human Inquiry
CZY-019 Human Prothrombin 9001-26-7 Human Inquiry

Related Reading

Introduction

Prothrombin, a glycoprotein derived from the liver, pervades a pivotal role in the coagulation cascade of hemostasis. As a precursor to thrombin, one of the most potent components of the clotting system, prothrombin acts as a linchpin in maintaining homeostasis in the body. Prothrombin, also known as coagulation factor II, is synthesized in the liver with vitamin K as a cofactor. It is a multi-domain protein that requires post-translational modifications to become a functional molecule. Once activated, it acts as a serine protease enzyme with a pivotal role in the cascade leading to blood coagulation. Monitoring prothrombin levels is vital, as deficiencies or excesses can lead to various bleeding disorders or thrombotic conditions.

Structure

Prothrombin, also known as factor II, is a glycoprotein synthesized in the liver and circulates in the blood as an inactive precursor. Structurally, prothrombin is composed of multiple domains, including an N-terminal Gla domain essential for calcium binding, two kringle domains involved in protein-protein interactions, and a catalytic serine protease domain responsible for its enzymatic activity. The presence of these domains underscores the intricate architecture of prothrombin, enabling its participation in the clotting cascade.

Functions

Primarily, prothrombin plays a crucial role in the process of blood coagulation. It undergoes enzymatic cleavage to form thrombin, which then catalyzes the conversion of fibrinogen to fibrin, paving the path for clot formation. Moreover, thrombin assists in the activation of platelets and stimulates endothelial cells, facilitating wound healing and other imperative processes impinging on vascular biology.

Mechanism

Prothrombin activation is an illustration of a proteolytic series of events that trigger homeostasis. The prothrombinase complex, composed of Factor Xa, Factor Va, calcium, and phospholipids, induces cleavage at two sites of the prothrombin molecule, generating the active enzyme thrombin. This freshly formed thrombin possesses proteolytic activity, catalyzing numerous reactions in the coagulation cascade, thereby ensuring an effective hemostatic response.

Regulation of Prothrombin Activation

Prothrombin activation is tightly regulated to prevent excessive clot formation and maintain hemostatic balance. Key regulatory mechanisms involve the intrinsic and extrinsic pathways of coagulation, where various factors, including tissue factor, Factor Xa, and thrombomodulin, modulate prothrombin activation. Furthermore, natural anticoagulants such as antithrombin and protein C inhibit thrombin activity, providing a counterbalance to prevent unchecked coagulation. The intricate regulatory network governing prothrombin activation underscores the complexity of hemostasis.

Applications

The estimation of prothrombin time and concentration is crucial in various medical applications. The most common include evaluating the efficiency of the extrinsic pathway of coagulation, examining liver functionalities, and determining the effectiveness of anticoagulant therapy, especially those targeting vitamin K. Furthermore, the prothrombin gene mutation study correlated with hypercoagulable conditions highlights its significance in genetic research too.

Clinical Significance

Clinically, levels of prothrombin are gauged using the Prothrombin Time (PT) test, used to evaluate the extrinsic clotting pathway and identify possible bleeding disorders. Increased PT may indicate conditions like vitamin K deficiency or dysfunction in the liver's synthetic ability. Additionally, prothrombin mutations are associated with an elevated risk of venous thromboembolism, thereby appreciating the genetic implication of prothrombin.

Therapeutic Targeting of Prothrombin

Pharmacological interventions targeting prothrombin aim to modulate coagulation levels in both thrombotic and bleeding disorders. Anticoagulants such as warfarin and direct oral anticoagulants (DOACs) inhibit prothrombin activation to prevent thrombus formation, reducing the risk of clot-related complications. Conversely, in cases of prothrombin deficiency, replacement therapy with prothrombin concentrates may be necessary to restore hemostatic function. The diverse therapeutic strategies targeting prothrombin underscore its significance in clinical practice.

Conclusion

In conclusion, prothrombin is more than just a building block of the coagulation cascade. It's a complex and vital component of the hemostatic system, influencing numerous aspects of vascular biology. Understanding the mechanistic action and clinical relevance of prothrombin provides a framework for diagnosing and managing several bleeding and clotting disorders. Deserving of the attention it gets, prothrombin continues to be a significant player in the field of hematology and beyond. With ongoing research, we anticipate gaining more insights into this essential protein and potentially identifying more novel roles and therapeutic targets.