User:Cody Couperus/Sandbox 1: Difference between revisions

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Further supporting coagulation, '''thrombin activates FXIII''', a [http://en.wikipedia.org/wiki/Transglutaminase transglutaminase] that crosslinks fibrin at lysine residues.

The structure of thrombin facilitates its inactivation. Once the endothelial lining is reached '''thrombin binds [http://en.wikipedia.org/wiki/Heparin heparin] [http://en.wikipedia.org/wiki/Glycosaminoglycan glycosaminoglycans]'''. This facilitates its inactivation by serpin inhibitors antithrombin and heparin cofactor II. In addition, '''thrombin will interact with [http://en.wikipedia.org/wiki/Thrombomodulin thrombomodulin]''' which significantly increases its catalytic efficiency activating protein C. Activated protein C inactivates FVIIa and FVa thus down regulating thrombin generation.

The structure of thrombin facilitates its inactivation. Once the endothelial lining is reached '''thrombin binds [http://en.wikipedia.org/wiki/Heparin heparin] and related [http://en.wikipedia.org/wiki/Glycosaminoglycan glycosaminoglycans]'''. This facilitates its inactivation by serpin inhibitors antithrombin and heparin cofactor II. In addition, '''thrombin will interact with [http://en.wikipedia.org/wiki/Thrombomodulin thrombomodulin]''' which significantly increases its catalytic efficiency activating protein C. '''Activated protein C inactivates FVIIa and FVa''' thus down regulating thrombin generation.

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'''Prothrombin is activated by prothrombinase''' which consists of FXa, FVa, calcium, and a phospholipid surface. In vivo the first cleavage occurs at the R320-I321 bond, corresponding to residues 15-16 in thrombin which is the N-terminus of the B chain, producing meizothrombin.<ref name='seven'>PMID: 22944689</ref> Subsequent cleavage at R271-T272 yields thrombin.<ref name='seven'/> The initial cleavage can also occur at R271 resulting in prethrombin-2 which will then be cleaved at R320 to produce thrombin.<ref>PMID: 1995649</ref>

After cleavage by prothrombinase the new B chain N-terminus (Ile16) folds into the core protease domain and forms a salt bridge with Asp194.<ref name='seven'/> This leads to stabilization of regions of the 180s-loop, Na+ binding loop, and γ-loop (zymogen activation domains). These changes provide the correct conformation for the S1 pocket and oxyanion hole for catalysis.<ref name='seven'/><ref>PMID: 15890651</ref>

After cleavage by prothrombinase the new B chain '''N-terminus (Ile16) folds into the core protease domain''' and forms a salt bridge with Asp194.<ref name='seven'/> This leads to stabilization of regions of the 180s-loop, Na+ binding loop, and γ-loop (zymogen activation domains). These changes provide the '''correct conformation for the S1 pocket and oxyanion hole for catalysis'''.<ref name='seven'/><ref>PMID: 15890651</ref>

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==Allostery==

Binding of thrombin by sodium or at exosite I stabilizes a form of thrombin that improves substrate recognition.<ref name='seven'/> This occurs due to energetic linkage between these sites to the S1 binding pocket and oxyanion hole. Rapid kinetic analysis suggests that thrombin is in a dynamic equilibrium that consists of a fast, slow, and inactive state<ref name='seven'/>. There is question as to the physiologic relevance of the inactive state. Regardless, there will be a proportion of fast:slow thrombin and sodium binding to the fast form stabilizes that conformation. Indeed, mutation of the residues involved in sodium binding diminishes the activity of thrombin.<ref name='seven'/> It should be restated, that current data suggest that sodium binding does not induce a conformation change, rather, it stabilizes a conformation of thrombin that has greater activity.

Binding of thrombin by sodium or at exosite I stabilizes a form of thrombin that improves substrate recognition.<ref name='seven'/> This occurs due to energetic linkage between these sites to the S1 binding pocket and oxyanion hole. Rapid kinetic analysis suggests that '''thrombin is in a dynamic equilibrium that consists of a fast, slow, and inactive state'''<ref name='seven'/>. There is question as to the physiologic relevance of the inactive state. Regardless, there will be a proportion of fast:slow thrombin and sodium binding to the fast form stabilizes that conformation. Indeed, mutation of the residues involved in sodium binding diminishes the activity of thrombin.<ref name='seven'/> ''It should be restated, that current data suggest that sodium binding does not induce a conformation change, rather, it stabilizes a conformation of thrombin that has greater activity.''

==Regulation and Inhibition==

@@ Line 30: / Line 30: @@
 Further supporting coagulation, '''thrombin activates FXIII''', a [http://en.wikipedia.org/wiki/Transglutaminase transglutaminase] that crosslinks fibrin at lysine residues.
-The structure of thrombin facilitates its inactivation. Once the endothelial lining is reached '''thrombin binds [http://en.wikipedia.org/wiki/Heparin heparin] [http://en.wikipedia.org/wiki/Glycosaminoglycan glycosaminoglycans]'''. This facilitates its inactivation by serpin inhibitors antithrombin and heparin cofactor II. In addition, '''thrombin will interact with [http://en.wikipedia.org/wiki/Thrombomodulin thrombomodulin]''' which significantly increases its catalytic efficiency activating protein C. Activated protein C inactivates FVIIa and FVa thus down regulating thrombin generation.
+The structure of thrombin facilitates its inactivation. Once the endothelial lining is reached '''thrombin binds [http://en.wikipedia.org/wiki/Heparin heparin] and related [http://en.wikipedia.org/wiki/Glycosaminoglycan glycosaminoglycans]'''. This facilitates its inactivation by serpin inhibitors antithrombin and heparin cofactor II. In addition, '''thrombin will interact with [http://en.wikipedia.org/wiki/Thrombomodulin thrombomodulin]''' which significantly increases its catalytic efficiency activating protein C. '''Activated protein C inactivates FVIIa and FVa''' thus down regulating thrombin generation.
@@ Line 42: / Line 42: @@
 '''Prothrombin is activated by prothrombinase''' which consists of FXa, FVa, calcium, and a phospholipid surface. In vivo the first cleavage occurs at the R320-I321 bond, corresponding to residues 15-16 in thrombin which is the N-terminus of the B chain, producing meizothrombin.<ref name='seven'>PMID: 22944689</ref> Subsequent cleavage at R271-T272 yields thrombin.<ref name='seven'/> The initial cleavage can also occur at R271 resulting in prethrombin-2 which will then be cleaved at R320 to produce thrombin.<ref>PMID: 1995649</ref>
-After cleavage by prothrombinase the new B chain N-terminus (Ile16) folds into the core protease domain and forms a salt bridge with Asp194.<ref name='seven'/> This leads to stabilization of regions of the 180s-loop, Na+ binding loop, and γ-loop (zymogen activation domains). These changes provide the correct conformation for the S1 pocket and oxyanion hole for catalysis.<ref name='seven'/><ref>PMID: 15890651</ref>
+After cleavage by prothrombinase the new B chain '''N-terminus (Ile16) folds into the core protease domain''' and forms a salt bridge with Asp194.<ref name='seven'/> This leads to stabilization of regions of the 180s-loop, Na+ binding loop, and γ-loop (zymogen activation domains). These changes provide the '''correct conformation for the S1 pocket and oxyanion hole for catalysis'''.<ref name='seven'/><ref>PMID: 15890651</ref>
@@ Line 72: / Line 72: @@
 ==Allostery==
-Binding of thrombin by sodium or at exosite I stabilizes a form of thrombin that improves substrate recognition.<ref name='seven'/> This occurs due to energetic linkage between these sites to the S1 binding pocket and oxyanion hole. Rapid kinetic analysis suggests that thrombin is in a dynamic equilibrium that consists of a fast, slow, and inactive state<ref name='seven'/>. There is question as to the physiologic relevance of the inactive state. Regardless, there will be a proportion of fast:slow thrombin and sodium binding to the fast form stabilizes that conformation. Indeed, mutation of the residues involved in sodium binding diminishes the activity of thrombin.<ref name='seven'/> It should be restated, that current data suggest that sodium binding does not induce a conformation change, rather, it stabilizes a conformation of thrombin that has greater activity.
+Binding of thrombin by sodium or at exosite I stabilizes a form of thrombin that improves substrate recognition.<ref name='seven'/> This occurs due to energetic linkage between these sites to the S1 binding pocket and oxyanion hole. Rapid kinetic analysis suggests that '''thrombin is in a dynamic equilibrium that consists of a fast, slow, and inactive state'''<ref name='seven'/>. There is question as to the physiologic relevance of the inactive state. Regardless, there will be a proportion of fast:slow thrombin and sodium binding to the fast form stabilizes that conformation. Indeed, mutation of the residues involved in sodium binding diminishes the activity of thrombin.<ref name='seven'/> ''It should be restated, that current data suggest that sodium binding does not induce a conformation change, rather, it stabilizes a conformation of thrombin that has greater activity.''
 ==Regulation and Inhibition==