UniProt functional annotation for Q56VR3



	UniProt functional annotation for Q56VR3

UniProt code: Q56VR3.

Organism: Pseudonaja textilis (Eastern brown snake).

Taxonomy: Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Lepidosauria; Squamata; Bifurcata; Unidentata; Episquamata; Toxicofera; Serpentes; Colubroidea; Elapidae; Acanthophiinae; Pseudonaja.

Function: Snake prothrombin activator that attacks the hemostatic system of prey. This non-catalytic subunit is functionally similar to blood coagulation factor V (PubMed:12362232, PubMed:23869089). It serves as a critical cofactor for the prothrombinase activity of the catalytic subunit, which is similar to the blood coagulation factor X (PubMed:12362232, PubMed:23869089). The complex converts prothrombin to thrombin by sequential cleavage at two positions, Arg-320 followed by Arg-271 (PubMed:23869089). Cleavage at Arg-320 produces an active intermediate known as meizothrombin (PubMed:23869089). Meizothrombin is the 'second' substrate for prothrombinase, and it docks in an altered manner to present the second cleavage site (271) (PubMed:23869089). Cleavage at Arg-271 releases active thrombin from its pro-fragment (PubMed:23869089). This order of events is reversed if the protease component of prothrombinase is used on its own, suggesting that the 271 site is inherently more accessible to proteolysis (PubMed:23869089). The complex converts prothrombin to thrombin in presence but also in the absence of membrane (PubMed:23869089). {ECO:0000269|PubMed:12362232, ECO:0000269|PubMed:23869089}.

Catalytic activity: Reaction=Selective cleavage of Arg-|-Thr and then Arg-|-Ile bonds in prothrombin to form thrombin.; EC=3.4.21.6; Evidence={ECO:0000269|PubMed:12362232, ECO:0000269|PubMed:23869089};

Activity regulation: Activated by calcium and negatively charged phospholipids. {ECO:0000269|PubMed:12362232, ECO:0000269|PubMed:23869089}.

Subunit: Heterodimer of a light and a heavy chains; disulfide-linked. Is associated with pseutarin-C non-catalytic subunit (AC Q7SZN0) in a non-covalent manner. {ECO:0000269|PubMed:12362232, ECO:0000269|PubMed:23869089, ECO:0000269|PubMed:3075905}.

Subcellular location: Secreted {ECO:0000269|PubMed:12362232, ECO:0000269|PubMed:3075905}.

Tissue specificity: Expressed by the venom gland. {ECO:0000269|PubMed:12362232, ECO:0000269|PubMed:3075905}.

Ptm: Gamma-carboxyglutamate residues are formed by vitamin K dependent carboxylation. These residues are essential for the binding of calcium. {ECO:0000255|PROSITE-ProRule:PRU00463, ECO:0000269|PubMed:12362232}.

Toxic dose: Intravenous injection (23 ug/kg bodyweight) of the group C prothrombin activator causes death in rats through disseminated intravascular coagulopathy (PubMed:3075905), whereas pseutarin-C is not lethal even at 10 mg/kg in mice when injected intraperitoneally (PubMed:15351847). {ECO:0000269|PubMed:15351847, ECO:0000269|PubMed:3075905}.

Pharmaceutical: Is under preclinical trial by the Australian biopharmaceutical company QRxPharma Ltd, its subsidiary Venomics Pty Ltd (VPL) and the University of Queensland (UQ) under the name Haempatch (Q8009). Tested as a topical hemostatic agent to reduce blood loss resulting from surgery or trauma.

Miscellaneous: Is classified in the group C of snake venom prothrombin activators, since it does not require the mammalian factor Va for the cleavage of prothrombin as the venom contains its own non-catalytic factor Va-like molecule. {ECO:0000305|PubMed:21184772}.

Miscellaneous: In contrast to blood coagulation factors that circulate as inactive zymogen in plasma, venom prothrombin activators are always found in the active form in the venom. Hence, catalytic and non- catalytic subunits are found naturally in venom as stable complexes.

Similarity: Belongs to the peptidase S1 family. Snake venom subfamily. {ECO:0000255|PROSITE-ProRule:PRU00274}.

Annotations taken from UniProtKB at the EBI.


Organism:		Pseudonaja textilis (Eastern brown snake).
Taxonomy:		Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Lepidosauria; Squamata; Bifurcata; Unidentata; Episquamata; Toxicofera; Serpentes; Colubroidea; Elapidae; Acanthophiinae; Pseudonaja.



Function:		Snake prothrombin activator that attacks the hemostatic system of prey. This non-catalytic subunit is functionally similar to blood coagulation factor V (PubMed:12362232, PubMed:23869089). It serves as a critical cofactor for the prothrombinase activity of the catalytic subunit, which is similar to the blood coagulation factor X (PubMed:12362232, PubMed:23869089). The complex converts prothrombin to thrombin by sequential cleavage at two positions, Arg-320 followed by Arg-271 (PubMed:23869089). Cleavage at Arg-320 produces an active intermediate known as meizothrombin (PubMed:23869089). Meizothrombin is the 'second' substrate for prothrombinase, and it docks in an altered manner to present the second cleavage site (271) (PubMed:23869089). Cleavage at Arg-271 releases active thrombin from its pro-fragment (PubMed:23869089). This order of events is reversed if the protease component of prothrombinase is used on its own, suggesting that the 271 site is inherently more accessible to proteolysis (PubMed:23869089). The complex converts prothrombin to thrombin in presence but also in the absence of membrane (PubMed:23869089). {ECO:0000269\|PubMed:12362232, ECO:0000269\|PubMed:23869089}.


Catalytic activity:		Reaction=Selective cleavage of Arg-\|-Thr and then Arg-\|-Ile bonds in prothrombin to form thrombin.; EC=3.4.21.6; Evidence={ECO:0000269\|PubMed:12362232, ECO:0000269\|PubMed:23869089};
Activity regulation:		Activated by calcium and negatively charged phospholipids. {ECO:0000269\|PubMed:12362232, ECO:0000269\|PubMed:23869089}.
Subunit:		Heterodimer of a light and a heavy chains; disulfide-linked. Is associated with pseutarin-C non-catalytic subunit (AC Q7SZN0) in a non-covalent manner. {ECO:0000269\|PubMed:12362232, ECO:0000269\|PubMed:23869089, ECO:0000269\|PubMed:3075905}.
Subcellular location:		Secreted {ECO:0000269\|PubMed:12362232, ECO:0000269\|PubMed:3075905}.
Tissue specificity:		Expressed by the venom gland. {ECO:0000269\|PubMed:12362232, ECO:0000269\|PubMed:3075905}.
Ptm:		Gamma-carboxyglutamate residues are formed by vitamin K dependent carboxylation. These residues are essential for the binding of calcium. {ECO:0000255\|PROSITE-ProRule:PRU00463, ECO:0000269\|PubMed:12362232}.
Toxic dose:		Intravenous injection (23 ug/kg bodyweight) of the group C prothrombin activator causes death in rats through disseminated intravascular coagulopathy (PubMed:3075905), whereas pseutarin-C is not lethal even at 10 mg/kg in mice when injected intraperitoneally (PubMed:15351847). {ECO:0000269\|PubMed:15351847, ECO:0000269\|PubMed:3075905}.
Pharmaceutical:		Is under preclinical trial by the Australian biopharmaceutical company QRxPharma Ltd, its subsidiary Venomics Pty Ltd (VPL) and the University of Queensland (UQ) under the name Haempatch (Q8009). Tested as a topical hemostatic agent to reduce blood loss resulting from surgery or trauma.
Miscellaneous:		Is classified in the group C of snake venom prothrombin activators, since it does not require the mammalian factor Va for the cleavage of prothrombin as the venom contains its own non-catalytic factor Va-like molecule. {ECO:0000305\|PubMed:21184772}.
Miscellaneous:		In contrast to blood coagulation factors that circulate as inactive zymogen in plasma, venom prothrombin activators are always found in the active form in the venom. Hence, catalytic and non- catalytic subunits are found naturally in venom as stable complexes.
Similarity:		Belongs to the peptidase S1 family. Snake venom subfamily. {ECO:0000255\|PROSITE-ProRule:PRU00274}.