ADAMTS13: Difference between revisions

Latest revision as of 06:11, 11 December 2024

ADAMTS13

ADAMTS13 is a zinc-containing metalloprotease enzyme that plays a crucial role in the regulation of blood coagulation. It is part of the ADAMTS (A Disintegrin And Metalloproteinase with Thrombospondin Motifs) family of proteins, which are involved in various biological processes, including coagulation, inflammation, and tissue remodeling.

Structure and Function[edit]

ADAMTS13 is primarily synthesized in the liver and circulates in the plasma. It is responsible for cleaving von Willebrand factor (vWF), a large multimeric protein that is essential for platelet adhesion and aggregation at sites of vascular injury. By cleaving vWF, ADAMTS13 regulates its size and activity, preventing excessive platelet aggregation and thrombus formation.

The enzyme specifically cleaves the Tyr1605-Met1606 bond in the A2 domain of vWF. This action reduces the size of vWF multimers, which are otherwise highly thrombogenic. The regulation of vWF by ADAMTS13 is critical for maintaining hemostatic balance.

Clinical Significance[edit]

Deficiency or dysfunction of ADAMTS13 is associated with a rare but serious condition known as Thrombotic Thrombocytopenic Purpura (TTP). TTP is characterized by the formation of small blood clots throughout the body, leading to thrombocytopenia, hemolytic anemia, and organ damage. There are two main types of TTP:

Congenital TTP (Upshaw-Schulman syndrome): Caused by inherited mutations in the ADAMTS13 gene, leading to a severe deficiency of the enzyme.
Acquired TTP: Often due to the development of autoantibodies against ADAMTS13, inhibiting its activity.

Diagnosis of TTP involves measuring ADAMTS13 activity levels and detecting the presence of inhibitors. Treatment typically includes plasma exchange and immunosuppressive therapy to remove inhibitors and restore enzyme activity.

Genetics[edit]

The ADAMTS13 gene is located on chromosome 9q34.2. Mutations in this gene can lead to congenital TTP. The gene encodes a protein of 1427 amino acids, which includes a signal peptide, a propeptide, a metalloprotease domain, a disintegrin-like domain, a thrombospondin type 1 motif, and other domains that contribute to its function and regulation.

Research and Developments[edit]

Ongoing research is focused on understanding the detailed mechanisms of ADAMTS13 function and regulation, as well as developing novel therapies for TTP. Recombinant ADAMTS13 and gene therapy are being explored as potential treatments for patients with congenital TTP.

Also see[edit]

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-<br>== ADAMTS13 ==
+ADAMTS13
-'''ADAMTS13''' (A Disintegrin and Metalloproteinase with Thrombospondin Motifs 13) is an enzyme that plays a crucial role in the regulation of blood clotting. It is a member of the ADAMTS family of proteins, which are characterized by their disintegrin and metalloproteinase domains, as well as thrombospondin type 1 motifs. ADAMTS13 is primarily known for its role in cleaving von Willebrand factor (vWF), a large multimeric protein that is essential for platelet adhesion and aggregation at sites of vascular injury.
+ADAMTS13 is a zinc-containing metalloprotease enzyme that plays a crucial role in the regulation of blood coagulation. It is part of the ADAMTS (A Disintegrin And Metalloproteinase with Thrombospondin Motifs) family of proteins, which are involved in various biological processes, including coagulation, inflammation, and tissue remodeling.
-== Structure ==
+==Structure and Function==
+ADAMTS13 is primarily synthesized in the liver and circulates in the plasma. It is responsible for cleaving von Willebrand factor (vWF), a large multimeric protein that is essential for platelet adhesion and aggregation at sites of vascular injury. By cleaving vWF, ADAMTS13 regulates its size and activity, preventing excessive platelet aggregation and thrombus formation.
-ADAMTS13 is a zinc-containing metalloprotease that is synthesized as a preproenzyme. It consists of several distinct domains:
+The enzyme specifically cleaves the Tyr1605-Met1606 bond in the A2 domain of vWF. This action reduces the size of vWF multimers, which are otherwise highly thrombogenic. The regulation of vWF by ADAMTS13 is critical for maintaining hemostatic balance.
-* A signal peptide that directs the nascent protein to the secretory pathway.
+==Clinical Significance==
-* A propeptide that is cleaved to activate the enzyme.
+Deficiency or dysfunction of ADAMTS13 is associated with a rare but serious condition known as [[Thrombotic Thrombocytopenic Purpura]] (TTP). TTP is characterized by the formation of small blood clots throughout the body, leading to thrombocytopenia, hemolytic anemia, and organ damage. There are two main types of TTP:
-* A metalloprotease domain that contains the active site.
-* A disintegrin-like domain.
-* A thrombospondin type 1 repeat (TSP1) domain.
-* A cysteine-rich domain.
-* A spacer domain.
-* Additional TSP1 repeats.
-* Two CUB domains at the C-terminus.
-== Function ==
+* '''Congenital TTP (Upshaw-Schulman syndrome):''' Caused by inherited mutations in the ADAMTS13 gene, leading to a severe deficiency of the enzyme.
+* '''Acquired TTP:''' Often due to the development of autoantibodies against ADAMTS13, inhibiting its activity.
-The primary function of ADAMTS13 is to cleave von Willebrand factor (vWF) at the Tyr1605-Met1606 bond in the A2 domain. This cleavage reduces the size of vWF multimers, which is essential for regulating their prothrombotic activity. Large vWF multimers are highly active in promoting platelet adhesion and aggregation, and their excessive accumulation can lead to pathological clot formation.
+Diagnosis of TTP involves measuring ADAMTS13 activity levels and detecting the presence of inhibitors. Treatment typically includes plasma exchange and immunosuppressive therapy to remove inhibitors and restore enzyme activity.
-== Clinical Significance ==
+==Genetics==
+The ADAMTS13 gene is located on chromosome 9q34.2. Mutations in this gene can lead to congenital TTP. The gene encodes a protein of 1427 amino acids, which includes a signal peptide, a propeptide, a metalloprotease domain, a disintegrin-like domain, a thrombospondin type 1 motif, and other domains that contribute to its function and regulation.
-Deficiency or dysfunction of ADAMTS13 is associated with thrombotic thrombocytopenic purpura (TTP), a rare but life-threatening disorder characterized by microangiopathic hemolytic anemia, thrombocytopenia, renal dysfunction, neurological symptoms, and fever. TTP can be hereditary, due to mutations in the ADAMTS13 gene, or acquired, often due to the development of inhibitory autoantibodies against ADAMTS13.
+==Research and Developments==
+Ongoing research is focused on understanding the detailed mechanisms of ADAMTS13 function and regulation, as well as developing novel therapies for TTP. Recombinant ADAMTS13 and gene therapy are being explored as potential treatments for patients with congenital TTP.
-=== Hereditary TTP ===
+==Also see==
+* [[Von Willebrand factor]]
+* [[Thrombotic Thrombocytopenic Purpura]]
+* [[Coagulation]]
+* [[Metalloprotease]]
-Hereditary TTP, also known as Upshaw-Schulman syndrome, is caused by mutations in the ADAMTS13 gene that lead to reduced enzyme activity. Patients with hereditary TTP typically present with episodes of microangiopathic hemolytic anemia and thrombocytopenia, often triggered by infections or other stressors.
+{{Enzyme-stub}}
+{{Medical-stub}}
-=== Acquired TTP ===
-Acquired TTP is more common and is usually caused by the development of autoantibodies that inhibit ADAMTS13 activity. This form of TTP can occur idiopathically or in association with other conditions such as autoimmune diseases, infections, or certain medications.
-== Diagnosis and Treatment ==
-The diagnosis of TTP involves clinical assessment and laboratory tests, including measurement of ADAMTS13 activity and the presence of ADAMTS13 inhibitors. A severe deficiency of ADAMTS13 activity (<10% of normal) is highly suggestive of TTP.
-Treatment of TTP typically involves plasma exchange therapy, which removes inhibitory antibodies and replenishes functional ADAMTS13. Immunosuppressive therapies, such as corticosteroids and rituximab, may also be used to reduce antibody production.
-== Research and Future Directions ==
-Ongoing research is focused on better understanding the regulation of ADAMTS13 activity, the mechanisms underlying the development of inhibitory antibodies, and the development of novel therapeutic approaches for TTP. Gene therapy and recombinant ADAMTS13 are potential future treatments that are currently under investigation.
-== References ==
-* Zheng, X. L., & Sadler, J. E. (2008). Pathogenesis of thrombotic microangiopathies. Annual Review of Pathology: Mechanisms of Disease, 3, 249-277.
-* Furlan, M., Robles, R., & Lämmle, B. (1998). Partial purification and characterization of a protease from human plasma cleaving von Willebrand factor to fragments produced by in vivo proteolysis. Blood, 91(10), 2839-2846.
-* Tsai, H. M. (2003). Advances in the pathogenesis, diagnosis, and treatment of thrombotic thrombocytopenic purpura. Journal of the American Society of Nephrology, 14(4), 1072-1081.
 [[Category:Enzymes]]
-[[Category:Blood proteins]]
+[[Category:Coagulation system]]
-[[Category:Thrombosis]]
+[[Category:Proteases]]
+[[Category:Human proteins]]