clinical aspects of biochemistry proteins and disease blood clotting enzymes
DESCRIPTION
Clinical Aspects of Biochemistry Proteins and Disease Blood clotting enzymes. Blood clotting. 1. Platelet aggregation 2. Constriction of injured vessels 3. Fibrin formation. THE CLOTTING CASCADE - A SIMPLE VIEW. FIBRIN FIBRE. FIBRINOGEN - FIBRIN CONVERSION. ~450Å. FIBRINOGEN. - PowerPoint PPT PresentationTRANSCRIPT
Clinical Aspects of Biochemistry
Proteins and Disease
Blood clotting enzymes
Blood clotting
1. Platelet aggregation
2. Constriction of injured vessels
3. Fibrin formation
THE CLOTTING CASCADE - A SIMPLE VIEW
FIBRIN FIBRE
FIBRINOGEN - FIBRIN CONVERSION
FIBRINOGEN
~450ÅFrom Voigt & Voigt
FIBRINOGEN - POLYPEPTIDE CHAIN ORGANIZATION
From Voigt & Voigt
FIBRIN AGGREGATION
From Voigt & Voigt
Transamidase (Factor XIIIa)
Gln
Lys
CROSSLINKING FIBRIN
From Stryer
-carboxy glutamic acid (Gla):• ~10 residues near N-terminus of prothrombin• also found in other enzymes of clotting cascade• synthesis requires vitamin K (antagonised by dicoumarol and warfarin)• facilitates binding to Ca2+ and membrane localisation
PROTHROMBIN
Factor X (Stuart factor)• Glycoprotein. Mr 55,000• L chain (16.5K) and H chain (39K) joined by S-S bridge. ‘Pro’ bit stays attached after activation• Activated by cleavage of 51 residues from N-terminus of H chain by factor IXa + factor VIII + Ca2+ + phospholipid or factor VIIa + tissue factor
Factor IX (Christmas factor)• Glycoprotein. Mr 55,000• ~ 15% of haemophilia• Activated by removal of 11K fragment from factor XIa:
27K
S S
17K
11KIXa:
FACTOR VIII (antihaemophilia factor)
Lack of factor VIII causes haemophilia A - 70-80% of all haemophiliaProtein of 2351 aas; gene ~186,000 bp:.
From Stryer
CONTROL OF CLOTTING
1. Dilution and localisation
2. Antithrombin (58K protein; a serpin)
3. Heparin (sulphated glycosaminoglycan)
4. Protein C (zymogen; activated by thrombin)
5. Thrombomodulin (74K glycoprotein)
[hirudin - leeches]
INTRINSIC PATHWAY - FEEDBACK
CLOT LYSIS
Plasmin:• a serine protease (trypsin like) which specifically breaks down fibrin• formed from plasminogen (86K protein), by action of other proteases : urokinase (kidney) or tissue plasminogen activator (tPA)
tPA:
From Stryer
From Stryer