Structural Biochemistry/Enzyme Regulation/Enzyme Cascades

An enzymatic cascade is a sequence of successive activation reactions involving enzymes, which is characterized by a series of amplifications stemming from an initial stimulus. The product of each preceding reaction catalyzes and is consumed in the next reaction. An example of an enzymatic cascade includes blood clotting, where a timely response is needed. The cascade first activates a clotting factor, followed by the activation of the next clotting factor and so forth until the final cross-linked fibrin clot is formed.

Another example of enzymatic cascade occurs following the binding of allergen to a receptor bound Ig on the mast cell. Spleen tyrosine kinases (Syk) plays an important role in this immunoglobulin E (IgE) signaling pathway. Using knowledge of the cascade and the role Syk plays, Syk inhibitors have been developed to inhibit IgE- driven mast cell degranulation, as well as to inhibit the release of inflammatory cytokines, thereby inhibiting an allergic response. [1]

Enzymatic cascades can also play roles in the immune system. Complement cascade works with the body’s innate immunity by cleaning pathogens from an organism. It proceeds though three major pathways; classical (CP), alternative (AP) and mannose-binding-lectin (MP). The end product results in large scale amplification of cell killing membrane attack complex. [2]

Blood Clotting

Blood coagulation is an example of this; each enzyme activates the next until a fibrin clot is formed. There are two pathways by which the clotting can proceed: intrinsically or extrinsically. Intrinsic clotting is activated by the exposure of anionic surfaces of blood vessels that is damaged by the trauma, while extrinsic clotting is initiated by the exposure of tissue factors (TF). Tissue factors are integral glycoprotein.

File:Blood clotting.jpg Inactive forms of clotting factors =pink Activated forms = yellow Stimulatory proteins (not enzymes) = blue

The final portion of the pathway is the same for both intrinsic and extrinsic cascades, in which factor X is activated. Once the Prothrombin is activated and catalyzed into thrombin, it catalyzes the conversion of fibrinogen into fibrin. Thrombin cleaves fibrinopeptides at the central globular region, the globular domains at the carboxyl-terminal ends of the beta and delta chains interact with the exposed regions of the chains at the amino terminal. This cross linking reaction forms fibrin clots. It should be noted that thrombin is also involved in the activation of enzymes in previous steps, such as factors VII and VIII, providing a positive feedback loop on the cascade. This fibrin clotting process must be fast acting and precisely regulated, it can only act on damaged tissues. Fibrin can't be flowing in the blood vessels to cause blood clots. This precise regulation is owe to the fact that clotting factors are short-lived and diluted in blood vessels. They are quickly removed by the liver.

File:Blood clot final path.jpg

Sources

Berg, Jeremy M. John L. Tymoczko. Lubert Stryer. Biochemistry Sixth Edition. W.H. Freeman and Company. New York, 2007.