Biochemistry - Chemical Reactions in Living Cells, Volume 2 - D. Metzler 1980

Enzymes: Protein Catalysts of Cells
Regulation of Enzymatic Activity
Amplification of Regulatory Signals

A regulatory change in enzyme activity is often amplified through a cascade mechanism: the first enzyme acts on the second, the second on the third, and so on. This mechanism ensures the rapid generation of large amounts of the active form of the final enzyme in the pathway. A classic example is the Blood Coagulation cascade [89], schematically illustrated in Fig. 6-16. We can observe a sequence consisting of five Enzymes starting with factor XII, where each enzyme activates the next by cleaving off a small portion of the peptide chain (Limited proteolysis). At The final stage, Thrombin acts on fibrinogen, cleaving a small peptide to convert it into fibrin—a specialized protein that spontaneously polymerizes into a clot. What prevents such a cascade from spinning out of control? Why doesn't a minor bruise convert all the prothrombin in our body into thrombin and cause all our blood to clot? The situation here is undoubtedly analogous to that of cAMP, which is rapidly cleared from the system by a specific enzyme: there are mechanisms to remove the activated enzyme from the cascade sequence shown in Fig. 6-16. In addition, a dedicated enzyme system dissolves the blood clot during wound healing [89].

For one of these enzyme cascades, the mechanism that halts the cascade effect is well understood. Muscle Glycogen Phosphorylase is activated by an enzyme cascade triggered by Autonomic Nervous system-controlled epinephrine release (Ch. 16, Sec. B, 3). The binding of epinephrine to The Cell membrane leads to the release of cAMP, which activates protein kinase. The kinase, in turn, catalyzes the phosphorylation of another enzyme, phosphorylase kinase. At this point, the muscle is primed for rapid glycogen breakdown. However, the direct signal initiating this process is the release of Ca²⁺ ions into the Cytoplasm in response to impulses from motor Neurons (Ch. 4, Sec. E, 1). Phosphorylase kinase is activated by Calcium Ions and, in their presence, catalyzes The conversion of inactive phosphorylase b into active phosphorylase a. Spontaneous return to the resting state is brought about by Phosphatases that catalyze the removal of the phosphoryl groups previously attached to Proteins by Kinases. Phosphodiesterase, which degrades cAMP, and the calcium pump, which rapidly lowers the concentration of activating calcium ions back to baseline levels, also play vital roles in this process.

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FIG. 6-16. The cascade mechanism leading to blood coagulation. There are two pathways for cascade initiation: the intrinsic pathway is triggered by surface contact, and the extrinsic pathway is initiated by the release of thromboplastin from damaged Tissues [89, 89a].

Another Amplification mechanism, the details of which are yet to be fully elucidated, operates in the retina. It is known that a single quantum of light striking a receptor cell can, under optimal conditions, generate a Nerve Impulse (Ch. 16, Sec. B, 3). For this impulse to propagate, A large number of Na⁺ ions must cross the membrane, and it is highly unlikely that the absorption of a single photon could initiate a photochemical reaction leading to such massive sodium ion transport without an appropriate signal amplification mechanism.

Amplification mechanisms can be of various types. One such mechanism, involving the cyclic conversion of a substrate, is discussed in Ch. 11, Sec. E, 6.

FIG. 6-17. Cross-Regulation of purine nucleoside triphosphate synthesis (ATP and GTP) [66].