Covalent Regulation of Enzyme Activity

There are two basic types of covalent control of enzyme activity: reversible and irreversible. An example of irreversible activation is the proteolytic cleavage of proenzymes in the digestive tract that lead to the active forms of trypsin and chymotrypsin. The activation of these proteolytic enzymes outside the cell is critical, as the presence of active enzymes within the cell could lead to the unwanted degradation of cellular components, or to the complete digestion of the contents of the secretory vesicles in which the proenzymes reside prior to secretion from the cell. Another example of irreversible inhibition of enzyme activity is the action of serpins on extracellular proteases. Proteases, in addition to their action during digestion, are essential contributors to the remodeling of the extracellular matrix and in the action of the clotting cascades. Following activation of these proteases, the duration of their activity is controlled by the presence of specific inhibitors, termed serpins (serine protease inhibitors), that form tight and irreversible complexes with the proteases. This complex is then rapidly cleared from the extracellular circulation and degraded.

The key reversible covalent modification of activity is phosphorylation. In eukaryotic systems, protein kinases utilize ATP to transfer a phosphate to the protein on the side chains of either serine, threonine, or tyrasine residues in the target protein's sequence (Fig. 3.14). The specificity of kinases determines both which amino acid is phosphorylated and which protein is phosphorylated. Protein phosphatases hydrolyze the phosphate moiety off of the phosphorylated protein using water to catalyze the reaction and release free phosphate groups (Fig. 3.14). Notice that if this process is not regulated, it becomes a "futile" cycle of ATP hydrolysis. Thus, the phosphorylation and dephosphorylation reactions must be highly specific and tightly controlled, and opposing activities must be coordinated by the cell. A principal way by which changes

Figure 3.14 The phosphorylation cycle of proteins. Phosphorylation is a key reversible covalent modification of enzyme activity. Protein kinases utilize ATP to transfer a phosphate to the protein, while protein phosphatases are enzymes that remove phosphate groups. Addition or removal of phosphate changes protein activity, but does not necessarily correspond with enzyme activation or inhibition.

Figure 3.14 The phosphorylation cycle of proteins. Phosphorylation is a key reversible covalent modification of enzyme activity. Protein kinases utilize ATP to transfer a phosphate to the protein, while protein phosphatases are enzymes that remove phosphate groups. Addition or removal of phosphate changes protein activity, but does not necessarily correspond with enzyme activation or inhibition.

in the phosphorylation state of proteins within the cell arise is as a response to some extracellular signal, such as hormone action (see Chap. 4 on Cellular Signaling).

A good example of coordinate regulation of a pathway is the control of glycogen synthesis and its breakdown. Glycogen synthase, as the name implies, synthesizes glycogen from glucose, and glycogen phosphorylase breaks down glycogen to glucose. Phosphorylation of glycogen synthase inactivates the enzyme, while phosphorylation of glycogen phosphorylase activates the enzyme. The cell responds to the hormone epinephrine by activating protein kinases that phosphorylate both enzymes, while the hormone insulin causes the opposite effects on the phosphorylation states of these two enzymes by activating phosphatases (Fig. 3.15).

The action of these hormones is directed to different kinases and phosphatases that are specific for their target enzymes, glycogen syn-thase and glycogen phosphorylase, in this example. This is a common theme in the regulation of cellular processes in response to changes in the external environment. In the above example, this type of coordinate regulation of activity is crucial, otherwise the activity of phosphorylase and glycogen synthase will oppose each other and no net synthesis of glycogen or net breakdown of glycogen will occur during periods of glucose excess or glucose deficiency, respectively.

Epinephrine

Epinephrine

Protein Kinase

Protein Kinase

Phosphorylase (active)

Phosphorylase (inactive)

Synthase (inactive)

Synthase (active)

Protein Phosphatase

Protein Phosphatase

Û Insulin

Figure 3.15 Glycogen regulation. Glycogen synthesis and glycogen breakdown are regulated by the hormones epinephrine and insulin. When glucose levels are high, the organism responds by releasing insulin which signals the activation of enzymes responsible for glucose storage. The action of epinephirine opposes that of insulin and leads to the activation of phosphorylase and inhibition of glycogen synthase.

Protein Kinase

Phosphorylase (active)

Phosphorylase (inactive)

Protein Kinase

Synthase (inactive)

Synthase (active)

Protein Phosphatase

Û Insulin

Protein Phosphatase

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