Principles of Biochemistry, Volume 3 - A. Lehninger 1985

Selected Aspects of Human Biochemistry
Hormones
cAMP stimulates protein kinase activity

How does cAMP stimulate The conversion of inactive phosphorylase b into active phosphorylase a? As we recall (Sec. 20.14), this conversion is mediated by phosphorylase kinase, which catalyzes The transfer of terminal phosphate groups from two ATP molecules to the hydroxyl groups of two specific Serine residues in phosphorylase b, leading to The formation of phosphorylase a:

Class="center">2АТР + Фосфорилаза b → 2ADP +

+ Фосфорилаза а

Cyclic adenosine monophosphate (cAMP) does not exert a direct effect on phosphorylase kinase on its own. This enzyme also exists in active and less active forms (Sec. 15.12). The inactive form of phosphorylase kinase is converted into the active form via phosphorylation using ATP.

We now turn to the regulatory link between cAMP and Glycogen phosphorylase activity. The only missing link is an enzyme called protein kinase, which also exists in active and inactive forms. Active protein kinase catalyzes the phosphorylation of inactive phosphorylase kinase by means of ATP to yield the active phosphorylated form; in this reaction, ATP serves as the donor of the phosphate groups, and Ca²⁺ ions act as its activator:

Phosphorylase kinase is a very large protein with a molecular weight exceeding 1 million. It consists of 16 subunits, each containing a specific serine residue that is phosphorylated by means of ATP under the action of activated protein kinase.

Protein kinase, which plays a pivotal role in the cAMP-mediated activation of phosphorylase, is an allosteric enzyme. In its inactive form, it is composed of two catalytic subunits (C) and two Regulatory Subunits (R) (Fig. 25-10). When these subunits are assembled into a complex of composition C₂R₂, the enzyme is inactive. cAMP acts as an allosteric activator of protein kinase. Upon binding of four cAMP molecules to specific sites on the two regulatory subunits, the C₂R₂ complex dissociates into free catalytic subunits possessing enzymatic activity and the R₂-cAMP₄ complex, in which cAMP remains bound. Thus, cAMP relieves the inhibition of protein kinase activity imposed by the bound regulatory subunit (Fig. 25-10).

Fig. 25-10. Activation of the inactive form of protein kinase by cyclic adenosine monophosphate (cAMP), which binds to two regulatory subunits (R), thereby releasing two active catalytic subunits (C) of protein kinase.

Table 25-4. Hormones whose action is mediated by cAMP

It was subsequently discovered that cAMP mediates the cellular action not only of epinephrine but also of many Other Hormones (Table 25-4). The protein kinase activated by cAMP can phosphorylate A number of Key Enzymes across a variety of target Cells.