Enzyme regulation protein kinases

An example for the reversible association of activator proteins with an enzyme is the Ca -calmodulin dependent enzymes. Calmodulin is a Ca -binding protein which can activate target enzymes, e.g. phosphorylase kinase (see 6.7.1 and 7.4) in its Ca -boimd form. Another example for activating proteins is the cyclins (see chapter 14). The cyc-lins are activators of protein kinases that regulate the cell cycle. 

The activity of the protein kinases are regulated allosterically. The serine- and threonine-specific protein kinases have a regulatory domain which, in the resting state, keeps the catalytic part of the enzyme inactive. When a second messenger or activator (cAMP, cGMP, Ca or DAG) binds to the regulatory domain, the enz)m e is activated. 

Yu R, Mandlekar S, Lei W, Fahl WE, Tan T-H, et al. 2000. p38 Mitogen-activated protein kinase negatively regulates the induction of Phase II drug-metabolizing enzymes that detoxify carcinogens. J. Biol. Chem. 275 2322-27... 

The multifunctional CaM kinases include the CaM kinases of types I, II and IV, all of which phosphorylate a rather broad spectrum of substrate proteins. These enzymes regulate many processes (see Table 7.1) such as glycogen metabolism, activity of transcription factors, microfilament formation, synaptic release of neurotransmitters from storage vesicles, biosynthesis of neurotransmitters, and many more. Some important substrates of CaM kinases are shown in Table 7.1. A primary function in synaptic transmission is ascribed to the CaM kinases of type II, which exhibit outstanding regulatory properties and will therefore be discussed in below in more detail. Among the class of CaM kinase II enzymes, subtypes a, fi, y and <5 are differentiated. The a and... 

FIGURE 15.2 Enzymes regulated by covalent modification are called interconvertible enzymes. The enzymes protein kinase and protein phosphatase, in the example shown here) catalyzing the conversion of the interconvertible enzyme between its two forms are called converter enzymes. In this example, the free enzyme form is catalytically active, whereas the phosphoryl-enzyme form represents an inactive state. The —OH on the interconvertible enzyme represents an —OH group on a specific amino acid side chain in the protein (for example, a particular Ser residue) capable of accepting the phosphoryl group. 

Pyruvate kinase possesses allosteric sites for numerous effectors. It is activated by AMP and fructose-1,6-bisphosphate and inhibited by ATP, acetyl-CoA, and alanine. (Note that alanine is the a-amino acid counterpart of the a-keto acid, pyruvate.) Furthermore, liver pyruvate kinase is regulated by covalent modification. Flormones such as glucagon activate a cAMP-dependent protein kinase, which transfers a phosphoryl group from ATP to the enzyme. The phos-phorylated form of pyruvate kinase is more strongly inhibited by ATP and alanine and has a higher for PEP, so that, in the presence of physiological levels of PEP, the enzyme is inactive. Then PEP is used as a substrate for glucose synthesis in the pathway (to be described in Chapter 23), instead... 

Protein kinase A (PKA) is a cyclic AMP-dependent protein kinase, a member of a family of protein kinases that are activated by binding of cAMP to their two regulatory subunits, which results in the release of two active catalytic subunits. Targets of PKA include L-type calcium channels (the relevant subunit and site of phosphorylation is still uncertain), phospholam-ban (the regulator of the sarcoplasmic calcium ATPase, SERCA) and key enzymes of glucose and lipid metabolism. 

Sarcoplasmic calcium ATPase this enzyme utilizes the energy gained from hydrolysis of ATP to pump calcium from the cytosol into the stores of the sarcoplasmic reticulum. Its activity is negatively regulated by the closely associated protein phospholamban, and this inhibition is relieved upon phosphorylation of phospholamban by protein kinase A (PKA). 

---