Regulatory Enzymes:- Phosphoryl Groups Affect the Structure and Catalytic Activity of Proteins

The attachment of phosphoryl groups to specific amino acid residues of a protein is catalyzed by protein kinases; removal of phosphoryl groups is catalyzed by protein phosphatases. The addition of a phosphoryl group to a Ser, Thr, or Tyr residue introduces a bulky, charged group into a region that was only moderately polar. The oxygen atoms of a phosphoryl group can hydrogen-bond with one or several groups in a protein, commonly the amide groups of the peptide backbone at the start of an helix or the charged guanidinium group of an Arg residue. The two negative charges on a phosphorylated side chain can also repel neighboring negatively charged (Asp or Glu) residues. When the modified side chain is located in a region of the protein critical to its three-dimensional structure, phosphorylation can have dramatic effects on protein conformation and thus on substrate binding and catalysis. An important example of regulation by phosphorylation is seen in glycogen phosphorylase (Mr 94,500) of muscle and liver (Chapter 15), which catalyzes the reaction

The glucose 1-phosphate so formed can be used for ATP synthesis in muscle or converted to free glucose in the liver. Glycogen phosphorylase occurs in two forms: the more active phosphorylase a and the less active phosphorylase b (Fig. 6–31). Phosphorylase a has two subunits, each with a specific Ser residue that is phosphorylated at its hydroxyl group. These serine phosphate residues are required for maximal activity of the enzyme.

FIGURE 6–30 Some enzyme modification reactions.

FIGURE 6–31 Regulation of glycogen phosphorylase activity by covalent modification. In the more active form of the enzyme, phosphorylase a, specific Ser residues, one on each subunit, are phosphorylated. Phosphorylase a is converted to the less active phosphorylase b by enzymatic loss of these phosphoryl groups, promoted by phosphorylase phosphatase. Phosphorylase b can be reconverted (reactivated) to phosphorylase a by the action of phosphorylase kinase.

The phosphoryl groups can be hydrolytically removed by a separate enzyme called phosphorylase phosphatase:

In this reaction, phosphorylase a is converted to phosphorylase b by the cleavage of two serine phosphate covalent bonds, one on each subunit of glycogen phosphorylase. Phosphorylase b can in turn be reactivated—covalently transformed back into active phosphorylase a— by another enzyme, phosphorylase kinase, which catalyzes the transfer of phosphoryl groups from ATP to the hydroxyl groups of the two specific Ser residues in phosphorylase b:

The breakdown of glycogen in skeletal muscles and the liver is regulated by variations in the ratio of the two forms of glycogen phosphorylase. The a and b forms dif fer in their secondary, tertiary, and quaternary struc tures; the active site undergoes changes in structure and, consequently, changes in catalytic activity as the two forms are interconverted. The regulation of glycogen phosphorylase by phos phorylation illustrates the effects on both structure and catalytic activity of adding a phosphoryl group. In the unphosphorylated state, each subunit of this protein is folded so as to bring the 20 residues at its amino termi nus, including a number of basic residues, into a region containing several acidic amino acids; this produces an electrostatic interaction that stabilizes the conformation. Phosphorylation of Ser14 interferes with this interaction, forcing the amino-terminal domain out of the acidic environment and into a conformation that allows interaction between the P–Ser and several Arg side chains. In this conformation, the enzyme is much more active. Phosphorylation of an enzyme can affect catalysis in another way: by altering substrate-binding affinity. For example, when isocitrate dehydrogenase (an en zyme of the citric acid cycle; Chapter 16) is phosphorylated, electrostatic repulsion by the phosphoryl group inhibits the binding of citrate (a tricarboxylic acid) at the active site.

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مواضيع ذات صلة

Regulatory Enzymes:- Multiple Phosphorylations Allow Exquisite Regulatory Control

Regulatory Enzymes:- Some Regulatory Enzymes Undergo Reversible Covalent Modification

Regulatory Enzymes: - The Kinetic Properties of Allosteric Enzymes Diverge from Michaelis-Menten Behavior

Regulatory Enzymes:- In Many Pathways a Regulated Step Is Catalyzed by an Allosteric Enzyme

Regulatory Enzymes: - Allosteric Enzymes Undergo Conformational Changes in Response to Modulator Binding

Examples of Enzymatic Reactions:- Hexokinase Undergoes Induced Fit on Substrate Binding

Examples of Enzymatic Reactions:-The Chymotrypsin Mechanism Involves Acylation and Deacylation of a Ser Residue

Enzyme Kinetics as an Approach to Understanding Mechanism: -Enzyme Activity Depends on pH

Enzyme Kinetics as an Approach to Understanding Mechanism: -Enzymes Are Subject to Reversible or Irreversible Inhibition

Enzyme Kinetics as an Approach to Understanding Mechanism: -Pre–Steady State Kinetics Can Provide Evidence for Specific Reaction Steps

Enzyme Kinetics as an Approach to Understanding Mechanism:- Many Enzymes Catalyze Reactions with Two or More Substrates

Enzyme Kinetics as an Approach to Understanding Mechanism: -Kinetic Parameters Are Used to Compare Enzyme Activities