Regulatory Enzymes:- Multiple Phosphorylations Allow Exquisite Regulatory Control

The Ser, Thr, or Tyr residues that are phosphorylated in regulated proteins occur within common structural motifs, called consensus sequences, that are recognized by specific protein kinases (Table 6–10). Some kinases are basophilic, preferring to phosphorylate a residue having basic neighbors; others have different substrate preferences, such as for a residue near a Pro residue.

Primary sequence is not the only important factor in determining whether a given residue will be phosphorylated, however. Protein folding brings together residues that are distant in the primary sequence; the resulting three-dimensional structure can determine whether a protein kinase has access to a given residue and can recognize it as a substrate. Another factor influencing the substrate specificity of certain protein kinases is the proximity of other phosphorylated residues. Regulation by phosphorylation is often complicated. Some proteins have consensus sequences recognized by several different protein kinases, each of which can phosphorylate the protein and alter its enzymatic activity. In some cases, phosphorylation is hierarchical: a certain residue can be phosphorylated only if a neigh boring residue has already been phosphorylated. For ex ample, glycogen synthase, the enzyme that catalyzes the condensation of glucose monomers to form glycogen (Chapter 15), is inactivated by phosphorylation of specific Ser residues and is also modulated by at least four other protein kinases that phosphorylate four other sites in the protein (Fig. 6–32). The protein is not a substrate for glycogen synthase kinase 3, for example, until one site has been phosphorylated by casein kinase II. Some phosphorylations inhibit glycogen synthase more than others, and some combinations of phosphorylations are cumulative. These multiple regulatory phosphorylations provide the potential for extremely subtle modulation of enzyme activity. To serve as an effective regulatory mechanism, phosphorylation must be reversible. In general, phos phoryl groups are added and removed by different en zymes, and the processes can therefore be separately regulated. Cells contain a family of phosphoprotein phosphatases that hydrolyze specific P–Ser, P–Thr, and P–Tyr esters, releasing Pi. The phosphoprotein phosphatases we know of thus far act only on a subset of phosphoproteins, but they show less substrate specificity than protein kinases.

FIGURE 6–32 Multiple regulatory phosphorylations. The enzyme glycogen synthase has at least nine separate sites in five designated regions susceptible to phosphorylation by one of the cellular protein kinases. Thus, regulation of this enzyme is a matter not of binary (on/off) switching but of finely tuned modulation of activity over a wide range in response to a variety of signals.

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مواضيع ذات صلة

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

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