Enzyme Regulation
Part IV. Feedback Regulation and Covalent Modification
Another type of allosteric regulation is via Feedback Inhibition:
Figure 9. Model of Feedback Inhibition using a metabolic pathway to illustrate this concept.
The biosynthesis of amino acids is often regulated by Feedback Inhibition (in those organisms that make amino acids since not all do). When the concentration of an amino acid is high, it inhibits its own biosynthesis until the level of the amino acid falls. Then, the inhibition is relieved by the consumption of the amino acid and its production is enhanced.
Basically, this is like allosteric modifier action which increases the activity of the enzyme but in this case the modifier is an inhibitor. The allosteric site for the feedback inhibitor is separate from the active site and the inhibitor acts via the framework of the enzyme to alter the shape of the active site. This is of course related to non-competitive inhibition of the enzyme, but we discussed only the case where the enzyme loses activity but can still bind its substrate normally, which we called a classic non-competitive inhibitor. In reality most non-competitive inhibitors impact both the Vmax and Km of the enzyme and this is generally the case for a feedback inhibitor.
Covalent Modification for Enzyme Activity Regulation
A more definitive control can be achieved by covalent modification of an enzyme and is used to switch an organism's cells from one metabolic state to another. For example, hormones like insulin can switch a liver cell from degrading and storing glucose to synthesizing it and exporting it to the blood. This is done by turning on enzymes via covalent modification.
Figure 10. Glycogen Phosphorylase catalyzes mobilization of stored carbohydrate reserves.
Phosphorylase exists in two forms 'A' and 'B'. Form A is active phosphorylated 'A'-P. Form B is inactive and not phosphorylated. The phosphate on form A is present as a phosphate ester:
Figure 11. Structure of Serine-Phosphate. The Ser residue is part of the polypeptide chain of phosphorylase and is converted to the phosphorylated form after the enzyme is synthesized on the ribosomes. So this is called post-translational modification.
The Ser residue which is phosphorylated is remote from the active site of phosphorylase and this mechanism for controlling enzyme activity also works (in most cases) by altering the shape of the enzyme by covalent modification. This modification system is run by two enzymes:
1. 'Protein Kinase' catalyzes: 'B' + ATP --> 'A'-P + ADP
The protein kinase converts the inactive B form of phosphorylase into the active A form.
2. 'Protein Phosphatase' catalyzes: 'A'-P + H2O --> 'B' + Pi (inorganic phosphate)
The protein phosphatase converts 'A'-P back into 'B' by catalyzing hydrolysis of the phosphate ester.
Thus, to change the metabolic state or mode of the cell, the protein kinase is turned on and the protein phosphatase is turned off. The hormone controls the activity of these controlling or regulatory enzymes and this involves several other proteins and receptors.
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©Wilbur H. Campbell, 1995; wcampbel@mtu.edu