70
Chapter 3
situation occurs, for example, when oxygen binds to hemoglo-
bin, a protein composed of four polypeptide chains, each con-
taining one binding site for oxygen (Chapter 13).
Covalent Modulation
The second way to alter the shape and therefore the activity of a
protein is by the covalent bonding of charged chemical groups
to some of the protein’s side chains. This is known as
cova-
lent modulation.
In most cases, a phosphate group, which
has a net negative charge, is covalently attached by a chemical
reaction called
phosphorylation,
in which a phosphate group
is transferred from one molecule to another. Phosphorylation
of one of the side chains of certain amino acids in a protein
introduces a negative charge into that region of the protein.
This charge alters the distribution of electric forces in the pro-
tein and produces a change in protein conformation (
Figure
3–32b
). If the conformational change affects a binding site,
it changes the binding site’s properties. Although the mecha-
nism is completely different, the effects produced by covalent
modulation are similar to those of allosteric modulation—that
is, a functional binding site may be turned on or off, or the
affi nity of the site for its ligand may be altered. Unlike allosteric
modulation, which involves noncovalent binding of modulator
molecules, covalent modulation requires chemical reactions in
which covalent bonds are formed.
Most chemical reactions in the body are mediated by a
special class of proteins known as enzymes, whose properties
will be discussed in Section D of this chapter. For now, suf-
fi ce it to say that enzymes accelerate the rate at which reac-
tant molecules, called substrates, are converted to different
molecules called products. Two enzymes control a protein’s
activity by covalent modulation: One adds phosphate, and one
removes it. Any enzyme that mediates protein phosphoryla-
tion is called a
protein kinase.
These enzymes catalyze the
transfer of phosphate from a molecule of ATP to a hydroxyl
group present on the side chain of certain amino acids:
protein kinase
Protein + ATP
⎯⎯⎯⎯→
Protein—PO
4
2–
+ ADP
The protein and ATP are the substrates for protein kinase, and
the phosphorylated protein and adenosine diphosphate (ADP)
are the products of the reaction.
There is also a mechanism for removing the phosphate
group and returning the protein to its original shape. This
dephosphorylation is accomplished by a second class of enzymes
known as
phosphoprotein phosphatases:
phosphoprotein
phosphatase
Protein—PO
4
2–
+ H
2
O
⎯⎯⎯⎯→
Protein + HPO
4
2–
The activity of the protein will depend on the relative
activity of the kinase and phosphatase that controls the extent of
the protein’s phosphorylation. There are many protein kinases,
each with specifi cities for different proteins, and several kinases
Figure 3–32
(a) Allosteric modulation and (b) covalent modulation of a protein’s functional binding site.
Activation of functional site
Protein kinase
Phosphoprotein phosphatase
ATP
P
i
Functional site
Functional site
Regulatory site
Modulator molecule
Ligand
OH
PO
4
Allosteric modulation
(a)
Covalent modulation
(b)
Ligand
2
Protein
Protein
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