Special Focus 467Cyclic AMP is an e

Special Focus 467
Cyclic AMP is an essential activator of cAMP-dependent protein kinase (PKA). Bind-
ing of cyclic AMP to the regulatory subunits induces a conformation change that
causes the dissociation of the C monomers from the R dimer (Figure 15.10). The
free C subunits are active and can phosphorylate other proteins. One of the many
proteins phosphorylated by PKA is phosphorylase kinase (Figure 15.17). Phosphory-
lase kinase is inactive in the unphosphorylated state and active in the phosphory-
lated form. As its name implies, phosphorylase kinase functions to phosphorylate
(and activate) glycogen phosphorylase. Thus, hormonal activation of adenylyl cy-
clase leads to activation of glycogen breakdown.
Is There an Example in Nature That Exemplifies the Relationship
Between Quaternary Structure and the Emergence of Allosteric
Properties? Hemoglobin and Myoglobin—Paradigms of Protein
Structure and Function
Ancient life forms evolved in the absence of oxygen and were capable only of anaer-
obic metabolism. As the earth’s atmosphere changed over time, so too did living
things. Indeed, the production of O2 by photosynthesis was a major factor in alter-
ing the atmosphere. Evolution to an oxygen-based metabolism was highly beneficial.
Aerobic metabolism of sugars, for example, yields far more energy than correspond-
ing anaerobic processes. Two important oxygen-binding proteins appeared in the
course of evolution so that aerobic metabolic processes were no longer limited by the
solubility of O2 in water. These proteins are represented in animals as hemoglobin
(Hb) in blood and myoglobin (Mb) in muscle. Because hemoglobin and myoglobin
are two of the most-studied proteins in nature, they have become paradigms of pro-
tein structure and function. Moreover, hemoglobin is a model for protein quater-
nary structure and allosteric function. The binding of O2 by hemoglobin, and its
modulation by effectors such as protons, CO2, and 2,3-bisphosphoglycerate, depend
on interactions between subunits in the Hb tetramer. Subunit–subunit interactions
in Hb reveal much about the functional significance of quaternary associations and
allosteric regulation.
The Comparative Biochemistry of Myoglobin and Hemoglobin
Reveals Insights into Allostery
A comparison of the properties of hemoglobin and myoglobin offers insights into
allosteric phenomena, even though these proteins are not enzymes. Hemoglobin
displays sigmoid-shaped O2-binding curves (Figure 15.20). The unusual shape of
these curves was once a great enigma in biochemistry. Such curves closely resemble
allosteric enzyme-
substrate saturation graphs (see Figure 15.6). In contrast, myo-
globin’s interaction with oxygen obeys classical Michaelis–Menten-type substrate
saturation behavior.
Before examining myoglobin and hemoglobin in detail, let us first encapsulate the
lesson: Myoglobin is a compact globular protein composed of a single polypeptide
chain 153 amino acids in length; its molecular mass is 17.2 kD (Figure 15.21). It con-
tains heme, a porphyrin ring system complexing an iron ion, as its prosthetic group
(Figure 15.22). Oxygen binds to Mb via its heme. Hemoglobin (Hb) is also a compact
globular protein, but Hb is a tetramer. It consists of four polypeptide chains, each of
which is very similar structurally to the myoglobin polypeptide chain, and each bears
a heme group. Thus, a hemoglobin molecule can bind four O2 molecules. In adult
human Hb, there are two identical chains of 141 amino acids, the -chains, and two
identical -chains, each of 146 residues. The human Hb molecule is an 22-type
tetramer of molecular mass 64.45 kD.
SPECIAL FOCUS