Page 85 - Color Atlas of Biochemistry

76 Biomolecules
Molecular models: insulin
Theoppositepagepresents models ofinsulin,
a small protein. The biosynthesis and function
of this important hormone are discussed else-
where in this book (pp.160, 388). Monomeric
insulin consists of 51 amino acids, and with a
molecular mass of 5.5 kDa it is only half the
size of the smallest enzymes. Nevertheless, it
has the typical properties of a globular pro-
tein.
Large quantities of pure insulin are re-
quired for the treatment of diabetes mellitus
(see p.160). The annual requirement for insu-
lin isover500 kg in a country thesizeof
Germany. Formerly, the hormone had to be
obtained from the pancreas of slaughtered
animals in a complicated and expensive
procedure. Human insulin,which is produced
by overexpression in genetically engineered
bacteria, is now mainly used (see p. 262).
A. Structure of insulin
There are various different structural levels in This model emphasizes the importance of the
proteins, and these can be briefly discussed
again here using the example of insulin.
The primary structure of a protein is its
amino acid sequence. During the biosynthesis
of insulin in the pancreas, a continuous pep-
tide chain with 84 residues is first synthesi-
zed—proinsulin (see p.160). After folding of
the molecule, the three disulfide bonds are
firstformed, and residues31to 63are then
proteolytically cleaved releasing the so-called hexameric forms of insulin.
Cpeptide. The molecule that is left over (1)
now consists of two peptide chains, the A
chain (21 residues, shown in yellow) and the
Bchain (30 residues, orange). One of the di-
sulfide bonds is located inside the A chain,
and the two others link the two chains to-
gether.
Secondary structures are regions of the
peptide chain with a defined conformation
(see p. 68) that are stabilized by H-bonds. In
insulin (2), the α-helical areas are predomi-
nant, making up 57% of the molecule; 6%
consists of β-pleated-sheet structures, and
10% of β-turns, while the remainder (27%)
cannot be assigned to any of the secondary
structures.
The three-dimensional conformation of a
protein, made up of secondary structural ele-
ments and unordered sections, is referred to
Koolman, Color Atlas of Biochemistry, 2nd edition © 2005 Thieme
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as the tertiary structure.In insulin,itis com-
pact and wedge-shaped (B). The tip of the
wedge is formed by the B chain, which
changes its direction at this point.
Quaternary structure. Due to non-covalent
interactions, many proteins assemble to form
symmetrical complexes (oligomers). The indi-
vidual components of oligomeric proteins
(usually 2–12) are termed subunits or mono-
mers. Insulin also forms quaternary struc-
tures. In the blood, it is partly present as a
dimer. In addition, there are also hexamers
stabilized by Zn 2+ ions (light blue) (3), which
represent the form in which insulin is stored
in thepancreas (seep.160).
B. Insulin (monomer)
The van der Waals model of monomeric in-
sulin (1) once again shows the wedge-shaped
tertiary structure formed by the two chains
together. In the second model (3,bottom), the
side chains of polar amino acids are shown in
blue, while apolar residues are yellow or pink.
“hydrophobic effect” for protein folding (see
p. 74). In insulin as well, most hydrophobic
side chains are located on the inside of the
molecule, while the hydrophilic residues are
located on the surface. Apparently in contra-
diction to this rule, several apolar side chains
(pink) are found on the surface. However, all
of these residues are involved in hydrophobic
interactions that stabilize the dimeric and
In the third model (2,right), thecolored
residues are those that are located on the
surface and occur invariably (red) or almost
invariably (orange) in all known insulins. It is
assumed that amino acid residues that are not
replaced by other residues during the course
of evolution are essential for the protein’s
function. In the case of insulin, almost all of
these residues are located on one side of the
molecule. They are probably involved in the
binding of the hormone to its receptor (see
p. 224).