Introduction to Enzyme and Coenzyme Chemistry - E-Library Home

Non-Enzymatic Biological Catalysis 259
tRNA
O
N
A 2486
pep
O
N
N
H
N
H
H
N
N
R
H
O
O-tRNA
N
N
A 2486 N +
H
tRNA O O−
N H
pep
H
N
N
R
H
O
O-tRNA
tRNA
N
H
N
N N
A 2486 N
R
N H
Figure 12.4 Mechanism for peptide bond formation in the catalytic site of the ribosome.
OH
pep
O
H
O
O-tRNA
12.3 Catalytic antibodies
The immune system acts as a major line of defence against foreign substances,
be they toxins, proteins, or invading micro-organisms. Upon detection of a
foreign antigen the immune system generates a ‘library’ of up to 10 9 antibodies,
some of which bind tightly and speciWcally to the antigen, allowing it to be
targeted and destroyed by the body’s ‘killer’ T-cells. The structure of antibodies
is illustrated in Figure 12.5. They are protein molecules consisting of four
polypeptide chains, two heavy (H) chains and two light (L) chains, linked
together by disulphide bridges. At the two ends of each Y-shaped antibody
are the ‘variable’ regions of the antibody in which variation in sequence is found
between antibodies, and at the extreme ends of the Y are the ‘hypervariable’
regions which make up the antigen combining sites. The three-dimensional
structure of an antibody is shown in Figure 12.6.
Antibodies bind their antigen target very tightly, typical K d values being
10 9 ---10 11 m, and very selectively. This selectivity of binding is reminiscent of
the selectivity of enzyme active sites for their substrates. So they satisfy one
of the criteria for enzyme catalysis: selective substrate recognition. Could
antibodies also catalyse chemical reactions This question was answered by
the groups of Lerner and Schultz in 1986. They recognised that the major factor
underlying enzymatic catalysis is transition state stabilisation. If an antibody
could be generated that speciWcally recognises the transition state of a chemical
reaction, and also binds less tightly the substrate and product of the reaction,
then it should catalyse the reaction.
Insight into the mechanisms of chemical reactions has provided us with
good models for the structures of their transition states. In many cases this has
permitted the synthesis of transition state analogues. We have seen earlier how
such molecules can act as potent inhibitors of enzyme-catalysed reactions,
precisely because enzymes bind the transition state more tightly than either
the substrate or product of the reaction. Using a synthetic transition state