Introduction to Enzyme and Coenzyme Chemistry - E-Library Home

90 Chapter 5
Figure 5.8 Structure of papain (PDB Wle 1POP), showing in red the catalytic residues Cys-25 and
His-159.
Given the similarities in mechanism between the serine proteases and the
cysteine proteases, it is interesting to note that the serine proteases may have
evolved from a forerunner of the cysteine proteases. This hypothesis was put
forward by Brenner, who observed that in some cases the triplet codons
encoding the active site serine have the UCX codon, whilst others have the
AGC/AGU codon for serine. The key point is that these two sub-families of
enzymes cannot be directly related in evolutionary terms, since two simultaneous
nucleotide base changes would be required to change from one to the
other, which is statistically improbable. However, they could both have
evolved from the UGC/UGU cysteine codon via one-base changes as shown
in Figure 5.10. So just on the basis of this one observation it seems probable
that a cysteine-containing enzyme was the forerunner of the serine-containing
enzymes. This makes a lot of sense in terms of the catalytic chemistry, since the
thiol side chain of cysteine has a lower pK a , is more nucleophilic and is a better
leaving group than the hydroxyl group of serine. So why do the serine proteases