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shuffling. Thus, mast cell chymase (
CMA1
; 14q11.2; Huang and Hellman, 1994),
the digestive pancreatic proteases [trypsin (
PRSS1
and
PRSS2
; 7q35), chy-
motrypsin (
CTRB1
; 16q23) and elastase (
ELA1
; 12q13)] and the hepatic pro-
teases of coagulation (e.g. thrombin;
F2
; 11p11-q12) have all evolved from the
same common ancestral precursor gene (Greer, 1990). This ancestral gene appears
to predate the divergence of eukaryotes and prokaryotes (Rypniewski
et al
., 1994)
and may itself have been the product of an internal duplication (McLachlan,
1979). Enormous structural and functional diversity has been generated both by
the addition of non-proteolytic domains and by changes in the enzyme active sites
which account for differences in their specificity.
The vitamin K-dependent serine proteases of coagulation exhibit substantial
sequence and structural homology and their evolution is described in some detail
in Section 4.3 and Chapter 3, section 3.6.3 and Chapter 10, section 10.2. Human
representatives of this serine protease family include factor VII (
F7
; 13q34), fac-
tor IX (
F9
; Xq27), factor X (
F10
; 13q34), prothrombin (
F2
; 11p11-q12), protein
C (
PROC
; 2q13-q14) and protein S (
PROS1
; 3p11). Various serine proteases have
also been recruited to functions in fibrinolysis e.g. plasminogen (
PLG
; 6q26-q27),
tissue-type plasminogen activator (
PLAT
; 8p11-q12) and urokinase (
PLAU
;
10q24-qter) and, phylogenetically, these are closely related to the contact factors:
factor XI (
F11
; 4q34), factor XII (
F12
; 5q33-qter) and plasma kallikrein (
KLK3
;
4q34-q35) (
Figure 3.7
).
The division between the proteases of coagulation and fibrinolysis is apparent
at the level of exon/intron organization but also in terms of codon usage for the
active site serine residue (Brenner, 1988). The genes encoding the vitamin K-
dependent factors of coagulation possess an AGY codon whereas the fibrinolytic
enzyme genes exhibit a TCN codon also found in the serine protease genes of
eubacteria and invertebrates. These alternative codons cannot be interconverted
by a single nucleotide substitution. Brenner (1988) proposed that the AGY codon
could have been derived from an active cysteine residue encoded by TGY in a cys-
teine protease that existed billions of years ago. Irwin (1988) has however argued
that the AGY codon evolved from a TCN codon on at least two separate occasions,
once on the lineage leading to the vitamin K-dependent factors of coagulation and
once on the lineage leading to plasminogen and apolipoprotein(a).
Hypervariability of the active site regions is apparent in some serine proteases
indicating that rapid evolution of the reactive center may have driven the func-
tional divergence of these enzymes (Creighton and Darby, 1989; Huang and
Hellman, 1994; Lesk and Fordham, 1996; Ohta, 1994). Since a similar phenome-
non is apparent for the serine protease inhibitors (see Section 4.2.3,
Serpin genes
),
it may be that the proteolytic enzymes and their inhibitors have coevolved.
Serpin genes.
The serine protease inhibitors (Serpins) are a superfamily of pro-
teins with over 100 members in mammals, and counterparts in invertebrates,
plants and even some viruses (Marshall, 1993). Serpins interact with the sub-
strate-binding sites of their cognate proteases via an exposed binding site of
canonical conformation (Bode and Huber, 1992). The protease and its inhibitor
rapidly form a tightly bound 1 : 1 stoichiometric complex with the reactive center
of the serpin acting as a bait for the appropriate serine protease. Mammalian
