Biomedical Engineering Reference
In-Depth Information
Figure 1.1 Proline-bond cleaving proteases. ACE, angiotensin-converting enzyme;
DP, dipeptidyl peptidase; FAP, fibroblast activation protein; PCP, prolyl-
carboxypeptidase; PEP, prolyl-endopeptidase.
1.3 DP4-Like Gene Family and Related Enzymes
Members of the DP4-like gene family, S9b, make up a sub-family of the
prolyl-oligopeptidase (POP) S9 family within the serine protease clan SC. 7,8
In total the S9b family consists of six homologous members; the four pro-
teases,DP4,FAP,DP8andDP9andtwoinactiveproteasehomologs,DP6
and DP10 (Figure 1.2). Sharing similar features, PEP from the parent S9
family is also capable of cleaving the N-terminal post-prolyl bond but with
endopeptidase specificity. 9,10 In contrast to DP4, PEP is limited in its ability
to cleave unblocked, free N-terminal dipeptides from substrates; 10 however,
inhibitors designed specifically for DPs can still bind to, and block, the
enzymatic function of PEP. 11,12 FAP, in addition to its DP activity, also
functions as an endopeptidase. 13,14 Structurally, the three crystallized S9b
family members DP4, FAP and DP6 contain an a/b hydrolase domain and
eight-bladed b-propeller domain (Figure 1.2) 13,15-18 distinguishing it from
that of parent PEP which contains a seven-bladed b-propeller domain. 19
Protease members of this family and PEP all contain the non-classical
arrangement of the serine protease catalytic triad (Ser, Asp, and His), located
within the C-terminal portion of the a/b hydrolase domain (Figure 1.2). The
inactive protease homologs DP6 and DP10 contain a mutation of the cata-
lytic serine residue to an aspartic acid 20 and glutamine residue 21 respectively.
All enzyme members contain the catalytic serine protease motif around the
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