Biomedical Engineering Reference
In-Depth Information
DPs play in human biology and disease, and evaluate further their suitability as
therapeutic targets.
In this chapter, we will provide an introduction to the significance of post-
proline cleavage, the DP4-like gene family enzymatic members, and the related
enzymes prolyl endopeptidase (PEP) and DP2. This will be followed by an in-
depth examination of the biochemical characteristics of DP4, FAP, DP8, and
DP9, their natural substrates, and biological relevance following DP cleavage.
Lastly, the suitability of targeting the DP family for the development of ther-
apeutics for the treatment of human health and disease will be discussed.
1.2 Post-Proline-Cleaving Enzymes
A number of biologically active proteins and regulatory peptides such as
cytokines, chemokines, growth hormones, and neuropeptides are protected
from general proteolysis due to an evolutionary conserved N-terminal proline
residue. 1-3 Such protection results from the unique cyclic and imino structure of
proline imposing conformational restrictions on the polypeptide backbone. 3
Even proteases exhibiting a very broad substrate specificity are unable to attack
peptide bonds where the prolyl residue is situated, and hence degradation of
such peptides requires the use of proline specific peptidases. 1-3
Although a number of proline-cleaving enzymes have been identified, only a
limited number of these proteases are capable of cleaving the N-terminal post-
prolyl, X-Pro-, bond 2,3 (Figure 1.1). The most notable of these enzymes are the
N-terminal-specific, dipeptidyl peptidases of the serine protease SC clan, S9b
sub-family such as DP4 (EC, the endopeptidase of the parent S9
family prolyl-endopeptidase (PEP; EC, and the S28 family member
DP2 (EC Lysosomal prolylcarboxypeptidase (PCP) (EC
also belongs to the S28 family, but in contrast to DP2, it functions as a C-
terminal-specific protease cleaving the Pro-Xaa bond at the C-termini of pro-
teins to release a single C-terminal amino acid. Carboxypeptidase P (EC is a membrane-localized protease with similar cleavage specificity to
lysosomal PCP; however, it is a metallo-, as opposed to serine, protease.
Aminopeptidase P (EC, prolidase (EC and prolinase are
additional proline-cleaving metalloproteases. Aminopeptidase P is an N-
terminal-specific protease, cleaving the pre-prolyl bond to release single amino
acids at the N-termini of proteins. Importantly, aminopeptidase P is involved in
cooperative activities with DP4 and related enzymes. 1 Prolidase and prolinase
cleave dipeptides with pre- and post-proline respectively to release two amino
acids. 1 The metalloprotease angiotensin-converting enzyme (ACE; EC
is also capable of cleaving prolyl bonds, although it is not renowned for its
ability to do this. DP4, first discovered in 1966 by Hopsu-Havu and Glenner as
the dipeptidyl cleaving glyclproline napthylamidase, 4 was the first N-terminal
post-proline-cleaving enzyme identified and hence the most readily investi-
gated. Since its discovery, related enzymes have been identified including
fibroblast activation FAP, 5 then DP8 and DP9. 6
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