Biomedical Engineering Reference
In-Depth Information
CHAPTER 1
Dipeptidyl Peptidases: Substrates
and Therapeutic Targeting in
HumanHealthandDisease
CLAIRE H. WILSON AND CATHERINE A. ABBOTT
School of Biological Sciences, Flinders University, GPO BOX 2100,
Adelaide 5001, South Australia, Australia
1.1 Introduction
Dipeptidyl peptidase 4 (DP4), fibroblast activation protein (FAP), DP8, and
DP9 are the enzymatic members of the serine protease S9b DP4-like gene
family. One of the most important features of the DPs is their ability to pre-
ferentially cleave the N-terminal post-prolyl bond of regulatory peptides and
small protein substrates. DP4 proteolysis results in the inactivation, activation,
or alteration of its substrates function via changes in receptor selectivity; thus
DP4 plays an important role in regulating biological function. Together, DP4
and FAP have been implicated in a number of diseases including liver disease,
obesity, type II diabetes, arthritis, inflammatory bowel disease and cancer.
Recently, evidence has emerged to implicate both DP8 and DP9 in innate
immunity, and DP8/9 in vitro cleavage of well-known DP4 substrates, including
neuropeptide Y (NPY), glucagon-like peptide (GLP)-1, and a number of che-
mokines, has been demonstrated. Despite this, the true pathophysiological
roles of DP8/9 and their involvement within human biology and disease are still
to be elucidated. Identification of the in vivo substrate repertoire of each DP will
be an important step toward elucidating the biochemical pathways in which
each protease is involved. This will allow us to unravel further the roles that the
