Biomedical Engineering Reference
In-Depth Information
The Metalloproteases Meprin a
and b: Pathophysiological Roles
in Inflammation, Cardiovascular
Disease, Cancer, and Fibrosis
Cell and Matrix Biology, Johannes Gutenberg-University,
Johannes-von-Mu¨ ller-Weg 6, D-55128 Mainz, Germany
2.1 Introduction
Meprins are members of the astacin family of metalloproteases and the met-
zincin superfamily (Figure 2.1). 1-6 The enzymes all contain the conserved motif
HExxHxxGxxHxxxRxDR, which is responsible for the coordination of a zinc
ion, stabilizing the water molecule required for catalysis. 4 This activated water
is further polarized by a glutamate residue. Mutation of this glutamate leads to
a complete loss of catalytic activity. 7,8 Additionally, the zinc ion is coordinated
by the three histidines present in the zinc-binding motif. The other common
feature of the metzincins is the 1,4-b-turn, termed the Met-turn, in close
proximity to the active site cleft, which enhances the thermal stability of the
The mechanism of proteolytic cleavage by the metzincins starts with the zinc-
activated water molecule that launches a nucleophilic attack on the bound
substrate. The a-carbonyl group of the P1 residue is then transformed into a
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