Biology Reference
In-Depth Information
9.5 Contributions of Elastases to Elastolysis
Proteinases represent the second largest collection of gene products in nature trailing
only the ubiquitins in number. Proteolytic enzymes fall into one of five classes, which
are based upon the mechanism of catalysis: aspartic, cysteine, threonine, metallo-,
and serine (Neurath
1999
). There are currently greater than 66,000 identified protei-
nases subdivided into 50 clans and 184 families. Very few of these enzymes have
been invested with the capacity to degrade elastin, limited to just a fewmembers each
of the metallo-, cysteine, and serine proteinase classes. Specific contributions of
individual proteinases to elastolysis in disease are discussed below.
9.5.1 Serine Proteinases
The serine proteinases comprise greater than one-third of all known proteinases, all
of which originate from a single gene that has been extensively duplicated over the
course of evolution (Page and Di Cera
2008
). They are expressed by virtually all
life forms ranging from prokaryotes to mammals. Serine proteinases play diverse
roles in humans including the digestion of food, the coagulation cascade, and the
degradation of ECM structures. The name of these proteinases derives from the
nucleophilic Ser residue that is essential for catalysis. The charge relay system in
serine proteinases is composed of conserved His-Asp-Ser residues that functions
via transfer of electrons from the carboxyl group of the Asp to the oxygen of the
Ser. This Ser group, now a powerful nucleophile, attacks the carbonyl carbon atom
of the peptide bond in the substrate (Hedstrom
2002
).
The serine proteinases have been subdivided into numerous clans and families.
With respect to mammalian serine proteinases, elastolysis is limited to clan PA,
family S1, subfamily A, also referred to as trypsin-like serine proteinases. With the
exception of pancreatic elastase, these enzymes are, for the most part, neutrophil
specific and include neutrophil elastase (NE), cathepsin G (CG), and proteinase-3
(PR3) (Pham
2006
). There have also been reports of tumor cell and endothelial cell-
derived serine elastases (Rabinovitch
1999
); however, these may yet prove to be
traditional neutrophil-derived serine proteinases that have been endocytosed by
neighboring cells.
The serine elastases are synthesized as pre-pro enzymes in the endoplasmic
reticulum before subsequent removal of the signal peptide (pre-) and dipeptide
(pro-) by dipeptidyl peptidase I (DPPI or cathepsin C) (Adkison et al.
2002
). These
active enzymes are then stored in intracellular granules, termed azurophilic gran-
ules when located within neutrophils. NE, CG, and PR3 are all approximately
28-30 kDa in size. They are housed together within azurophil granules and secreted
together as well. They possess similar substrate specificities although differential
potency with NE
CG in general. These enzymes are rarely dumped into
the ECM, as previously thought. Upon physiological stimulation, PMN mobilize
~12% of their NE content to the cell surface, where it is catalytically active and
PR3
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