A number of proteases dependent on divalent cations for their activity have
been shown [1,2] to belong to one family, on the basis of sequence similarity.
These enzymes are listed below.
Insulinase (EC 18.104.22.168) (also known as insulysin or insulin-degrading
enzyme or IDE), a cytoplasmic enzyme which seems to be involved in the
cellular processing of insulin, glucagon and other small polypeptides.
Escherichia coli protease III (EC 22.214.171.124) (pitrilysin) (gene ptr), a
periplasmic enzyme that degrades small peptides.
Mitochondrial processing peptidase (EC 126.96.36.199) (MPP). This enzyme
removes the transit peptide from the precursor form of proteins imported
from the cytoplasm across the mitochondrial inner membrane. It is composed
of two nonidentical homologous subunits termed α and β. The β
subunit seems to be catalytically active while the α subunit has
probably lost its activity.
Nardilysin (EC 188.8.131.52) (N-arginine dibasic convertase or NRD convertase)
this mammalian enzyme cleaves peptide substrates on the N-terminus of Arg
residues in dibasic stretches.
Klebsiella pneumoniae protein pqqF. This protein is required for the
biosynthesis of the coenzyme pyrrolo-quinoline-quinone (PQQ). It is thought
to be protease that cleaves peptide bonds in a small peptide (gene pqqA)
thus providing the glutamate and tyrosine residues necessary for the
synthesis of PQQ.
Yeast protein AXL1, which is involved in axial budding .
Eimeria bovis sporozoite developmental protein.
Escherichia coli hypothetical protein yddC and HI1368, the corresponding
Haemophilus influenzae protein.
Bacillus subtilis hypothetical protein ymxG.
Caenorhabditis elegans hypothetical proteins C28F5.4 and F56D2.1.
It should be noted that in addition to the above enzymes, this family also
includes the core proteins I and II of the mitochondrial bc1 complex (also
called cytochrome c reductase or complex III), but the situation as to the
activity or lack of activity of these subunits is quite complex:
In mammals and yeast, core proteins I and II lack enzymatic activity.
In Neurospora crassa and in potato core protein I is equivalent to the β
subunit of MPP.
In Euglena gracilis, core protein I seems to be active, while subunit II is
These proteins do not share many regions of sequence similarity; the most
noticeable is in the N-terminal section. This region includes a conserved
histidine followed, two residues later by a glutamate and another histidine.
In pitrilysin, it has been shown  that this H-x-x-E-H motif is involved in
enzyme activity; the two histidines bind zinc and the glutamate is necessary
for catalytic activity. Non active members of this family have lost from one
to three of these active site residues. We developed a signature pattern that
detect active members of this family as well as some inactive members.
These proteins belong to family M16 in the classification of peptidases
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