Activation of extracellular matrix metalloproteases by proteases and organomercurials.
Extracellular matrix metalloproteases are synthesized as proenzymes and are activated by certain physiological agents after secretion into the extracellular space. The identity of these agents and the stimulus that elicits their response in vivo is only recently becoming clear, but a variety of agents or stimuli are capable of activating these metalloproteases in vitro also. Of these, the most well studied and characterized are trypsin, plasmin and the organomercurials. These agents appear to have in common an ability to disrupt the structure of the stable latent enzyme in such a way as to allow the generation of a proteolytic active site. In the case of organomercurial activation, intramolecular proteolytic cleavage of the amino-terminus of the enzyme occurs subsequent to generation of activity. A similar intramolecular process is seen with trypsin and plasmin activation except that it is initiated by a single trypsin or plasmin catalyzed cleavage in the amino-terminus prior to the autocatalytic cleavages. A possible explanation for organomercurial activation is that the mercurial disrupts a cysteinyl residue coordination bond with the active site zinc that prevents interaction with substrate. Disruption of this complex would allow productive enzyme-substrate interaction via the newly available coordination site. In addition, activated stromelysin is capable of increasing the specific activity of active interstitial collagenase by approximately ten-fold through what appears to be proteolytic removal of a small peptide.
Grant
G A
GA
Division of Dermatology, Washington University School of Medicine, St. Louis, MO 63110.
Goldberg
G I
GI
Wilhelm
S M
SM
He
C
C
Eisen
A Z
AZ
D000595:Amino Acid Sequence; D000818:Animals; D001665:Binding Sites; D010450:Endopeptidases / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D004792:Enzyme Precursors / Q000187:drug effects*; D016326:Extracellular Matrix Proteins / Q000737:chemistry / Q000187:drug effects / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000737:chemistry / Q000378:metabolism*; D008969:Molecular Sequence Data; D005810:Multigene Family; D009941:Organomercury Compounds / Q000494:pharmacology*; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D015032:Zinc
D004792:Enzyme Precursors; D016326:Extracellular Matrix Proteins; D009941:Organomercury Compounds; D010450:Endopeptidases; D008666:Metalloendopeptidases; D015032:Zinc