Inhibition of prostate-specific antigen (PSA) by alpha(1)-antichymotrypsin: salt-dependent activation mediated by a conformational change.
Prostate-specific antigen (PSA) and its SDS-stable complex with the serine proteinase inhibitor (serpin) alpha(1)-antichymotrypsin (ACT), which is the dominant form of PSA in serum, are in widespread use as markers for the diagnosis of prostate cancer, and there is increasing evidence for the involvement of PSA proteinase activity itself in the development of prostate and other cancers. However, both the formation and degradation of the PSA-ACT complex, denoted PSA*ACT* to indicate substantial changes in the structure of both proteins on complex formation, have been incompletely studied. Here we determine rate and equilibrium constants for the steps involved in PSA*ACT* formation and demonstrate that (a) the effects of added NaCl, polyamines, and Zn(2+) on this process parallel their effects on PSA catalytic activity [Hsieh, M.-C., and Cooperman, B. S. (2000) Biochim. Biophys. Acta 1481, 75-87], (b) the effect of added NaCl in dramatically increasing the rate of ACT inhibition of PSA correlates with salt-induced changes in PSA conformation, and (c) the PSA*ACT* complex is subject to proteolysis by human neutrophil elastase. Possible clinical implications of these findings are considered.
Hsieh
Ming-Ching
MC
Department of Chemistry, University of Pennsylvania, Philadelphia, Pennsylvania 19104-6323, USA.
Cooperman
Barry S
BS
D004591:Electrophoresis, Polyacrylamide Gel; D006801:Humans; D008297:Male; D009994:Osmolar Concentration; D010447:Peptide Hydrolases / Q000378:metabolism; D011073:Polyamines / Q000494:pharmacology; D017430:Prostate-Specific Antigen / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011487:Protein Conformation / Q000187:drug effects; D012965:Sodium Chloride / Q000494:pharmacology; D015032:Zinc / Q000494:pharmacology; D000514:alpha 1-Antichymotrypsin / Q000494:pharmacology*
D011073:Polyamines; D000514:alpha 1-Antichymotrypsin; D012965:Sodium Chloride; D010447:Peptide Hydrolases; D017430:Prostate-Specific Antigen; D015032:Zinc