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Activation of latent protease function of pro-hK2, but not pro-PSA, involves autoprocessing

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Author

  • Samuel R. Denmeade
  • Janita Lövgren
  • Saeed R. Khan
  • Hans Lilja
  • John T. Isaacs

Summary, in English

BACKGROUND: Human glandular kallikrein 2 (hK2) and prostate-specific antigen (PSA) are members of an extensive kallikrein family of proteases. Both proteases are secreted as zymogens or proenzymes containing a seven amino acid propeptide that must be proteolytically removed for enzymatic activation. The physiological proteases that activate pro-hK2 and pro-PSA are not known. METHODS: The pro-hK2 peptide sequence is Val-Pro-Leu-Ile-Gln-Ser-Arg (VPLIQSR). For PSA, the amino acid sequence of the propeptide is Ala-Pro-Leu-Ile-Leu-Ser-Arg (APLILSR). Fluorescent substrates were made by coupling these peptide sequences to 7-amino-4-methylcoumarin (AMC). The hydrolysis of the VPLIQSR-AMC and APLILSR-AMC substrates by hK2, PSA, and a panel of purified proteases was determined. RESULTS: HK2 readily cleaved the pro-hK2 peptide substrate VPLIQSR-AMC with a rate of hydrolysis that was approximately 8-fold higher than an equimolar amount of purified trypsin. HK2 also had the highest hydrolysis rate from among a group of other trypsin-like proteases. In contrast, neither hK2 nor PSA was able to appreciably cleave the pro-PSA substrate APLILSR-AMC. The pro-PSA substrate was most readily hydrolyzed by urokinase and trypsin. CONCLUSIONS: HK2 can hydrolyze the pro-hK2 substrate suggesting that maturation of pro-hK2 to enzymatically active hK2 involves autoprocessing. As expected, PSA, a chymotrypsin-like protease, was unable to hydrolyze either of the propeptide substrates. Therefore, it is unlikely that PSA can auto-process its own enzymatic function. HK2 has trypsin-like specificity but was unable to hydrolyze the pro-PSA substrate. These results raise the possibility that an additional processing protease may be required to fully process PSA to an enzymatically active form.

Publishing year

2001

Language

English

Pages

122-126

Publication/Series

The Prostate

Volume

48

Issue

2

Document type

Journal article

Publisher

John Wiley & Sons Inc.

Topic

  • Obstetrics, Gynecology and Reproductive Medicine

Keywords

  • auto-processing
  • prostate cancer
  • prostate-specific antigen (PSA)
  • human glandular kallikrein 2 (hK2)
  • propeptide

Status

Published

Research group

  • Clinical Chemistry, Malmö

ISBN/ISSN/Other

  • ISSN: 0270-4137