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BACKGROUND: In semen, prostate-specific antigen (PSA or hK3) digests the gel proteins semenogelin I and II, resulting in liquefaction and the release of motile spermatozoa. We characterized the substrate specificity and zinc-mediated inhibition of PSA. METHODS: The proteolysis of human semenogelin I (SgI) and II (SgII) by PSA was characterized by purification of generated SgI and SgII fragments, N-terminal sequencing, and mass spectrometry. Zn(2+)-inhibition of PSA was studied using a chromogenic substrate. RESULTS: Eighteen cleavage sites in SgI and 16 in SgII were identified. Cleavages were identified mainly as the C-terminal of certain tyrosine and glutamine residues, but also the C-terminal of histidine, aspartic acid, leucine, serine, and asparagine residues. No cleavages were identified at any arginine, lysine, phenylalanine, tryptophan, or methionine residues, indicating that the substrate specificity of PSA is distinct from that of trypsin, chymotrypsin, tissue kallkrein (hK1), and kallikrein 2 (hK2). Zn(2+) ions have a dramatic effect on PSA activity; the data indicate that Zn(2+) is a tight-binding inhibitor of PSA activity. CONCLUSIONS: The data will enable the optimized design of PSA activity assays, which may prove instrumental to uncovering the role of PSA in cancer and reproduction. The inhibition data indicate that Zn(2+) could regulate PSA activity, which may prove important in the development of efficient inhibitors of PSA activity.

Type

Journal article

Journal

Prostate

Publication Date

01/10/2000

Volume

45

Pages

132 - 139

Keywords

Amino Acid Sequence, Cations, Divalent, Enzyme Inhibitors, Enzymes, Gonadal Steroid Hormones, Humans, Hydrolysis, Molecular Sequence Data, Prostate-Specific Antigen, Semen, Seminal Plasma Proteins, Seminal Vesicle Secretory Proteins, Sequence Homology, Amino Acid, Substrate Specificity, Zinc, alpha 1-Antichymotrypsin