The chymotrypsin‐like activity of human prostate‐specific antigen, γ‐seminoprotein

Akiyama, Kanji; Nakamura, Takanori; Iwanaga, Sadaaki; Hara, Mitsuwo

doi:10.1016/0014-5793(87)81151-1

Cited by 128 publications

(67 citation statements)

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“…The N-terminus of the 38-kDa component was blocked, but from the sequences of the peptide fragments generated by proteolytic digestion, the protein was unequivocally identified as semenoclotin. However, the outcome of the experiment was quite unexpected as only one out of five peptides seemed to have been generated by an enzyme with the restricted chymotrypsin-like properties as PSA has been reported to have (Watt et al, 1986;Akiyama et al, 1987;Christensson et al, 1990). The rest of the peptides were generated by cleavage on the Cterminal side of Lys residues.…”

Section: Discussionmentioning

confidence: 99%

Chemical Characterization of the Predominant Proteins Secreted by Mouse Seminal Vesicles

Lundwall¹,

Peter²,

Lövgren³

et al. 1997

European Journal of Biochemistry

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Mouse seminal vesicles secrete four major protein components with estimated molecular masses of 95, 38, 17, and 16 kDa. Amino acid sequencing revealed that the 95-kDa component represents a protein with an unknown structure, while the 38-kDa component was identified as semenoclotin, the 17-kDa component as seminal-vesicle-secreted protein IV, and the 16-kDa component as seminal-vesicle-secreted protein V. Semenoclotin and the 95-kDa component were readily cross-linked by transglutaminase, suggesting that the two proteins are involved in the formation of the mouse copulatory plug. Treatment of mouse seminal vesicle fluid with human prostate-specific antigen rapidly degraded semenoclotin, indicating a structural resemblance of this protein to human semenogelins, despite the vast difference in primary structure. As previously reported for other seminal-vesicle-secreted proteins, the semenoclotin transcripts are shown to be under androgen control.Keywords: seminal vesicle ; semen ; androgen; transglutaminase ; coagulation.Mammalian semen is formed by the mixing of spermatozoarich fluid from epididymis with secretions from the accessory sex glands during ejaculation, that mainly consists of fluids from the seminal vesicles and the prostate (Mann and Lutwark-Mann, 1981). In most species, the major contribution is provided by the seminal vesicles, amounting to more than half of the semen volume. The newly ejaculated sperm is highly viscous or gellike, but within a short time it will either liquefy, as in man, or transform into a firm coagulum, yielding a copulatory plug through the action of a prostate-secreted transglutaminase, as seen in rodents.The proteins responsible for gel and clot formation are present at very high concentrations in the seminal vesicle fluid. Somewhat unexpectedly, the primary structure of these proteins are highly dissimilar between species (Lundwall and Lazure, 1995; Lundwall and Ulvsback, 1996). This is caused by a relatively recent evolution of an ancestral gene, involving duplications, exon expansion, and varying selection of splice sites. The genes constitute the REST gene family (abbreviation for rapidly evolving substrates for transglutaminase) as most members seem to encode substrates for transglutaminase (Lundwall, 1996 : Lundwall and Ulvsback, 1996).The rat seminal vesicle secretion consists of five predominant protein components, designated seminal-vesicle-secreted proteins I-V (SVS I-V) in order of size (Ostrowski et al., 1979). The SVS IV and V components are also referred to as S and F proteins by some authors (Higgins et al., 1976). The strucCorrespondence to A. Lundwall,

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Section: Discussionmentioning

confidence: 99%

Chemical Characterization of the Predominant Proteins Secreted by Mouse Seminal Vesicles

Lundwall¹,

Peter²,

Lövgren³

et al. 1997

European Journal of Biochemistry

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“…2,3 PSA is a serine protease that belongs to the kallikrein gene family with chymotrypsin-like activity that is involved in the hydrolytic processing of semenogelins (cleavage of the semenal fluid proteins semenogelin I and II), which is required for liquefaction of seminal fluids. 2,3 Over-expression of PSA has primarily been demonstrated in prostate carcinoma and at low levels in breast cancer. [4][5][6][7][8] We have recently developed an albumin-binding prodrug of doxorubicin that is cleaved by PSA, i.e., EMC-Arg-Arg-Ser-SerTyr-Tyr-Ser-Gly-DOXO (EMC 5 6-maleimidocaproic acid; DOXO 5 doxorubicin.…”

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confidence: 99%

Synthesis and biological evaluation of an albumin‐binding prodrug of doxorubicin that is cleaved by prostate‐specific antigen (PSA) in a PSA‐positive orthotopic prostate carcinoma model (LNCaP)

Graeser¹,

Chung

Esser³

et al. 2007

Intl Journal of Cancer

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The prostate-specific antigen (PSA) is a serine protease that is over-expressed in prostate carcinoma and represents a molecular target for selectively releasing an anticancer agent from a prodrug formulation. We have recently investigated a macromolecular prodrug strategy for improved cancer chemotherapy based on 2 features: (i) rapid and selective binding of thiol-reactive prodrugs to the cysteine-34 position of endogenous albumin after intravenous administration, and (ii) enzymatic release of the albuminbound drug at the tumor site (Mansour et al., Cancer Res 2003, 63, 4062-4066). In this work, we describe an albumin-binding prodrug, EMC-Arg-Ser-Ser-Tyr-Tyr-Ser-Arg-DOXO [EMC: e-Maleimidocaproic acid; DOXO 5 doxorubicin; X 5 amino acid] that is cleaved by PSA. Because of the incorporation of 2 arginine residues, the prodrug exhibited excellent water-solubility and was rapidly and selectively bound to endogenous albumin. Incubation studies with PSA and tumor homogenates from PSA-positive tumors (LNCaP) demonstrated that the albumin-bound form of the prodrug was efficiently cleaved by PSA at the P 1 -P 0 1 scissile bond releasing the doxorubicin dipeptide H-Ser-Arg-DOXO, which was further degraded to doxorubicin as the final cleavage product. In cell culture experiments, the prodrug was 100-fold less active against LNCaP cells than the free drug. In contrast, in a mouse model of human prostate cancer using luciferase transduced LNCaP cells orthotopically implanted in SCID mice, the prodrug showed enhanced antitumor efficacy when compared to doxorubicin. Doxorubicin treatment at a dose of 2 3 4 mg/kg caused significant weight loss and mortality (225%), and did not result in a significant antitumor response at the end of the experiment. The prodrug at 3 3 12 mg/kg doxorubicin equivalents, however, was well tolerated and induced a significant reduction in tumor size of 62% (625%, **p 5 0.003) as well as a decrease of the metastatic burden in the lungs as detected in luciferase assays (250%, SD 6 115%, *p 5 0.038). ' 2007 Wiley-Liss, Inc.Key words: doxorubicin; macromolecular prodrug; human serum albumin; PSA; orthotopic animal model; LNCaP; luciferase; in vivo bioluminescence Hormone refractory prostate cancer responds unfavorably to chemotherapy. The best results to date are achieved with Taxotere. 1 To improve prostate cancer therapy, tumor-specific delivery of anticancer agents to the primary tumor and metastases is a goal worth pursuing.For selectively releasing anticancer agents, the prostate-specific antigen (PSA) is especially attractive as a target protease because it is solely expressed in prostate tissue and prostate carcinoma in prostate cancer patients with high levels up to mg/g present in human prostate carcinoma. 2,3 PSA is a serine protease that belongs to the kallikrein gene family with chymotrypsin-like activity that is involved in the hydrolytic processing of semenogelins (cleavage of the semenal fluid proteins semenogelin I and II), which is required for liquefaction of seminal fluids. 2,3 Over...

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“…We hypothesized that the F protein cleavage site of NDV could be made cleavable by prostate-specific antigen (PSA) so as to restrict its replication to PSA-producing CaP cells. PSA is a serine protease with chymotrypsin-like substrate specificity (8)(9)(10)(11) that is found in high concentrations (mg/ ml) in the seminal plasma (12). Increased serum PSA levels correlate with tumor volume (13) and most probably result from leakage of PSA from the prostatic ductal system into the prostatic stroma and subsequently into the bloodstream.…”

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confidence: 99%

Prostate-Specific Antigen-Retargeted Recombinant Newcastle Disease Virus for Prostate Cancer Virotherapy

Raghunath

Samal

Elankumaran

2013

J Virol

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The chymotrypsin‐like activity of human prostate‐specific antigen, γ‐seminoprotein

Cited by 128 publications

References 11 publications

Chemical Characterization of the Predominant Proteins Secreted by Mouse Seminal Vesicles

Chemical Characterization of the Predominant Proteins Secreted by Mouse Seminal Vesicles

Synthesis and biological evaluation of an albumin‐binding prodrug of doxorubicin that is cleaved by prostate‐specific antigen (PSA) in a PSA‐positive orthotopic prostate carcinoma model (LNCaP)

Prostate-Specific Antigen-Retargeted Recombinant Newcastle Disease Virus for Prostate Cancer Virotherapy

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