Eppin (epididymal protease inhibitor) is one of several serine protease (or serine protease-like) inhibitors that are encoded by genes on human chromosome 20 and on mouse chromosome 2. Here we review our current knowledge of human and mouse Eppin genes and the Eppin protein in the context of protease inhibitors. Antibodies to Eppin in immunized male monkeys provide an effective and reversible contraceptive and these antibodies may be effective by interfering with Eppin's interaction with semenogelin during ejaculation. We review Eppin-semenogelin interaction and present a working model in the context of the hydrolysis of semenogelin by prostate specific antigen.
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Proc Natl Acad Sci U S A
December 2024
Center for Drug Discovery, Department of Pathology & Immunology, Baylor College of Medicine, Houston, TX 77030.
Despite 96 million years of evolution separating humans and rodents, 11 closely related reproductive tract-specific genes in humans-, , , , , , , , , , and -and the 13 reproductive tract-specific orthologous genes in mice, form highly conserved syntenic gene clusters indicative of conserved, combined critical functions. Further, despite significant progress toward a nonhormonal male contraceptive targeting the protein encoded by one of these genes, epididymal peptidase inhibitor (EPPIN), and associations found between mutations in and an increased risk of male infertility, neither EPPIN nor any closely related whey acidic protein four-disulfide core (WFDC) gene have been explored functionally. To clarify the involvement of WFDC genes in male fertility, we strategically used CRISPR/Cas9 to generate mice lacking 13, 10, 5, or 4 genes within the cluster and demonstrated that males with deletions of 13, 10, or 4 genes (Wfdc6a, Eppin, Wfdc8, and Wfdc6a) were sterile due to an arrest in spermatogenesis, preventing formation beyond round spermatids.
View Article and Find Full Text PDFSci Rep
September 2023
Department of Biophysics and Pharmacology, Institute of Biosciences of Botucatu, São Paulo State University, Botucatu, SP, Brazil.
Novel male contraceptives will promote gender equality in sharing contraceptive responsibility. The sperm-associated protein epididymal protease inhibitor (EPPIN) is a promising target for non-hormonal male contraception. EPPIN interacts with the semen coagulum protein semenogelin-1 (SEMG1) on the sperm surface, leading to transient inhibition of sperm motility after ejaculation.
View Article and Find Full Text PDFInt J Biol Macromol
June 2022
Department of Biotechnology, College of Science and Humanities, SRM Institute of Science and Technology, Kattankulathur, 603 203 Chennai, Tamil Nadu, India. Electronic address:
Human male infertility affects approximately 1/10 couples worldwide, and its prevalence is found more in developed countries. Along with sperm cells, the secretions of the prostate, seminal vesicle and epididymis plays a major role in proper fertilization. Many studies have proven the functions of seminal vesicle secretions, especially semenogelin protein, as an optimiser for fertilization.
View Article and Find Full Text PDFMol Hum Reprod
November 2021
Department of Biophysics and Pharmacology, Institute of Biosciences, São Paulo State University, Botucatu-SP, Brazil.
EPPIN (epididymal protease inhibitor) is a mammalian conserved sperm-binding protein displaying an N-terminal WFDC (whey-acidic protein four-disulfide core) and a C-terminal Kunitz protease inhibitor domains. EPPIN plays a key role in regulating sperm motility after ejaculation via interaction with the seminal plasma protein SEMG1 (semenogelin-1). EPPIN ligands targeting the SEMG1 binding site in the Kunitz domain are under development as male contraceptive drugs.
View Article and Find Full Text PDFReprod Biol
June 2021
Department of Toxicology, School of Public Health, Medical College of Soochow University, Suzhou, China; Jiangsu Key Laboratory of Preventive and Translational Medicine for Geriatric Diseases, School of Public Health, Medical College of Soochow University, Suzhou, China. Electronic address:
Epididymal protease inhibitor (EPPIN) is differentially expressed in the reproductive tissues (such as testicles, outlet tubes, epididymis, vas deferens, and seminal vesicles). Its critical role in sperm function and male reproduction has shed light on EPPIN as a candidate target for male contraceptive vaccines. In this study, we endeavored to further reveal the mechanism through which EPPIN exerts its function.
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