Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Journal of Assisted Reproduction and Genetics
Published in: Journal of Assisted Reproduction and Genetics 9/2019

01-09-2019 | Infertility | Gamete Biology

Identification and characterization of RSIY-11, a novel seminal peptide derived from semenogelin-1, which acts as a neutral endopeptidase inhibitor modulating sperm motility

Authors: Rani Fritz, Amarnath Mukherjee, Sahar Zaghi, Ilir Agalliu, Sangita Jindal, Alexandre K. Tashima, Lloyd D. Fricker, Kelvin P. Davies

Published in: Journal of Assisted Reproduction and Genetics | Issue 9/2019

Login to get access

Abstract

Purpose

Based on prior reports demonstrating that neutral endopeptidase (NEP) inhibitors increase sperm motility, the goal of our studies was to identify endogenous seminal peptides that inhibit NEP and investigate their potential effect on sperm motility.

Methods

Peptidomic analysis was performed on human seminal fluid, identifying 22 novel peptides. One peptide, named RSIY-11, derived from semenogelin-1, was predicted through sequence analysis to be a substrate and/or potential inhibitor of NEP. Enzymatic analysis was conducted to determine the inhibitory constant (Ki) of RSIY-11 as an inhibitor of NEP. Total and progressive sperm motility was determined at baseline and 30 and 60 min following addition of RSIY-11 to seminal fluid in 59 patients undergoing an infertility workup at an urban medical center. Additionally, the effects of RSIY-11 on sperm motility were evaluated in 15 of the 59 patients that met criteria for asthenospermia.

Results

RSIY-11 was shown to act as a competitive inhibitor of NEP with a Ki of 18.4 ± 1.6 μM. Addition of RSIY-11 at concentrations of 0.75 μM, 7.5 μM, and 75 μM significantly increased sperm motility at all time points investigated, with increases of 6.1%, 6.9%, and 9.2% at 60 min, respectively. Additionally, within the subgroup of patients with asthenospermia, RSIY-11 at concentrations of 0.75 μM, 7.5 μM, and 75 μM significantly increased sperm motility at all time points investigated, with increases of 7.6%, 8.8%, and 10.6% at 60 min, respectively.

Conclusions

RSIY-11 is a newly identified semenogelin-1-derived peptide present in seminal fluid. RSIY-11 acts as a potent competitive inhibitor of NEP, which when added to seminal fluid significantly increases sperm motility. RSIY-11 could play a potential role in the treatment for male factor infertility related to asthenospermia and improve intrauterine insemination outcomes.
Appendix
Available only for authorised users
Literature
1.
Centers for Disease Control and Prevention. vol. 2017, 2016.
2.
Larsen L, Scheike T, Jensen TK, Bonde JP, Ernst E, Hjollund NH, et al. Computer-assisted semen analysis parameters as predictors for fertility of men from the general population. The Danish First Pregnancy Planner Study Team. Hum Reprod. 2000;15:1562–7.CrossRefPubMed
3.
Jouannet P, Ducot B, Feneux D, Spira A. Male factors and the likelihood of pregnancy in infertile couples. I. Study of sperm characteristics. Int J Androl. 1988;11:379–94.CrossRefPubMed
4.
Zinaman MJ, Brown CC, Selevan SG, Clegg ED. Semen quality and human fertility: a prospective study with healthy couples. J Androl. 2000;21:145–53.PubMed
5.
de Lamirande E. Semenogelin, the main protein of the human semen coagulum, regulates sperm function. Semin Thromb Hemost. 2007;33:60–8.CrossRefPubMed
6.
Turner RM. Moving to the beat: a review of mammalian sperm motility regulation. Reprod Fertil Dev. 2006;18:25–38.CrossRefPubMed
7.
Cooper TG, Noonan E, von Eckardstein S, Auger J, Baker HW, Behre HM, et al. World Health Organization reference values for human semen characteristics. Hum Reprod Update. 2010;16:231–45.CrossRef
8.
9.
Fung KY, Glode LM, Green S, Duncan MW. A comprehensive characterization of the peptide and protein constituents of human seminal fluid. Prostate. 2004;61:171–81.CrossRefPubMed
10.
Pinto FM, Ravina CG, Subiran N, Cejudo-Roman A, Fernandez-Sanchez M, Irazusta J, et al. Autocrine regulation of human sperm motility by tachykinins. Reprod Biol Endocrinol. 2010;8:104.CrossRefPubMedPubMedCentral
11.
Subiran N, Agirregoitia E, Valdivia A, Ochoa C, Casis L, Irazusta J. Expression of enkephalin-degrading enzymes in human semen and implications for sperm motility. Fertil Steril. 2008;89:1571–7.CrossRefPubMed
12.
13.
Iwamoto T, Gagnon C. Purification and characterization of a sperm motility inhibitor in human seminal plasma. J Androl. 1988;9:377–83.CrossRefPubMed
14.
Iwamoto T, Gagnon C. A human seminal plasma protein blocks the motility of human spermatozoa. J Urol. 1988;140:1045–8.CrossRefPubMed
15.
Robert M, Gibbs BF, Jacobson E, Gagnon C. Characterization of prostate-specific antigen proteolytic activity on its major physiological substrate, the sperm motility inhibitor precursor/semenogelin I. Biochemistry. 1997;36:3811–9.CrossRefPubMed
16.
Lilja H, Abrahamsson PA, Lundwall A. Semenogelin, the predominant protein in human semen. Primary structure and identification of closely related proteins in the male accessory sex glands and on the spermatozoa. J Biol Chem. 1989;264:1894–900.PubMed
17.
Rougeot C, Messaoudi M, Hermitte V, Rigault AG, Blisnick T, Dugave C, et al. Sialorphin, a natural inhibitor of rat membrane-bound neutral endopeptidase that displays analgesic activity. Proc Natl Acad Sci U S A. 2003;100:8549–54.CrossRefPubMedPubMedCentral
18.
Bosler JS, Davies KP, Neal-Perry GS. Peptides in seminal fluid and their role in infertility: a potential role for opiorphin inhibition of neutral endopeptidase activity as a clinically relevant modulator of sperm motility: a review. Reprod Sci. 2014;21:1334–40.CrossRefPubMedPubMedCentral
19.
Wisner A, Dufour E, Messaoudi M, Nejdi A, Marcel A, Ungeheuer MN, et al. Human opiorphin, a natural antinociceptive modulator of opioid-dependent pathways. Proc Natl Acad Sci U S A. 2006;103:17979–84.CrossRefPubMedPubMedCentral
20.
Fricker L. Quantitative peptidomics: general considerations. Methods Mol Biol. 1719;2018:121–40.
21.
Fricker LD, Lim J, Pan H, Che FY. Peptidomics: identification and quantification of endogenous peptides in neuroendocrine tissues. Mass Spectrom Rev. 2006;25:327–44.CrossRefPubMed
22.
Morano C, Zhang X, Fricker LD. Multiple isotopic labels for quantitative mass spectrometry. AnalChem. 2008;80:9298–309.
23.
24.
Rawlings ND, Barrett AJ, Thomas PD, Huang X, Bateman A, Finn RD. The MEROPS database of proteolytic enzymes, their substrates and inhibitors in 2017 and a comparison with peptidases in the PANTHER database. Nucleic Acids Res. 2018;46:D624–D32.CrossRefPubMed
25.
26.
Ulvsback M, Lazure C, Lilja H, Spurr NK, Rao VV, Loffler C, et al. Gene structure of semenogelin I and II. The predominant proteins in human semen are encoded by two homologous genes on chromosome 20. J Biol Chem. 1992;267:18080–4.PubMed
27.
Fujisawa M, Kanzaki M, Okada H, Arakawa S, Kamidono S. Metenkephalin in seminal plasma of infertile men. Int J Urol. 1996;3:297–300.CrossRefPubMed
28.
Siems WE, Maul B, Wiesner B, Becker M, Walther T, Rothe L, et al. Effects of kinins on mammalian spermatozoa and the impact of peptidolytic enzymes. Andrologia. 2003;35:44–54.CrossRefPubMed
29.
Fernandez D, Valdivia A, Irazusta J, Ochoa C, Casis L. Peptidase activities in human semen. Peptides. 2002;23:461–8.CrossRefPubMed
30.
Barazani Y, Agarwal A, Sabanegh ES Jr. Functional sperm testing and the role of proteomics in the evaluation of male infertility. Urology. 2014;84:255–61.CrossRefPubMed
31.
Legare C, Droit A, Fournier F, Bourassa S, Force A, Cloutier F, et al. Investigation of male infertility using quantitative comparative proteomics. J Proteome Res. 2014;13:5403–14.CrossRefPubMed
32.
Gilany K, Minai-Tehrani A, Amini M, Agharezaee N, Arjmand B. The challenge of human spermatozoa proteome: a systematic review. J Reprod Infertil. 2017;18:267–79.PubMedPubMedCentral
33.
Jodar M, Soler-Ventura A, Oliva R, Molecular Biology of R, Development Research G. Semen proteomics and male infertility. J Proteome. 2017;162:125–34.CrossRef
34.
Samanta L, Parida R, Dias TR, Agarwal A. The enigmatic seminal plasma: a proteomics insight from ejaculation to fertilization. Reprod Biol Endocrinol. 2018;16:41.CrossRefPubMedPubMedCentral
35.
Pinto M, Rougeot C, Gracia L, Rosa M, Garcia A, Arsequell G, et al. Proposed bioactive conformations of opiorphin, an endogenous dual APN/NEP inhibitor. ACS Med Chem Lett. 2012;3:20–4.CrossRefPubMed
36.
Irazusta J, Valdivia A, Fernandez D, Agirregoitia E, Ochoa C, Casis L. Enkephalin-degrading enzymes in normal and subfertile human semen. J Androl. 2004;25:733–9.CrossRefPubMed
37.
Carlsson L, Ronquist G, Stridsberg M, Johansson L. Motility stimulant effects of prostasome inclusion in swim-up medium on cryopreserved human spermatozoa. Arch Androl. 1997;38:215–21.CrossRefPubMed
38.
Ronquist G, Brody I. The prostasome: its secretion and function in man. Biochim Biophys Acta. 1985;822:203–18.CrossRefPubMed
39.
Erdos EG, Skidgel RA. Human neutral endopeptidase 24.11 (NEP, enkephalinase); function, distribution and release. Adv Exp Med Biol. 1988;240:13–21.CrossRefPubMed
40.
Erdos EG, Skidgel RA. Neutral endopeptidase 24.11 (enkephalinase) and related regulators of peptide hormones. FASEB J. 1989;3:145–51.CrossRefPubMed
41.
Connelly JC, Skidgel RA, Schulz WW, Johnson AR, Erdos EG. Neutral endopeptidase 24.11 in human neutrophils: cleavage of chemotactic peptide. Proc Natl Acad Sci U S A. 1985;82:8737–41.CrossRefPubMedPubMedCentral
42.
Pierart ME, Najdovski T, Appelboom TE, Deschodt-Lanckman MM. Effect of human endopeptidase 24.11 (“enkephalinase”) on IL-1-induced thymocyte proliferation activity. J Immunol. 1988;140:3808–11.PubMed
43.
Akiyama H, Kondo H, Ikeda K, Kato M, McGeer PL. Immunohistochemical localization of neprilysin in the human cerebral cortex: inverse association with vulnerability to amyloid beta-protein (Abeta) deposition. Brain Res. 2001;902:277–81.CrossRefPubMed
Metadata
Title
Identification and characterization of RSIY-11, a novel seminal peptide derived from semenogelin-1, which acts as a neutral endopeptidase inhibitor modulating sperm motility
Authors
Rani Fritz
Amarnath Mukherjee
Sahar Zaghi
Ilir Agalliu
Sangita Jindal
Alexandre K. Tashima
Lloyd D. Fricker
Kelvin P. Davies
Publication date
01-09-2019
Publisher
Springer US
Published in
Journal of Assisted Reproduction and Genetics / Issue 9/2019
Print ISSN: 1058-0468
Electronic ISSN: 1573-7330
DOI
https://doi.org/10.1007/s10815-019-01524-8

Other articles of this Issue 9/2019

Journal of Assisted Reproduction and Genetics 9/2019 Go to the issue

Embryo Biology

Adjusted mitochondrial DNA quantification in human embryos may not be applicable as a biomarker of implantation potential

Letter to Editor

Letter to Editor

Commentary

Nature beyond control: how expectations should inform decisions about human germline engineering

EditorialNotes

Phase transitions in human ARTs: fertility preservation comes of age

Assisted Reproduction Technologies

Review of 10 years of preimplantation genetic diagnosis in South Africa: implications for a low-to-middle-income country

Fertility Preservation

Pharmacological administration of recombinant human AMH rescues ovarian reserve and preserves fertility in a mouse model of chemotherapy, without interfering with anti-tumoural effects