Fertilization (Homo sapiens)

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4, 95, 7, 14, 16, 171, 132, 14118, 1036612cytosolplasma membranecytosolEggplasma membraneSpermADAM2 ZP1 IZUMO2 ACR(20-42)ZP3 H+CD9:IzumoZP3 SPAM1 CATSPERD B4GALT1 CATSPER4 ZP1 Ca2+Acrosin Heavy:lightchainHUAB4GALT1SPAM1CATSPERD HV1 ChannelK+K+P4 IZUMO3 IZUMO1 ADAM20 Adam ComplexCa2+ZP4 ZP2 ACR(20-421)ADAM30 CATSPERB CATSPERB SPAM1:HyaluronicacidZP4 ACR(20-42) Activated CatSperChannelH+CATSPER1 IZUMO1 ADAM2 KCNU1 CatSper ChannelIZUMO3 ADAM21 CATSPER3 HVCN1 Zonapellucida:B4GALT1CD9 CATSPER4 IZUMO2 CATSPER1 HUA CD9CATSPERG ACR(43-343) Slo3 ChannelOVGP1 ADAM30 CATSPER3 ADAM20 IzumoADAM21 OVGP1 IZUMO4 P4CATSPER2 Zona pellucidaCATSPER2 CATSPERG ZP2 IZUMO4 ACR(43-343)1515


Mammalian fertilization comprises sperm migration through the female reproductive tract, biochemical and morphological changes to sperm, and sperm-egg interaction in the oviduct. Although the broad concepts of fertilization are well defined, our understanding of the biochemical mechanisms underlying sperm-egg binding is limited. View original pathway at:Reactome.


Pathway is converted from Reactome ID: 1187000
Reactome version: 66
Reactome Author 
Reactome Author: Gillespie, Marc E

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  1. Ellerman DA, Pei J, Gupta S, Snell WJ, Myles D, Primakoff P.; ''Izumo is part of a multiprotein family whose members form large complexes on mammalian sperm.''; PubMed Europe PMC Scholia
  2. Str√ľnker T, Goodwin N, Brenker C, Kashikar ND, Weyand I, Seifert R, Kaupp UB.; ''The CatSper channel mediates progesterone-induced Ca2+ influx in human sperm.''; PubMed Europe PMC Scholia
  3. Lin Y, Mahan K, Lathrop WF, Myles DG, Primakoff P.; ''A hyaluronidase activity of the sperm plasma membrane protein PH-20 enables sperm to penetrate the cumulus cell layer surrounding the egg.''; PubMed Europe PMC Scholia
  4. Evans JP, Florman HM.; ''The state of the union: the cell biology of fertilization.''; PubMed Europe PMC Scholia
  5. Smith JF, Syritsyna O, Fellous M, Serres C, Mannowetz N, Kirichok Y, Lishko PV.; ''Disruption of the principal, progesterone-activated sperm Ca2+ channel in a CatSper2-deficient infertile patient.''; PubMed Europe PMC Scholia
  6. Tranter R, Read JA, Jones R, Brady RL.; ''Effector sites in the three-dimensional structure of mammalian sperm beta-acrosin.''; PubMed Europe PMC Scholia
  7. Qi H, Moran MM, Navarro B, Chong JA, Krapivinsky G, Krapivinsky L, Kirichok Y, Ramsey IS, Quill TA, Clapham DE.; ''All four CatSper ion channel proteins are required for male fertility and sperm cell hyperactivated motility.''; PubMed Europe PMC Scholia
  8. Navarro B, Kirichok Y, Clapham DE.; ''KSper, a pH-sensitive K+ current that controls sperm membrane potential.''; PubMed Europe PMC Scholia
  9. Johnston DS, Wooters J, Kopf GS, Qiu Y, Roberts KP.; ''Analysis of the human sperm proteome.''; PubMed Europe PMC Scholia
  10. Schreiber M, Wei A, Yuan A, Gaut J, Saito M, Salkoff L.; ''Slo3, a novel pH-sensitive K+ channel from mammalian spermatocytes.''; PubMed Europe PMC Scholia
  11. Lishko PV, Botchkina IL, Fedorenko A, Kirichok Y.; ''Acid extrusion from human spermatozoa is mediated by flagellar voltage-gated proton channel.''; PubMed Europe PMC Scholia
  12. Ikawa M, Inoue N, Benham AM, Okabe M.; ''Fertilization: a sperm's journey to and interaction with the oocyte.''; PubMed Europe PMC Scholia
  13. Sutovsky P.; ''Sperm-egg adhesion and fusion in mammals.''; PubMed Europe PMC Scholia
  14. Lishko PV, Botchkina IL, Kirichok Y.; ''Progesterone activates the principal Ca2+ channel of human sperm.''; PubMed Europe PMC Scholia
  15. Iwamoto R, Higashiyama S, Mitamura T, Taniguchi N, Klagsbrun M, Mekada E.; ''Heparin-binding EGF-like growth factor, which acts as the diphtheria toxin receptor, forms a complex with membrane protein DRAP27/CD9, which up-regulates functional receptors and diphtheria toxin sensitivity.''; PubMed Europe PMC Scholia
  16. Ren D, Navarro B, Perez G, Jackson AC, Hsu S, Shi Q, Tilly JL, Clapham DE.; ''A sperm ion channel required for sperm motility and male fertility.''; PubMed Europe PMC Scholia
  17. Hildebrand MS, Avenarius MR, Fellous M, Zhang Y, Meyer NC, Auer J, Serres C, Kahrizi K, Najmabadi H, Beckmann JS, Smith RJ.; ''Genetic male infertility and mutation of CATSPER ion channels.''; PubMed Europe PMC Scholia


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101475view11:34, 1 November 2018ReactomeTeamreactome version 66
101013view21:13, 31 October 2018ReactomeTeamreactome version 65
100549view19:47, 31 October 2018ReactomeTeamreactome version 64
100097view16:32, 31 October 2018ReactomeTeamreactome version 63
99647view15:03, 31 October 2018ReactomeTeamreactome version 62 (2nd attempt)
99249view12:44, 31 October 2018ReactomeTeamreactome version 62
93331view11:20, 9 August 2017ReactomeTeamreactome version 61
86417view09:17, 11 July 2016ReactomeTeamreactome version 56
83300view10:40, 18 November 2015ReactomeTeamVersion54
81434view12:57, 21 August 2015ReactomeTeamVersion53
76906view08:17, 17 July 2014ReactomeTeamFixed remaining interactions
76611view11:58, 16 July 2014ReactomeTeamFixed remaining interactions
75942view09:59, 11 June 2014ReactomeTeamRe-fixing comment source
75642view10:52, 10 June 2014ReactomeTeamReactome 48 Update
74997view13:51, 8 May 2014AnweshaFixing comment source for displaying WikiPathways description
74641view08:41, 30 April 2014ReactomeTeamNew pathway

External references


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NameTypeDatabase referenceComment
ACR(20-42) ProteinP10323 (Uniprot-TrEMBL)
ACR(20-42)ProteinP10323 (Uniprot-TrEMBL)
ACR(20-421)ProteinP10323 (Uniprot-TrEMBL)
ACR(43-343) ProteinP10323 (Uniprot-TrEMBL)
ACR(43-343)ProteinP10323 (Uniprot-TrEMBL)
ADAM2 ProteinQ99965 (Uniprot-TrEMBL)
ADAM20 ProteinO43506 (Uniprot-TrEMBL)
ADAM21 ProteinQ9UKJ8 (Uniprot-TrEMBL)
ADAM30 ProteinQ9UKF2 (Uniprot-TrEMBL)
Acrosin Heavy:light chainComplexR-HSA-1297314 (Reactome)
Activated CatSper ChannelComplexR-HSA-2534353 (Reactome)
Adam ComplexComplexR-HSA-1297290 (Reactome)
B4GALT1 ProteinP15291 (Uniprot-TrEMBL)
B4GALT1ProteinP15291 (Uniprot-TrEMBL)
CATSPER1 ProteinQ8NEC5 (Uniprot-TrEMBL)
CATSPER2 ProteinQ96P56 (Uniprot-TrEMBL)
CATSPER3 ProteinQ86XQ3 (Uniprot-TrEMBL)
CATSPER4 ProteinQ7RTX7 (Uniprot-TrEMBL)
CATSPERB ProteinQ9H7T0 (Uniprot-TrEMBL)
CATSPERD ProteinQ86XM0 (Uniprot-TrEMBL)
CATSPERG ProteinQ6ZRH7 (Uniprot-TrEMBL)
CD9 ProteinP21926 (Uniprot-TrEMBL)
CD9:IzumoComplexR-HSA-1297262 (Reactome)
CD9ProteinP21926 (Uniprot-TrEMBL)
Ca2+MetaboliteCHEBI:29108 (ChEBI)
CatSper ChannelComplexR-HSA-2534382 (Reactome)
H+MetaboliteCHEBI:15378 (ChEBI)
HUA MetaboliteCHEBI:16336 (ChEBI)
HUAMetaboliteCHEBI:16336 (ChEBI)
HV1 ChannelComplexR-HSA-2534381 (Reactome)
HVCN1 ProteinQ96D96 (Uniprot-TrEMBL)
IZUMO1 ProteinQ8IYV9 (Uniprot-TrEMBL)
IZUMO2 ProteinQ6UXV1 (Uniprot-TrEMBL)
IZUMO3 ProteinQ5VZ72 (Uniprot-TrEMBL)
IZUMO4 ProteinQ1ZYL8 (Uniprot-TrEMBL)
IzumoComplexR-HSA-1297355 (Reactome)
K+MetaboliteCHEBI:29103 (ChEBI)
KCNU1 ProteinA8MYU2 (Uniprot-TrEMBL)
OVGP1 ProteinQ12889 (Uniprot-TrEMBL)
P4 MetaboliteCHEBI:17026 (ChEBI)
P4MetaboliteCHEBI:17026 (ChEBI)
SPAM1 ProteinP38567 (Uniprot-TrEMBL)
SPAM1:Hyaluronic acidComplexR-HSA-1297353 (Reactome)
SPAM1ProteinP38567 (Uniprot-TrEMBL)
Slo3 ChannelComplexR-HSA-2534372 (Reactome)
ZP1 ProteinP60852 (Uniprot-TrEMBL)
ZP2 ProteinQ05996 (Uniprot-TrEMBL)
ZP3 ProteinP21754 (Uniprot-TrEMBL)
ZP4 ProteinQ12836 (Uniprot-TrEMBL)
Zona pellucida:B4GALT1ComplexR-HSA-1297296 (Reactome)
Zona pellucidaComplexR-HSA-1297292 (Reactome)

Annotated Interactions

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SourceTargetTypeDatabase referenceComment
ACR(20-42)ArrowR-HSA-1297354 (Reactome)
ACR(20-42)R-HSA-1297333 (Reactome)
ACR(20-421)R-HSA-1297354 (Reactome)
ACR(20-421)mim-catalysisR-HSA-1297354 (Reactome)
ACR(43-343)ArrowR-HSA-1297354 (Reactome)
ACR(43-343)R-HSA-1297333 (Reactome)
Acrosin Heavy:light chainArrowR-HSA-1297333 (Reactome)
Activated CatSper ChannelArrowR-HSA-2534388 (Reactome)
Activated CatSper Channelmim-catalysisR-HSA-2534359 (Reactome)
Adam ComplexR-HSA-1297338 (Reactome)
B4GALT1R-HSA-1297338 (Reactome)
CD9:IzumoArrowR-HSA-1297275 (Reactome)
CD9R-HSA-1297275 (Reactome)
Ca2+ArrowR-HSA-2534359 (Reactome)
Ca2+R-HSA-2534359 (Reactome)
CatSper ChannelR-HSA-2534388 (Reactome)
H+ArrowR-HSA-2534378 (Reactome)
H+R-HSA-2534378 (Reactome)
HUAR-HSA-2534346 (Reactome)
HV1 Channelmim-catalysisR-HSA-2534378 (Reactome)
IzumoR-HSA-1297275 (Reactome)
K+ArrowR-HSA-2534365 (Reactome)
K+R-HSA-2534365 (Reactome)
P4R-HSA-2534388 (Reactome)
R-HSA-1297275 (Reactome) The mebrane of the post-acrosomal reaction sperm and the membrane of the oocyte are bound to one another by the CD9 transmembrane protein on the oocyte and the Izumo transmembrane protein on the sperm.
R-HSA-1297333 (Reactome) The heavy and light chain proacrosin cleavage products bind to form an active acrosin complex.
R-HSA-1297338 (Reactome) In humans induction of acrosome reaction is mediated by ADAM and B4GALT1 binding to ZP3 and ZP4. Binding of ZP3 to its putative sperm receptor zona receptor kinase, leads to its aggregation and downstream cAMP signaling.
R-HSA-1297354 (Reactome) Acrosin is localized in the acrosomal matrix as an enzymatically inactive zymogen, proacrosin. Upon stimulation by zona pellucida binding and ca2+ influx, proacrosin is cleaved into a heavy and light chain.
R-HSA-2534346 (Reactome) The fertilizing spermatozoon must penetrate the surrounding cumulus mass, (or cumulus oophorus), consisting of follicular cells dispersed in a polymerized matrix composed mainly of hyaluronic acid.
R-HSA-2534359 (Reactome) CatSper (CATionic channel of SPERm), a pH regulated, principal flagellar calcium ion channel. CatSper is a core regulator of sperm tail calcium entry and sperm motility. All CatSper subunits are sperm specific proteins and are located in the principal piece of the sperm flagellum. The sperm specific CatSper channel controls the intracellular Ca(2+) concentration. Progesterone activates human CatSper, but not mouse, at low nanomolar concentrations by shifting the voltage dependency of the human CatSper channel into the physiological range. The pore of the CatSper channel is formed by four different CATSPER proteins (CATSPER 1, 2, 3, and -4) and all four are required for formation of the functional channel. In addition, three auxiliary subunits (CATSPERB, CATSPERG and CATSPERD) make this complex to be the one of the most sophisticated mammalian ion channels known. Only CATSPER1 is believed to be regulated by pH. The absence of any of the pore-forming CATSPER proteins, or gamma or beta auxiliary subunits- leads to disappearance of the whole CatSper channel. Syndromic male infertility (SMI) in association with CATSPER mutations is described in a number of human gene mutation studies. The absence of CatSper channel leads to male infertility both in mice and humans.
R-HSA-2534365 (Reactome) Slo3 represents a new and unique type of potassium channel regulated by intracellular pH. Slo3 is sperm specific and controls membrane potential. Incapacitated murine spermatozoa hyperpolarize to approximately 60 mV during capacitation, an effect attributed to an increase in K+ permeability. KSper (potassium transport in sperm) is the dominant, if not the only, K+ selective channel in mouse epididymal spermatozoa.
R-HSA-2534378 (Reactome) Intracellular alkalinization is essential for the initiation of motility, capacitation, hyperactivation, and the acrosome reaction. Hv1 mediates the voltage-dependent proton permeability of excitable membranes. Hv1 is abundantly expressed in human sperm cells within the principal piece of the sperm flagellum, making it ideally positioned to activate pH-dependent proteins of the axoneme and thus to control sperm motility.
R-HSA-2534388 (Reactome) Steroid hormone progesterone released by cumulus cells surrounding the egg is a potent stimulator of human spermatozoa. It attracts spermatozoa towards the egg and helps them penetrate the egg's protective vestments. Progesterone induces Ca2+ influx into spermatozoa and triggers multiple Ca2+-dependent physiological responses essential for successful fertilization, such as sperm hyperactivation, acrosome reaction and chemotaxis towards the egg. Progesterone dramatically potentiates CatSper calcium transport activity, identifying CatSper as the progesterone receptor of sperm.
SPAM1:Hyaluronic acidArrowR-HSA-2534346 (Reactome)
SPAM1R-HSA-2534346 (Reactome)
Slo3 Channelmim-catalysisR-HSA-2534365 (Reactome)
Zona pellucida:B4GALT1ArrowR-HSA-1297338 (Reactome)
Zona pellucidaR-HSA-1297338 (Reactome)
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