ID   HYALP_HUMAN             Reviewed;         509 AA.
AC   P38567; Q8TC30;
DT   01-OCT-1994, integrated into UniProtKB/Swiss-Prot.
DT   01-OCT-1994, sequence version 1.
DT   24-JAN-2024, entry version 193.
DE   RecName: Full=Hyaluronidase PH-20;
DE            Short=Hyal-PH20;
DE            EC=3.2.1.35;
DE   AltName: Full=Hyaluronoglucosaminidase PH-20;
DE   AltName: Full=Sperm adhesion molecule 1;
DE   AltName: Full=Sperm surface protein PH-20;
DE   Flags: Precursor;
GN   Name=SPAM1; Synonyms=HYAL3, PH20;
OS   Homo sapiens (Human).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC   Homo.
OX   NCBI_TaxID=9606;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC   TISSUE=Testis;
RX   PubMed=8234258; DOI=10.1073/pnas.90.21.10071;
RA   Lin Y., Kimmel L.H., Myles D.G., Primakoff P.;
RT   "Molecular cloning of the human and monkey sperm surface protein PH-20.";
RL   Proc. Natl. Acad. Sci. U.S.A. 90:10071-10075(1993).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND FUNCTION.
RC   TISSUE=Testis;
RX   PubMed=8282124; DOI=10.1016/0014-5793(93)80873-s;
RA   Gmachl M., Sagan S., Ketter S., Kreil G.;
RT   "The human sperm protein PH-20 has hyaluronidase activity.";
RL   FEBS Lett. 336:545-548(1993).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1).
RC   TISSUE=Testis;
RX   PubMed=8575780; DOI=10.1006/geno.1995.9931;
RA   Jones M.H., Davey P.M., Aplin H., Affara N.A.;
RT   "Expression analysis, genomic structure, and mapping to 7q31 of the human
RT   sperm adhesion molecule gene SPAM1.";
RL   Genomics 29:796-800(1995).
RN   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=12853948; DOI=10.1038/nature01782;
RA   Hillier L.W., Fulton R.S., Fulton L.A., Graves T.A., Pepin K.H.,
RA   Wagner-McPherson C., Layman D., Maas J., Jaeger S., Walker R., Wylie K.,
RA   Sekhon M., Becker M.C., O'Laughlin M.D., Schaller M.E., Fewell G.A.,
RA   Delehaunty K.D., Miner T.L., Nash W.E., Cordes M., Du H., Sun H.,
RA   Edwards J., Bradshaw-Cordum H., Ali J., Andrews S., Isak A., Vanbrunt A.,
RA   Nguyen C., Du F., Lamar B., Courtney L., Kalicki J., Ozersky P.,
RA   Bielicki L., Scott K., Holmes A., Harkins R., Harris A., Strong C.M.,
RA   Hou S., Tomlinson C., Dauphin-Kohlberg S., Kozlowicz-Reilly A., Leonard S.,
RA   Rohlfing T., Rock S.M., Tin-Wollam A.-M., Abbott A., Minx P., Maupin R.,
RA   Strowmatt C., Latreille P., Miller N., Johnson D., Murray J.,
RA   Woessner J.P., Wendl M.C., Yang S.-P., Schultz B.R., Wallis J.W.,
RA   Spieth J., Bieri T.A., Nelson J.O., Berkowicz N., Wohldmann P.E.,
RA   Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Bedell J.A.,
RA   Mardis E.R., Clifton S.W., Chissoe S.L., Marra M.A., Raymond C., Haugen E.,
RA   Gillett W., Zhou Y., James R., Phelps K., Iadanoto S., Bubb K., Simms E.,
RA   Levy R., Clendenning J., Kaul R., Kent W.J., Furey T.S., Baertsch R.A.,
RA   Brent M.R., Keibler E., Flicek P., Bork P., Suyama M., Bailey J.A.,
RA   Portnoy M.E., Torrents D., Chinwalla A.T., Gish W.R., Eddy S.R.,
RA   McPherson J.D., Olson M.V., Eichler E.E., Green E.D., Waterston R.H.,
RA   Wilson R.K.;
RT   "The DNA sequence of human chromosome 7.";
RL   Nature 424:157-164(2003).
RN   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=12690205; DOI=10.1126/science.1083423;
RA   Scherer S.W., Cheung J., MacDonald J.R., Osborne L.R., Nakabayashi K.,
RA   Herbrick J.-A., Carson A.R., Parker-Katiraee L., Skaug J., Khaja R.,
RA   Zhang J., Hudek A.K., Li M., Haddad M., Duggan G.E., Fernandez B.A.,
RA   Kanematsu E., Gentles S., Christopoulos C.C., Choufani S., Kwasnicka D.,
RA   Zheng X.H., Lai Z., Nusskern D.R., Zhang Q., Gu Z., Lu F., Zeesman S.,
RA   Nowaczyk M.J., Teshima I., Chitayat D., Shuman C., Weksberg R.,
RA   Zackai E.H., Grebe T.A., Cox S.R., Kirkpatrick S.J., Rahman N.,
RA   Friedman J.M., Heng H.H.Q., Pelicci P.G., Lo-Coco F., Belloni E.,
RA   Shaffer L.G., Pober B., Morton C.C., Gusella J.F., Bruns G.A.P., Korf B.R.,
RA   Quade B.J., Ligon A.H., Ferguson H., Higgins A.W., Leach N.T.,
RA   Herrick S.R., Lemyre E., Farra C.G., Kim H.-G., Summers A.M., Gripp K.W.,
RA   Roberts W., Szatmari P., Winsor E.J.T., Grzeschik K.-H., Teebi A.,
RA   Minassian B.A., Kere J., Armengol L., Pujana M.A., Estivill X.,
RA   Wilson M.D., Koop B.F., Tosi S., Moore G.E., Boright A.P., Zlotorynski E.,
RA   Kerem B., Kroisel P.M., Petek E., Oscier D.G., Mould S.J., Doehner H.,
RA   Doehner K., Rommens J.M., Vincent J.B., Venter J.C., Li P.W., Mural R.J.,
RA   Adams M.D., Tsui L.-C.;
RT   "Human chromosome 7: DNA sequence and biology.";
RL   Science 300:767-772(2003).
RN   [6]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G., Florea L., Halpern A.L., Mobarry C.M.,
RA   Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA   Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA   Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA   Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA   Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA   Hunkapiller M.W., Myers E.W., Venter J.C.;
RL   Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN   [7]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC   TISSUE=Testis;
RX   PubMed=15489334; DOI=10.1101/gr.2596504;
RG   The MGC Project Team;
RT   "The status, quality, and expansion of the NIH full-length cDNA project:
RT   the Mammalian Gene Collection (MGC).";
RL   Genome Res. 14:2121-2127(2004).
RN   [8]
RP   MUTAGENESIS OF ASP-146; GLU-148; ARG-211; GLU-284 AND ARG-287, AND
RP   GLYCOSYLATION.
RX   PubMed=9288901; DOI=10.1111/j.1432-1033.1997.t01-1-00810.x;
RA   Arming S., Strobl B., Wechselberger C., Kreil G.;
RT   "In vitro mutagenesis of PH-20 hyaluronidase from human sperm.";
RL   Eur. J. Biochem. 247:810-814(1997).
RN   [9]
RP   VARIANT GLN-5.
RX   PubMed=21248752; DOI=10.1038/nature09639;
RA   Varela I., Tarpey P., Raine K., Huang D., Ong C.K., Stephens P., Davies H.,
RA   Jones D., Lin M.L., Teague J., Bignell G., Butler A., Cho J.,
RA   Dalgliesh G.L., Galappaththige D., Greenman C., Hardy C., Jia M.,
RA   Latimer C., Lau K.W., Marshall J., McLaren S., Menzies A., Mudie L.,
RA   Stebbings L., Largaespada D.A., Wessels L.F.A., Richard S., Kahnoski R.J.,
RA   Anema J., Tuveson D.A., Perez-Mancera P.A., Mustonen V., Fischer A.,
RA   Adams D.J., Rust A., Chan-On W., Subimerb C., Dykema K., Furge K.,
RA   Campbell P.J., Teh B.T., Stratton M.R., Futreal P.A.;
RT   "Exome sequencing identifies frequent mutation of the SWI/SNF complex gene
RT   PBRM1 in renal carcinoma.";
RL   Nature 469:539-542(2011).
CC   -!- FUNCTION: Involved in sperm-egg adhesion. Upon fertilization sperm must
CC       first penetrate a layer of cumulus cells that surrounds the egg before
CC       reaching the zona pellucida. The cumulus cells are embedded in a matrix
CC       containing hyaluronic acid which is formed prior to ovulation. This
CC       protein aids in penetrating the layer of cumulus cells by digesting
CC       hyaluronic acid. {ECO:0000269|PubMed:8282124}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Random hydrolysis of (1->4)-linkages between N-acetyl-beta-D-
CC         glucosamine and D-glucuronate residues in hyaluronate.; EC=3.2.1.35;
CC   -!- SUBCELLULAR LOCATION: Cell membrane; Lipid-anchor, GPI-anchor.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=P38567-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=P38567-2; Sequence=VSP_042714;
CC   -!- TISSUE SPECIFICITY: Testis. {ECO:0000269|PubMed:8234258}.
CC   -!- PTM: N-glycosylated. {ECO:0000269|PubMed:9288901}.
CC   -!- SIMILARITY: Belongs to the glycosyl hydrolase 56 family. {ECO:0000305}.
CC   -!- WEB RESOURCE: Name=Atlas of Genetics and Cytogenetics in Oncology and
CC       Haematology;
CC       URL="https://atlasgeneticsoncology.org/gene/42361/SPAM1";
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DR   EMBL; L13781; -; NOT_ANNOTATED_CDS; mRNA.
DR   EMBL; S67798; AAC60607.2; -; mRNA.
DR   EMBL; X84347; CAA59086.1; -; mRNA.
DR   EMBL; AC004690; AAQ96882.1; -; Genomic_DNA.
DR   EMBL; CH236947; EAL24329.1; -; Genomic_DNA.
DR   EMBL; CH471070; EAW83606.1; -; Genomic_DNA.
DR   EMBL; BC026163; AAH26163.1; -; mRNA.
DR   CCDS; CCDS5790.1; -. [P38567-2]
DR   CCDS; CCDS5791.1; -. [P38567-1]
DR   PIR; S40465; S40465.
DR   RefSeq; NP_001167515.1; NM_001174044.1. [P38567-1]
DR   RefSeq; NP_001167516.1; NM_001174045.1. [P38567-1]
DR   RefSeq; NP_001167517.1; NM_001174046.1. [P38567-1]
DR   RefSeq; NP_003108.2; NM_003117.4. [P38567-2]
DR   RefSeq; NP_694859.1; NM_153189.2. [P38567-1]
DR   AlphaFoldDB; P38567; -.
DR   SMR; P38567; -.
DR   BioGRID; 112559; 1.
DR   STRING; 9606.ENSP00000345849; -.
DR   DrugBank; DB08818; Hyaluronic acid.
DR   CAZy; GH56; Glycoside Hydrolase Family 56.
DR   GlyCosmos; P38567; 6 sites, No reported glycans.
DR   GlyGen; P38567; 6 sites.
DR   iPTMnet; P38567; -.
DR   PhosphoSitePlus; P38567; -.
DR   BioMuta; SPAM1; -.
DR   DMDM; 585673; -.
DR   MassIVE; P38567; -.
DR   PaxDb; 9606-ENSP00000345849; -.
DR   PeptideAtlas; P38567; -.
DR   ProteomicsDB; 55298; -. [P38567-1]
DR   ProteomicsDB; 55299; -. [P38567-2]
DR   Antibodypedia; 2991; 206 antibodies from 25 providers.
DR   DNASU; 6677; -.
DR   Ensembl; ENST00000223028.11; ENSP00000223028.7; ENSG00000106304.16. [P38567-1]
DR   Ensembl; ENST00000340011.9; ENSP00000345849.5; ENSG00000106304.16. [P38567-2]
DR   Ensembl; ENST00000402183.3; ENSP00000386028.3; ENSG00000106304.16. [P38567-2]
DR   Ensembl; ENST00000439500.5; ENSP00000402123.1; ENSG00000106304.16. [P38567-1]
DR   Ensembl; ENST00000460182.5; ENSP00000417934.1; ENSG00000106304.16. [P38567-1]
DR   Ensembl; ENST00000682466.1; ENSP00000508393.1; ENSG00000106304.16. [P38567-1]
DR   GeneID; 6677; -.
DR   KEGG; hsa:6677; -.
DR   MANE-Select; ENST00000682466.1; ENSP00000508393.1; NM_153189.3; NP_694859.1.
DR   UCSC; uc003vle.4; human. [P38567-1]
DR   AGR; HGNC:11217; -.
DR   CTD; 6677; -.
DR   DisGeNET; 6677; -.
DR   GeneCards; SPAM1; -.
DR   HGNC; HGNC:11217; SPAM1.
DR   HPA; ENSG00000106304; Tissue enriched (testis).
DR   MIM; 600930; gene.
DR   neXtProt; NX_P38567; -.
DR   OpenTargets; ENSG00000106304; -.
DR   PharmGKB; PA36053; -.
DR   VEuPathDB; HostDB:ENSG00000106304; -.
DR   eggNOG; ENOG502R6HD; Eukaryota.
DR   GeneTree; ENSGT01020000230364; -.
DR   HOGENOM; CLU_036366_0_1_1; -.
DR   InParanoid; P38567; -.
DR   OMA; RAKIVFE; -.
DR   OrthoDB; 5344684at2759; -.
DR   PhylomeDB; P38567; -.
DR   TreeFam; TF321598; -.
DR   BioCyc; MetaCyc:HS02884-MONOMER; -.
DR   BRENDA; 3.2.1.35; 2681.
DR   PathwayCommons; P38567; -.
DR   Reactome; R-HSA-2534343; Interaction With Cumulus Cells And The Zona Pellucida.
DR   BioGRID-ORCS; 6677; 7 hits in 1134 CRISPR screens.
DR   GeneWiki; SPAM1; -.
DR   GenomeRNAi; 6677; -.
DR   Pharos; P38567; Tbio.
DR   PRO; PR:P38567; -.
DR   Proteomes; UP000005640; Chromosome 7.
DR   RNAct; P38567; Protein.
DR   Bgee; ENSG00000106304; Expressed in sperm and 25 other cell types or tissues.
DR   ExpressionAtlas; P38567; baseline and differential.
DR   GO; GO:0001669; C:acrosomal vesicle; IBA:GO_Central.
DR   GO; GO:0005886; C:plasma membrane; TAS:Reactome.
DR   GO; GO:0098552; C:side of membrane; IEA:UniProtKB-KW.
DR   GO; GO:0004415; F:hyalurononglucosaminidase activity; IBA:GO_Central.
DR   GO; GO:0007339; P:binding of sperm to zona pellucida; TAS:ProtInc.
DR   GO; GO:0005975; P:carbohydrate metabolic process; TAS:ProtInc.
DR   GO; GO:0007155; P:cell adhesion; IEA:UniProtKB-KW.
DR   GO; GO:0007342; P:fusion of sperm to egg plasma membrane involved in single fertilization; IEA:InterPro.
DR   GO; GO:0030214; P:hyaluronan catabolic process; IBA:GO_Central.
DR   Gene3D; 3.20.20.70; Aldolase class I; 1.
DR   InterPro; IPR013785; Aldolase_TIM.
DR   InterPro; IPR017853; Glycoside_hydrolase_SF.
DR   InterPro; IPR018155; Hyaluronidase.
DR   InterPro; IPR001439; Hyaluronidase_PH20/Hyal5.
DR   PANTHER; PTHR11769; HYALURONIDASE; 1.
DR   PANTHER; PTHR11769:SF20; HYALURONIDASE PH-20; 1.
DR   Pfam; PF01630; Glyco_hydro_56; 1.
DR   PIRSF; PIRSF038193; Hyaluronidase; 1.
DR   PIRSF; PIRSF500773; Hyaluronidase_PH20_Hyal5; 1.
DR   PRINTS; PR00846; GLHYDRLASE56.
DR   PRINTS; PR00848; SPERMPH20.
DR   SUPFAM; SSF51445; (Trans)glycosidases; 1.
DR   Genevisible; P38567; HS.
PE   1: Evidence at protein level;
KW   Alternative splicing; Cell adhesion; Cell membrane; Disulfide bond;
KW   Glycoprotein; Glycosidase; GPI-anchor; Hydrolase; Lipoprotein; Membrane;
KW   Reference proteome; Signal.
FT   SIGNAL          1..35
FT                   /evidence="ECO:0000250"
FT   CHAIN           36..490
FT                   /note="Hyaluronidase PH-20"
FT                   /id="PRO_0000012089"
FT   PROPEP          491..509
FT                   /note="Removed in mature form"
FT                   /evidence="ECO:0000255"
FT                   /id="PRO_0000012090"
FT   ACT_SITE        148
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000250"
FT   LIPID           490
FT                   /note="GPI-anchor amidated serine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        82
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        166
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        235
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        254
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        368
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   CARBOHYD        393
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
FT   DISULFID        60..351
FT                   /evidence="ECO:0000250"
FT   DISULFID        224..238
FT                   /evidence="ECO:0000250"
FT   DISULFID        376..387
FT                   /evidence="ECO:0000250"
FT   DISULFID        381..435
FT                   /evidence="ECO:0000250"
FT   DISULFID        437..464
FT                   /evidence="ECO:0000250"
FT   VAR_SEQ         496..509
FT                   /note="VSILFLIISSVASL -> WRLEVWDQGISRIGFF (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_042714"
FT   VARIANT         5
FT                   /note="K -> Q (found in a renal cell carcinoma sample;
FT                   somatic mutation)"
FT                   /evidence="ECO:0000269|PubMed:21248752"
FT                   /id="VAR_064756"
FT   VARIANT         47
FT                   /note="V -> A (in dbSNP:rs34633019)"
FT                   /id="VAR_049213"
FT   MUTAGEN         146
FT                   /note="D->N: Reduces activity by 80%."
FT                   /evidence="ECO:0000269|PubMed:9288901"
FT   MUTAGEN         148
FT                   /note="E->Q: Loss of activity."
FT                   /evidence="ECO:0000269|PubMed:9288901"
FT   MUTAGEN         211
FT                   /note="R->G: Reduces activity by over 90%."
FT                   /evidence="ECO:0000269|PubMed:9288901"
FT   MUTAGEN         284
FT                   /note="E->Q: Loss of activity."
FT                   /evidence="ECO:0000269|PubMed:9288901"
FT   MUTAGEN         287
FT                   /note="R->T: Loss of activity."
FT                   /evidence="ECO:0000269|PubMed:9288901"
FT   CONFLICT        48
FT                   /note="P -> A (in Ref. 2; AAC60607)"
FT                   /evidence="ECO:0000305"
FT   CONFLICT        499
FT                   /note="L -> W (in Ref. 2; AAC60607)"
FT                   /evidence="ECO:0000305"
SQ   SEQUENCE   509 AA;  57848 MW;  5ADB4739747E32E8 CRC64;
     MGVLKFKHIF FRSFVKSSGV SQIVFTFLLI PCCLTLNFRA PPVIPNVPFL WAWNAPSEFC
     LGKFDEPLDM SLFSFIGSPR INATGQGVTI FYVDRLGYYP YIDSITGVTV NGGIPQKISL
     QDHLDKAKKD ITFYMPVDNL GMAVIDWEEW RPTWARNWKP KDVYKNRSIE LVQQQNVQLS
     LTEATEKAKQ EFEKAGKDFL VETIKLGKLL RPNHLWGYYL FPDCYNHHYK KPGYNGSCFN
     VEIKRNDDLS WLWNESTALY PSIYLNTQQS PVAATLYVRN RVREAIRVSK IPDAKSPLPV
     FAYTRIVFTD QVLKFLSQDE LVYTFGETVA LGASGIVIWG TLSIMRSMKS CLLLDNYMET
     ILNPYIINVT LAAKMCSQVL CQEQGVCIRK NWNSSDYLHL NPDNFAIQLE KGGKFTVRGK
     PTLEDLEQFS EKFYCSCYST LSCKEKADVK DTDAVDVCIA DGVCIDAFLK PPMETEEPQI
     FYNASPSTLS ATMFIVSILF LIISSVASL
//