ID   HEXD_HUMAN              Reviewed;         486 AA.
AC   Q8WVB3; B7UUP6; Q8IYN4; Q8TE81;
DT   05-FEB-2008, integrated into UniProtKB/Swiss-Prot.
DT   05-FEB-2008, sequence version 3.
DT   24-JAN-2024, entry version 145.
DE   RecName: Full=Hexosaminidase D {ECO:0000305};
DE            EC=3.2.1.52 {ECO:0000269|PubMed:23099419};
DE   AltName: Full=Beta-N-acetylhexosaminidase;
DE   AltName: Full=Beta-hexosaminidase D;
DE   AltName: Full=Hexosaminidase domain-containing protein;
DE   AltName: Full=N-acetyl-beta-galactosaminidase;
GN   Name=HEXD {ECO:0000312|HGNC:HGNC:26307};
GN   Synonyms=HEXDC {ECO:0000312|HGNC:HGNC:26307};
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 FUNCTION.
RX   PubMed=19040401; DOI=10.1042/bj20081630;
RA   Gutternigg M., Rendic D., Voglauer R., Iskratsch T., Wilson I.B.;
RT   "Mammalian cells contain a second nucleocytoplasmic hexosaminidase.";
RL   Biochem. J. 419:83-90(2009).
RN   [2]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX   PubMed=16625196; DOI=10.1038/nature04689;
RA   Zody M.C., Garber M., Adams D.J., Sharpe T., Harrow J., Lupski J.R.,
RA   Nicholson C., Searle S.M., Wilming L., Young S.K., Abouelleil A.,
RA   Allen N.R., Bi W., Bloom T., Borowsky M.L., Bugalter B.E., Butler J.,
RA   Chang J.L., Chen C.-K., Cook A., Corum B., Cuomo C.A., de Jong P.J.,
RA   DeCaprio D., Dewar K., FitzGerald M., Gilbert J., Gibson R., Gnerre S.,
RA   Goldstein S., Grafham D.V., Grocock R., Hafez N., Hagopian D.S., Hart E.,
RA   Norman C.H., Humphray S., Jaffe D.B., Jones M., Kamal M., Khodiyar V.K.,
RA   LaButti K., Laird G., Lehoczky J., Liu X., Lokyitsang T., Loveland J.,
RA   Lui A., Macdonald P., Major J.E., Matthews L., Mauceli E., McCarroll S.A.,
RA   Mihalev A.H., Mudge J., Nguyen C., Nicol R., O'Leary S.B., Osoegawa K.,
RA   Schwartz D.C., Shaw-Smith C., Stankiewicz P., Steward C., Swarbreck D.,
RA   Venkataraman V., Whittaker C.A., Yang X., Zimmer A.R., Bradley A.,
RA   Hubbard T., Birren B.W., Rogers J., Lander E.S., Nusbaum C.;
RT   "DNA sequence of human chromosome 17 and analysis of rearrangement in the
RT   human lineage.";
RL   Nature 440:1045-1049(2006).
RN   [3]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA   Mural R.J., Istrail S., Sutton G.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   [4]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORMS 1 AND 2), AND VARIANT
RP   TYR-232.
RC   TISSUE=Blood, and Cervix;
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   [5]
RP   NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] OF 8-486 (ISOFORM 1).
RX   PubMed=14702039; DOI=10.1038/ng1285;
RA   Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA   Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA   Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA   Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA   Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA   Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA   Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA   Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA   Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA   Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA   Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA   Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA   Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA   Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA   Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA   Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA   Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA   Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA   Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA   Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA   Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA   Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA   Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA   Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA   Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA   Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA   Isogai T., Sugano S.;
RT   "Complete sequencing and characterization of 21,243 full-length human
RT   cDNAs.";
RL   Nat. Genet. 36:40-45(2004).
RN   [6]
RP   FUNCTION, TISSUE SPECIFICITY, CATALYTIC ACTIVITY, INDUCTION BY TGFB1, AND
RP   SUBCELLULAR LOCATION.
RX   PubMed=23099419; DOI=10.1016/j.imlet.2012.10.012;
RA   Pasztoi M., Sodar B., Misjak P., Paloczi K., Kittel A., Toth K.,
RA   Wellinger K., Geher P., Nagy G., Lakatos T., Falus A., Buzas E.I.;
RT   "The recently identified extre D enzyme substantially contributes to the
RT   elevated hexosaminidase activity in rheumatoid arthritis.";
RL   Immunol. Lett. 149:71-76(2013).
RN   [7]
RP   FUNCTION, CATALYTIC ACTIVITY, BIOPHYSICOCHEMICAL PROPERTIES, AND
RP   MUTAGENESIS OF HIS-92; ASP-148 AND GLU-149.
RX   PubMed=27149221; DOI=10.1021/acs.biochem.5b01285;
RA   Alteen M.G., Oehler V., Nemcovicova I., Wilson I.B., Vocadlo D.J.,
RA   Gloster T.M.;
RT   "Mechanism of Human Nucleocytoplasmic Hexosaminidase D.";
RL   Biochemistry 55:2735-2747(2016).
CC   -!- FUNCTION: Has hexosaminidase activity. Responsible for the cleavage of
CC       the monosaccharides N-acetylglucosamine (GlcNAc) and N-
CC       acetylgalactosamine (GalNAc) from cellular substrates. Has a preference
CC       for galactosaminide over glucosaminide substrates (PubMed:27149221).
CC       {ECO:0000269|PubMed:19040401, ECO:0000269|PubMed:23099419,
CC       ECO:0000269|PubMed:27149221}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=Hydrolysis of terminal non-reducing N-acetyl-D-hexosamine
CC         residues in N-acetyl-beta-D-hexosaminides.; EC=3.2.1.52;
CC         Evidence={ECO:0000269|PubMed:23099419, ECO:0000269|PubMed:27149221};
CC   -!- ACTIVITY REGULATION: Inhibited by O-(2-acetamido-2-deoxy-D-
CC       glucopyranosylidene)amino N-phenylcarbamate (PUGNAc) (By similarity).
CC       Inhibited by galacto-NAG-thiazoline (PubMed:27149221).
CC       {ECO:0000250|UniProtKB:Q3U4H6, ECO:0000269|PubMed:27149221}.
CC   -!- BIOPHYSICOCHEMICAL PROPERTIES:
CC       Kinetic parameters:
CC         KM=0.0721 mM for 4-nitrophenyl N-acetylgalactosamine (PNP-GalNAc)
CC         {ECO:0000269|PubMed:27149221};
CC         KM=0.607 mM for 4-nitrophenyl-N-acetylglucosamine (PNP-GlcNAc)
CC         {ECO:0000269|PubMed:27149221};
CC         KM=0.172 mM for 3-fluoro-4-nitrophenyl-N-acetylgalactosamine
CC         (3F4NP-GalNAc) {ECO:0000269|PubMed:27149221};
CC         KM=0.852 mM for 3-fluoro-4-nitrophenyl-N-acetylglucosamine
CC         (3F4NP-GlcNAc) {ECO:0000269|PubMed:27149221};
CC         Note=kcat is 79.3 min(-1), 30.4 min(-1), 122 min(-1) and 92.4 min(-1)
CC         for PNP-GalNAc, PNP-GlcNAc, 3F4NP-GalNAc and 3F4NP-GlcNAc,
CC         respectively. {ECO:0000269|PubMed:27149221};
CC       pH dependence:
CC         Optimum pH is 6.7. {ECO:0000269|PubMed:27149221};
CC   -!- SUBUNIT: Homodimer; disulfide-linked. {ECO:0000250|UniProtKB:Q3U4H6}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasm {ECO:0000250|UniProtKB:Q3U4H6}. Nucleus
CC       {ECO:0000250|UniProtKB:Q3U4H6}. Extracellular vesicle
CC       {ECO:0000269|PubMed:23099419}.
CC   -!- ALTERNATIVE PRODUCTS:
CC       Event=Alternative splicing; Named isoforms=2;
CC       Name=1;
CC         IsoId=Q8WVB3-1; Sequence=Displayed;
CC       Name=2;
CC         IsoId=Q8WVB3-2; Sequence=VSP_030777;
CC   -!- TISSUE SPECIFICITY: Expressed in synovial fibroblasts and synovial
CC       membranes. {ECO:0000269|PubMed:23099419}.
CC   -!- INDUCTION: Expression is inhibited by TGFB1.
CC       {ECO:0000269|PubMed:23099419}.
CC   -!- SIMILARITY: Belongs to the glycosyl hydrolase 20 family. {ECO:0000305}.
CC   -!- SEQUENCE CAUTION:
CC       Sequence=AAH18205.2; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC       Sequence=AAH35561.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
CC       Sequence=BAB85072.1; Type=Erroneous initiation; Note=Truncated N-terminus.; Evidence={ECO:0000305};
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DR   EMBL; FM204887; CAR57925.1; -; mRNA.
DR   EMBL; AC132938; -; NOT_ANNOTATED_CDS; Genomic_DNA.
DR   EMBL; CH471099; EAW89773.1; -; Genomic_DNA.
DR   EMBL; BC018205; AAH18205.2; ALT_INIT; mRNA.
DR   EMBL; BC035561; AAH35561.1; ALT_INIT; mRNA.
DR   EMBL; AK074405; BAB85072.1; ALT_INIT; mRNA.
DR   CCDS; CCDS42402.1; -. [Q8WVB3-2]
DR   CCDS; CCDS82231.1; -. [Q8WVB3-1]
DR   RefSeq; NP_001317471.1; NM_001330542.1. [Q8WVB3-1]
DR   RefSeq; NP_775891.2; NM_173620.2. [Q8WVB3-2]
DR   RefSeq; XP_016879974.1; XM_017024485.1.
DR   AlphaFoldDB; Q8WVB3; -.
DR   SMR; Q8WVB3; -.
DR   BioGRID; 129726; 19.
DR   IntAct; Q8WVB3; 10.
DR   STRING; 9606.ENSP00000337854; -.
DR   ChEMBL; CHEMBL5169180; -.
DR   CAZy; GH20; Glycoside Hydrolase Family 20.
DR   iPTMnet; Q8WVB3; -.
DR   PhosphoSitePlus; Q8WVB3; -.
DR   BioMuta; HEXDC; -.
DR   DMDM; 167008870; -.
DR   EPD; Q8WVB3; -.
DR   jPOST; Q8WVB3; -.
DR   MassIVE; Q8WVB3; -.
DR   MaxQB; Q8WVB3; -.
DR   PaxDb; 9606-ENSP00000337854; -.
DR   PeptideAtlas; Q8WVB3; -.
DR   ProteomicsDB; 74768; -. [Q8WVB3-1]
DR   ProteomicsDB; 74769; -. [Q8WVB3-2]
DR   Pumba; Q8WVB3; -.
DR   Antibodypedia; 10115; 83 antibodies from 18 providers.
DR   DNASU; 284004; -.
DR   Ensembl; ENST00000327949.15; ENSP00000332634.9; ENSG00000169660.17. [Q8WVB3-1]
DR   Ensembl; ENST00000337014.10; ENSP00000337854.6; ENSG00000169660.17. [Q8WVB3-2]
DR   Ensembl; ENST00000644009.1; ENSP00000496193.1; ENSG00000169660.17. [Q8WVB3-1]
DR   GeneID; 284004; -.
DR   KEGG; hsa:284004; -.
DR   MANE-Select; ENST00000327949.15; ENSP00000332634.9; NM_001330542.2; NP_001317471.1.
DR   UCSC; uc002kev.5; human. [Q8WVB3-1]
DR   AGR; HGNC:26307; -.
DR   CTD; 284004; -.
DR   DisGeNET; 284004; -.
DR   GeneCards; HEXD; -.
DR   HGNC; HGNC:26307; HEXD.
DR   HPA; ENSG00000169660; Low tissue specificity.
DR   MIM; 616864; gene.
DR   neXtProt; NX_Q8WVB3; -.
DR   OpenTargets; ENSG00000169660; -.
DR   PharmGKB; PA142671693; -.
DR   VEuPathDB; HostDB:ENSG00000169660; -.
DR   eggNOG; ENOG502QRCP; Eukaryota.
DR   GeneTree; ENSGT00390000014852; -.
DR   HOGENOM; CLU_019666_1_1_1; -.
DR   InParanoid; Q8WVB3; -.
DR   OMA; WEVYDEH; -.
DR   OrthoDB; 2876932at2759; -.
DR   PhylomeDB; Q8WVB3; -.
DR   TreeFam; TF314313; -.
DR   PathwayCommons; Q8WVB3; -.
DR   SignaLink; Q8WVB3; -.
DR   BioGRID-ORCS; 284004; 12 hits in 1156 CRISPR screens.
DR   ChiTaRS; HEXDC; human.
DR   GenomeRNAi; 284004; -.
DR   Pharos; Q8WVB3; Tbio.
DR   PRO; PR:Q8WVB3; -.
DR   Proteomes; UP000005640; Chromosome 17.
DR   RNAct; Q8WVB3; Protein.
DR   Bgee; ENSG00000169660; Expressed in right uterine tube and 144 other cell types or tissues.
DR   ExpressionAtlas; Q8WVB3; baseline and differential.
DR   GO; GO:0005737; C:cytoplasm; IEA:UniProtKB-SubCell.
DR   GO; GO:1903561; C:extracellular vesicle; IDA:UniProtKB.
DR   GO; GO:0005634; C:nucleus; IEA:UniProtKB-SubCell.
DR   GO; GO:0004563; F:beta-N-acetylhexosaminidase activity; IDA:UniProtKB.
DR   GO; GO:0015929; F:hexosaminidase activity; IDA:UniProtKB.
DR   GO; GO:0102148; F:N-acetyl-beta-D-galactosaminidase activity; IEA:UniProtKB-EC.
DR   GO; GO:0005975; P:carbohydrate metabolic process; IEA:InterPro.
DR   CDD; cd06565; GH20_GcnA-like; 1.
DR   Gene3D; 3.20.20.80; Glycosidases; 1.
DR   InterPro; IPR015883; Glyco_hydro_20_cat.
DR   InterPro; IPR017853; Glycoside_hydrolase_SF.
DR   InterPro; IPR038901; HEXDC-like.
DR   PANTHER; PTHR21040:SF6; HEXOSAMINIDASE D; 1.
DR   PANTHER; PTHR21040; UNCHARACTERIZED; 1.
DR   Pfam; PF00728; Glyco_hydro_20; 1.
DR   SUPFAM; SSF51445; (Trans)glycosidases; 1.
DR   Genevisible; Q8WVB3; HS.
PE   1: Evidence at protein level;
KW   Alternative splicing; Cytoplasm; Disulfide bond; Glycosidase; Hydrolase;
KW   Nucleus; Reference proteome.
FT   CHAIN           1..486
FT                   /note="Hexosaminidase D"
FT                   /id="PRO_0000316790"
FT   ACT_SITE        149
FT                   /note="Proton donor"
FT                   /evidence="ECO:0000250"
FT   VAR_SEQ         355..486
FT                   /note="EGAGSFPGSNILALVTQVSLHLRSSVDALLEGNRYVTGWFSPYHRQRKLIHP
FT                   VMVQHIQPAALSLLAQWSTLVQELEAALQLAFYPDAVEEWLEENVHPSLQRLQALLQDL
FT                   SEVSAPPLPPTSPGRDVAQDP -> QAPCSPPCPLLPLPFPRPWRQLFSAGLSAGRGPA
FT                   PSLAATSLPLSHKSASICAALWMRCWRATGMSLAGSAPTTASGSSSTRSWFSTSSPQRS
FT                   ASWHSGAPSCRSWRLPCSWLSTRMPWRSGWRKTCTPACSGCKLCCRTSARCLPPRCHPP
FT                   ALAGTLLRTPEGRAHARGLLLEAGGALHCQMAWAIRAHVGVVPSGPAVSCPHSVPEGPG
FT                   QPLGERLENTEGSSTGRPAL (in isoform 2)"
FT                   /evidence="ECO:0000303|PubMed:15489334"
FT                   /id="VSP_030777"
FT   VARIANT         145
FT                   /note="I -> V (in dbSNP:rs4789773)"
FT                   /id="VAR_038395"
FT   VARIANT         232
FT                   /note="H -> Y (in dbSNP:rs17853433)"
FT                   /evidence="ECO:0000269|PubMed:15489334"
FT                   /id="VAR_060726"
FT   MUTAGEN         92
FT                   /note="H->A: Decreases hexosaminidase activity."
FT                   /evidence="ECO:0000269|PubMed:27149221"
FT   MUTAGEN         148
FT                   /note="D->A,N: Loss of hexosaminidase activity."
FT                   /evidence="ECO:0000269|PubMed:27149221"
FT   MUTAGEN         149
FT                   /note="E->A,N: Decreases hexosaminidase activity. Optimum
FT                   pH shifts to 7.5."
FT                   /evidence="ECO:0000269|PubMed:27149221"
SQ   SEQUENCE   486 AA;  53790 MW;  8634D2CC438EA5DA CRC64;
     MSGSTPFQMR LVHLDLKGAP PKVSYLSEIF PLFRALGANG LLIEYEDMFP YEGPLRLLRA
     KYAYSPSEIK EILHLAGLNE LEVIPLVQTF GHMEFVLKHT AFAHLREVGS FPCTLNPHEA
     ESLALVGAMI DQVLELHPGA QRLHIGCDEV YYLGEGEASR RWLQQEQNST GKLCLSHMRA
     VASGVKARRP SVTPLVWDDM LRDLPEDQLA ASGVPQLVEP VLWDYTADLD VHGKVLLMQK
     YRRCGFPQLW AASAFKGATG PSQAVPPVEH HLRNHVQWLQ VAGSGPTDSL QGIILTGWQR
     YDHYSVLCEL LPAGVPSLAA CLQLLLRGGF DEDVKAKVEN LLGISSLEKT DPVREGAGSF
     PGSNILALVT QVSLHLRSSV DALLEGNRYV TGWFSPYHRQ RKLIHPVMVQ HIQPAALSLL
     AQWSTLVQEL EAALQLAFYP DAVEEWLEEN VHPSLQRLQA LLQDLSEVSA PPLPPTSPGR
     DVAQDP
//