HEXD_HUMAN
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 03-AUG-2022, entry version 139.
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 (3F4NP-
CC GalNAc) {ECO:0000269|PubMed:27149221};
CC KM=0.852 mM for 3-fluoro-4-nitrophenyl-N-acetylglucosamine (3F4NP-
CC 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 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; Q8WVB3; -.
DR PeptideAtlas; Q8WVB3; -.
DR PRIDE; Q8WVB3; -.
DR ProteomicsDB; 74768; -. [Q8WVB3-1]
DR ProteomicsDB; 74769; -. [Q8WVB3-2]
DR Antibodypedia; 10115; 80 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 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; 1021041at2759; -.
DR PhylomeDB; Q8WVB3; -.
DR TreeFam; TF314313; -.
DR PathwayCommons; Q8WVB3; -.
DR SignaLink; Q8WVB3; -.
DR BioGRID-ORCS; 284004; 12 hits in 1082 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 142 other tissues.
DR ExpressionAtlas; Q8WVB3; baseline and differential.
DR Genevisible; Q8WVB3; HS.
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 InterPro; IPR015883; Glyco_hydro_20_cat.
DR InterPro; IPR017853; Glycoside_hydrolase_SF.
DR InterPro; IPR038901; HEXDC-like.
DR PANTHER; PTHR21040; PTHR21040; 1.
DR Pfam; PF00728; Glyco_hydro_20; 1.
DR SUPFAM; SSF51445; SSF51445; 1.
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
