ID HEXA_HUMAN Reviewed; 529 AA. AC P06865; B4DKE7; E7ENH7; Q53HS8; Q6AI32; DT 01-JAN-1988, integrated into UniProtKB/Swiss-Prot. DT 02-NOV-2010, sequence version 2. DT 27-MAR-2024, entry version 244. DE RecName: Full=Beta-hexosaminidase subunit alpha {ECO:0000305}; DE EC=3.2.1.52 {ECO:0000269|PubMed:11707436, ECO:0000269|PubMed:8123671, ECO:0000269|PubMed:8672428, ECO:0000269|PubMed:9694901}; DE AltName: Full=Beta-N-acetylhexosaminidase subunit alpha; DE Short=Hexosaminidase subunit A; DE AltName: Full=N-acetyl-beta-glucosaminidase subunit alpha; DE Flags: Precursor; GN Name=HEXA {ECO:0000312|HGNC:HGNC:4878}; 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 VARIANT VAL-436. RX PubMed=2933746; DOI=10.1073/pnas.82.23.7830; RA Myerowitz R., Piekarz R., Neufeld E.F., Shows T.B., Suzuki K.; RT "Human beta-hexosaminidase alpha chain: coding sequence and homology with RT the beta chain."; RL Proc. Natl. Acad. Sci. U.S.A. 82:7830-7834(1985). RN [2] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT VAL-436. RX PubMed=2952641; DOI=10.1016/s0021-9258(18)45628-1; RA Proia R.L., Soravia E.; RT "Organization of the gene encoding the human beta-hexosaminidase alpha- RT chain."; RL J. Biol. Chem. 262:5677-5681(1987). RN [3] RP NUCLEOTIDE SEQUENCE [GENOMIC DNA], AND VARIANT VAL-436. RX PubMed=1833974; RA Triggs-Raine B.L., Akerman B.R., Clarke J.T.R., Gravel R.A.; RT "Sequence of DNA flanking the exons of the HEXA gene, and identification of RT mutations in Tay-Sachs disease."; RL Am. J. Hum. Genet. 49:1041-1054(1991). RN [4] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2). RC TISSUE=Thalamus; 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 [5] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT VAL-436. RC TISSUE=Adipose tissue; RA Suzuki Y., Sugano S., Totoki Y., Toyoda A., Takeda T., Sakaki Y., RA Tanaka A., Yokoyama S.; RL Submitted (APR-2005) to the EMBL/GenBank/DDBJ databases. RN [6] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANTS RP PSEUDODEFICIENCY TRP-249 AND VAL-436. RX PubMed=17974005; DOI=10.1186/1471-2164-8-399; RA Bechtel S., Rosenfelder H., Duda A., Schmidt C.P., Ernst U., RA Wellenreuther R., Mehrle A., Schuster C., Bahr A., Bloecker H., Heubner D., RA Hoerlein A., Michel G., Wedler H., Koehrer K., Ottenwaelder B., Poustka A., RA Wiemann S., Schupp I.; RT "The full-ORF clone resource of the German cDNA consortium."; RL BMC Genomics 8:399-399(2007). RN [7] RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA]. RX PubMed=16572171; DOI=10.1038/nature04601; RA Zody M.C., Garber M., Sharpe T., Young S.K., Rowen L., O'Neill K., RA Whittaker C.A., Kamal M., Chang J.L., Cuomo C.A., Dewar K., RA FitzGerald M.G., Kodira C.D., Madan A., Qin S., Yang X., Abbasi N., RA Abouelleil A., Arachchi H.M., Baradarani L., Birditt B., Bloom S., RA Bloom T., Borowsky M.L., Burke J., Butler J., Cook A., DeArellano K., RA DeCaprio D., Dorris L. III, Dors M., Eichler E.E., Engels R., Fahey J., RA Fleetwood P., Friedman C., Gearin G., Hall J.L., Hensley G., Johnson E., RA Jones C., Kamat A., Kaur A., Locke D.P., Madan A., Munson G., Jaffe D.B., RA Lui A., Macdonald P., Mauceli E., Naylor J.W., Nesbitt R., Nicol R., RA O'Leary S.B., Ratcliffe A., Rounsley S., She X., Sneddon K.M.B., RA Stewart S., Sougnez C., Stone S.M., Topham K., Vincent D., Wang S., RA Zimmer A.R., Birren B.W., Hood L., Lander E.S., Nusbaum C.; RT "Analysis of the DNA sequence and duplication history of human chromosome RT 15."; RL Nature 440:671-675(2006). RN [8] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 1), AND VARIANT VAL-436. RC TISSUE=Brain, and Eye; 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 [9] RP PROTEIN SEQUENCE OF 23-32 AND 85-94, FUNCTION, CATALYTIC ACTIVITY, RP GLYCOSYLATION AT ASN-115; ASN-157 AND ASN-295, DISULFIDE BOND, AND ACTIVITY RP REGULATION. RX PubMed=11707436; DOI=10.1074/jbc.m105457200; RA Hepbildikler S.T., Sandhoff R., Kolzer M., Proia R.L., Sandhoff K.; RT "Physiological substrates for human lysosomal beta -hexosaminidase S."; RL J. Biol. Chem. 277:2562-2572(2002). RN [10] RP NUCLEOTIDE SEQUENCE [MRNA] OF 40-529 (ISOFORM 1), AND VARIANT VAL-436. RX PubMed=3013851; DOI=10.1016/s0021-9258(19)83927-3; RA Korneluk R.G., Mahuran D.J., Neote K., Klavins M.H., O'Dowd B.F., RA Tropak M., Willard H.F., Anderson M.-J., Lowden J.A., Gravel R.A.; RT "Isolation of cDNA clones coding for the alpha-subunit of human beta- RT hexosaminidase. Extensive homology between the alpha- and beta-subunits and RT studies on Tay-Sachs disease."; RL J. Biol. Chem. 261:8407-8413(1986). RN [11] RP PROTEIN SEQUENCE OF 89-99. RX PubMed=2965147; DOI=10.1016/s0021-9258(18)68826-x; RA Mahuran D.J., Neote K., Klavins M.H., Leung A., Gravel R.A.; RT "Proteolytic processing of pro-alpha and pro-beta precursors from human RT beta-hexosaminidase. Generation of the mature alpha and beta a beta b RT subunits."; RL J. Biol. Chem. 263:4612-4618(1988). RN [12] RP PROTEIN SEQUENCE OF 96-105, AND STRUCTURE OF CARBOHYDRATES. RX PubMed=2971395; DOI=10.1021/bi00414a041; RA O'Dowd B.F., Cumming D.A., Gravel R.A., Mahuran D.J.; RT "Oligosaccharide structure and amino acid sequence of the major RT glycopeptides of mature human beta-hexosaminidase."; RL Biochemistry 27:5216-5226(1988). RN [13] RP GLYCOSYLATION AT ASN-115; ASN-157 AND ASN-295, AND MUTAGENESIS OF ASN-115; RP ASN-157 AND ASN-295. RX PubMed=1533633; DOI=10.1016/s0021-9258(19)50196-x; RA Weitz G., Proia R.L.; RT "Analysis of the glycosylation and phosphorylation of the alpha-subunit of RT the lysosomal enzyme, beta-hexosaminidase A, by site-directed RT mutagenesis."; RL J. Biol. Chem. 267:10039-10044(1992). RN [14] RP CATALYTIC ACTIVITY, AND FUNCTION. RX PubMed=8123671; DOI=10.1016/0304-4165(94)90118-x; RA Novak A., Callahan J.W., Lowden J.A.; RT "Classification of disorders of GM2 ganglioside hydrolysis using 3H-GM2 as RT substrate."; RL Biochim. Biophys. Acta 1199:215-223(1994). RN [15] RP CATALYTIC ACTIVITY, FUNCTION, AND SUBUNIT. RX PubMed=8672428; DOI=10.1021/bi9524575; RA Hou Y., Tse R., Mahuran D.J.; RT "Direct determination of the substrate specificity of the alpha-active site RT in heterodimeric beta-hexosaminidase A."; RL Biochemistry 35:3963-3969(1996). RN [16] RP ACTIVE SITES. RX PubMed=8652542; DOI=10.1021/bi960246+; RA Tse R., Vavougios G., Hou Y., Mahuran D.J.; RT "Identification of an active acidic residue in the catalytic site of beta- RT hexosaminidase."; RL Biochemistry 35:7599-7607(1996). RN [17] RP CATALYTIC ACTIVITY, AND FUNCTION. RX PubMed=9694901; DOI=10.1074/jbc.273.33.21386; RA Hou Y., McInnes B., Hinek A., Karpati G., Mahuran D.; RT "A Pro504 --> Ser substitution in the beta-subunit of beta-hexosaminidase A RT inhibits alpha-subunit hydrolysis of GM2 ganglioside, resulting in chronic RT Sandhoff disease."; RL J. Biol. Chem. 273:21386-21392(1998). RN [18] RP GLYCOSYLATION [LARGE SCALE ANALYSIS] AT ASN-157 AND ASN-295. RC TISSUE=Liver; RX PubMed=19159218; DOI=10.1021/pr8008012; RA Chen R., Jiang X., Sun D., Han G., Wang F., Ye M., Wang L., Zou H.; RT "Glycoproteomics analysis of human liver tissue by combination of multiple RT enzyme digestion and hydrazide chemistry."; RL J. Proteome Res. 8:651-661(2009). RN [19] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RC TISSUE=Liver; RX PubMed=24275569; DOI=10.1016/j.jprot.2013.11.014; RA Bian Y., Song C., Cheng K., Dong M., Wang F., Huang J., Sun D., Wang L., RA Ye M., Zou H.; RT "An enzyme assisted RP-RPLC approach for in-depth analysis of human liver RT phosphoproteome."; RL J. Proteomics 96:253-262(2014). RN [20] RP IDENTIFICATION BY MASS SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=25944712; DOI=10.1002/pmic.201400617; RA Vaca Jacome A.S., Rabilloud T., Schaeffer-Reiss C., Rompais M., Ayoub D., RA Lane L., Bairoch A., Van Dorsselaer A., Carapito C.; RT "N-terminome analysis of the human mitochondrial proteome."; RL Proteomics 15:2519-2524(2015). RN [21] RP 3D-STRUCTURE MODELING. RX PubMed=8673609; DOI=10.1038/nsb0796-638; RA Tews I., Perrakis A., Oppenheim A., Dauter Z., Wilson K.S., Vorgias C.E.; RT "Bacterial chitobiase structure provides insight into catalytic mechanism RT and the basis of Tay-Sachs disease."; RL Nat. Struct. Biol. 3:638-648(1996). RN [22] RP REVIEW ON VARIANTS. RX PubMed=1825792; DOI=10.1016/0925-4439(91)90044-a; RA Mahuran D.J.; RT "The biochemistry of HEXA and HEXB gene mutations causing GM2 RT gangliosidosis."; RL Biochim. Biophys. Acta 1096:87-94(1991). RN [23] RP REVIEW ON VARIANTS. RX PubMed=9090523; RX DOI=10.1002/(sici)1098-1004(1997)9:3<195::aid-humu1>3.0.co;2-7; RA Myerowitz R.; RT "Tay-Sachs disease-causing mutations and neutral polymorphisms in the Hex A RT gene."; RL Hum. Mutat. 9:195-208(1997). RN [24] RP X-RAY CRYSTALLOGRAPHY (2.8 ANGSTROMS) OF 23-529 IN COMPLEX WITH HEXB, RP GLYCOSYLATION AT ASN-115; ASN-157 AND ASN-295, DISULFIDE BONDS, SUBUNIT, RP AND ACTIVE SITE. RX PubMed=16698036; DOI=10.1016/j.jmb.2006.04.004; RA Lemieux M.J., Mark B.L., Cherney M.M., Withers S.G., Mahuran D.J., RA James M.N.; RT "Crystallographic structure of human beta-hexosaminidase A: interpretation RT of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis."; RL J. Mol. Biol. 359:913-929(2006). RN [25] RP VARIANT GM2G1 LYS-482. RX PubMed=2970528; DOI=10.1111/j.1471-4159.1988.tb01836.x; RA Nakano T., Muscillo M., Ohno K., Hoffman A.J., Suzuki K.; RT "A point mutation in the coding sequence of the beta-hexosaminidase alpha RT gene results in defective processing of the enzyme protein in an unusual RT GM2-gangliosidosis variant."; RL J. Neurochem. 51:984-987(1988). RN [26] RP VARIANT GM2G1 SER-269. RX PubMed=2522679; DOI=10.1126/science.2522679; RA Navon R., Proia R.L.; RT "The mutations in Ashkenazi Jews with adult GM2 gangliosidosis, the adult RT form of Tay-Sachs disease."; RL Science 243:1471-1474(1989). RN [27] RP VARIANT GM2G1 CYS-420. RX PubMed=2144098; RA Tanaka A., Punnett H.H., Suzuki K.; RT "A new point mutation in the beta-hexosaminidase alpha subunit gene RT responsible for infantile Tay-Sachs disease in a non-Jewish Caucasian RT patient (a Kpn mutant)."; RL Am. J. Hum. Genet. 47:568-574(1990). RN [28] RP VARIANT GM2G1 HIS-504, AND CHARACTERIZATION OF VARIANT GM2G1 HIS-504. RX PubMed=2140574; DOI=10.1016/s0021-9258(19)38870-2; RA Paw B.H., Moskowitz S.M., Uhrhammer N., Wright N., Kaback M.M., RA Neufeld E.F.; RT "Juvenile GM2 gangliosidosis caused by substitution of histidine for RT arginine at position 499 or 504 of the alpha-subunit of beta- RT hexosaminidase."; RL J. Biol. Chem. 265:9452-9457(1990). RN [29] RP VARIANTS GM2G1 PHE-210 AND CYS-504. RX PubMed=1837283; DOI=10.1016/0888-7543(91)90109-r; RA Akli S., Lacorte J.-M., Poenaru L., Khan A.; RT "Seven novel Tay-Sachs mutations detected by chemical mismatch cleavage of RT PCR-amplified cDNA fragments."; RL Genomics 11:124-134(1991). RN [30] RP VARIANT GM2G1 GLY-320 DEL, AND VARIANTS ASP-399 AND VAL-436. RX PubMed=1532289; RA Mules E.H., Hayflick S., Miller C.S., Reynolds L.W., Thomas G.H.; RT "Six novel deleterious and three neutral mutations in the gene encoding the RT alpha-subunit of hexosaminidase A in non-Jewish individuals."; RL Am. J. Hum. Genet. 50:834-841(1992). RN [31] RP VARIANT PSEUDODEFICIENCY TRP-247. RX PubMed=1384323; RA Triggs-Raine B.L., Mules E.H., Kaback M.M., Lim-Steele J.S.T., RA Dowling C.E., Akerman B.R., Natowicz M.R., Grebner E.E., Navon R., RA Welch J.P., Greenberg C.R., Thomas G.H., Gravel R.A.; RT "A pseudodeficiency allele common in non-Jewish Tay-Sachs carriers: RT implications for carrier screening."; RL Am. J. Hum. Genet. 51:793-801(1992). RN [32] RP VARIANTS GM2G1 TRP-170 AND HIS-258. RX PubMed=1302612; DOI=10.1093/hmg/1.9.759; RA Fernandes M., Kaplan F., Natowicz M., Prence E., Kolodny E., Kaback M., RA Hechtman P.; RT "A new Tay-Sachs disease B1 allele in exon 7 in two compound heterozygotes RT each with a second novel mutation."; RL Hum. Mol. Genet. 1:759-761(1992). RN [33] RP VARIANT GM2G1 ASP-250. RX PubMed=1301189; DOI=10.1002/humu.1380010106; RA Trop I., Kaplan F., Brown C., Mahuran D., Hechtman P.; RT "A glycine250--> aspartate substitution in the alpha-subunit of RT hexosaminidase A causes juvenile-onset Tay-Sachs disease in a Lebanese- RT Canadian family."; RL Hum. Mutat. 1:35-39(1992). RN [34] RP VARIANT GM2G1 ARG-485. RX PubMed=1301190; DOI=10.1002/humu.1380010107; RA Akalin N., Shi H.-P., Vavougios G., Hechtman P., Lo W., Scriver C.R., RA Mahuran D., Kaplan F.; RT "Novel Tay-Sachs disease mutations from China."; RL Hum. Mutat. 1:40-46(1992). RN [35] RP VARIANT PSEUDODEFICIENCY TRP-249. RX PubMed=7902672; RA Cao Z., Natowicz M.R., Kaback M.M., Lim-Steele J.S.T., Prence E.M., RA Brown D., Chabot T., Triggs-Raine B.L.; RT "A second mutation associated with apparent beta-hexosaminidase A RT pseudodeficiency: identification and frequency estimation."; RL Am. J. Hum. Genet. 53:1198-1205(1993). RN [36] RP VARIANTS GM2G1. RX PubMed=8490625; DOI=10.1093/hmg/2.1.61; RA Akli S., Chomel J.-C., Lacorte J.-M., Bachner L., Poenaru A., Poenaru L.; RT "Ten novel mutations in the HEXA gene in non-Jewish Tay-Sachs patients."; RL Hum. Mol. Genet. 2:61-67(1993). RN [37] RP VARIANT GM2G1 SER-25. RX PubMed=8445615; DOI=10.1136/jmg.30.2.123; RA Harmon D.L., Gardner-Medwin D., Stirling J.L.; RT "Two new mutations in a late infantile Tay-Sachs patient are both in exon 1 RT of the beta-hexosaminidase alpha subunit gene."; RL J. Med. Genet. 30:123-128(1993). RN [38] RP VARIANTS GM2G1 PHE-335 AND 347-ASP--GLU-352 DEL. RX PubMed=7951261; DOI=10.1002/humu.1380040112; RA Tomczak J., Grebner E.E.; RT "Three novel beta-hexosaminidase A mutations in obligate carriers of Tay- RT Sachs disease."; RL Hum. Mutat. 4:71-72(1994). RN [39] RP VARIANTS GM2G1 TYR-458 AND GLN-484. RX PubMed=7837766; DOI=10.1007/bf00711597; RA Tanaka A., Sakazaki H., Murakami H., Isshiki G., Suzuki K.; RT "Molecular genetics of Tay-Sachs disease in Japan."; RL J. Inherit. Metab. Dis. 17:593-600(1994). RN [40] RP VARIANTS GM2G1 SER-196 AND SER-250. RX PubMed=7717398; RA Triggs-Raine B.L., Richard M., Wasel N., Prence E.M., Natowicz M.R.; RT "Mutational analyses of Tay-Sachs disease: studies on Tay-Sachs carriers of RT French Canadian background living in New England."; RL Am. J. Hum. Genet. 56:870-879(1995). RN [41] RP VARIANT GM2G1 GLY-166. RX PubMed=8581357; DOI=10.1006/bmme.1995.1018; RA Peleg L., Meltzer F., Karpati M., Goldman B.; RT "GM2 gangliosidosis B1 variant: biochemical and molecular characterization RT of hexosaminidase A."; RL Biochem. Mol. Med. 54:126-132(1995). RN [42] RP VARIANT GM2G1 MET-391. RX PubMed=7898712; DOI=10.1212/wnl.45.3.539; RA Navon R., Khosravi R., Korczyn T., Masson M., Sonnino S., Fardeau M., RA Eymard B., Lefevre N., Turpin J.C., Rondot P.; RT "A new mutation in the HEXA gene associated with a spinal muscular atrophy RT phenotype."; RL Neurology 45:539-543(1995). RN [43] RP VARIANTS GM2G1 HIS-178 AND HIS-252. RX PubMed=8730294; DOI=10.1136/jmg.33.4.341; RA Ribeiro M.G., Sonin T., Pinto R.A., Fontes A., Ribeiro H., Pinto E., RA Palmeira M.M., Sa Miranda M.C.; RT "Clinical, enzymatic, and molecular characterisation of a Portuguese family RT with a chronic form of GM2-gangliosidosis B1 variant."; RL J. Med. Genet. 33:341-343(1996). RN [44] RP VARIANT GM2G1 HIS-180. RX PubMed=8757036; DOI=10.1212/wnl.47.2.547; RA de Gasperi R., Gama Sosa M.A., Battistini S., Yeretsian J., Raghavan S., RA Zelnik N., Leshinsky E., Kolodny E.H.; RT "Late-onset GM2 gangliosidosis: Ashkenazi Jewish family with an exon 5 RT mutation (Tyr180-->His) in the Hex A alpha-chain gene."; RL Neurology 47:547-552(1996). RN [45] RP VARIANTS GM2G1 PHE-127; PHE-226; ASP-269 AND VAL-314. RX PubMed=9150157; RA Akerman B.R., Natowicz M.R., Kaback M.M., Loyer M., Campeau E., RA Gravel R.A.; RT "Novel mutations and DNA-based screening in non-Jewish carriers of Tay- RT Sachs disease."; RL Am. J. Hum. Genet. 60:1099-1106(1997). RN [46] RP VARIANTS GM2G1 GLN-170; PHE-304 DEL AND LYS-482. RX PubMed=9338583; RX DOI=10.1002/(sici)1098-1004(1997)10:4<295::aid-humu5>3.0.co;2-g; RA Kaufman M., Grinshpun-Cohen J., Karpati M., Peleg L., Goldman B., RA Akstein E., Adam A., Navon R.; RT "Tay-Sachs disease and HEXA mutations among Moroccan Jews."; RL Hum. Mutat. 10:295-300(1997). RN [47] RP VARIANT GM2G1 ARG-455. RX PubMed=9375850; RX DOI=10.1002/(sici)1098-1004(1997)10:5<359::aid-humu4>3.0.co;2-a; RA Ribeiro M.G., Pinto R.A., Suzuki K., Sa Miranda M.C.; RT "Two novel (1334delC and 1363G to A, G455R) mutations in exon 12 of the RT beta-hexosaminidase alpha-chain gene in two Portuguese patients."; RL Hum. Mutat. 10:359-360(1997). RN [48] RP VARIANT GM2G1 PRO-279. RX PubMed=9401008; RX DOI=10.1002/(sici)1098-1004(1997)10:6<451::aid-humu6>3.0.co;2-g; RA Drucker L., Hemli J.A., Navon R.; RT "Two mutated HEXA alleles in a Druze patient with late-infantile Tay-Sachs RT disease."; RL Hum. Mutat. 10:451-457(1997). RN [49] RP VARIANT GM2G1 CYS-474. RX PubMed=9603435; RX DOI=10.1002/(sici)1098-1004(1998)11:6<432::aid-humu3>3.0.co;2-z; RA Petroulakis E., Cao Z., Clarke J.T.R., Mahuran D.J., Lee G., RA Triggs-Raine B.; RT "W474C amino acid substitution affects early processing of the alpha- RT subunit of beta-hexosaminidase A and is associated with subacute G(M2) RT gangliosidosis."; RL Hum. Mutat. 11:432-442(1998). RN [50] RP VARIANTS GM2G1 LEU-252; SER-295; CYS-420; CYS-499 AND HIS-499. RX PubMed=14566483; DOI=10.1007/s10038-003-0080-9; RA Tanaka A., Hoang L.T., Nishi Y., Maniwa S., Oka M., Yamano T.; RT "Different attenuated phenotypes of GM2 gangliosidosis variant B in RT Japanese patients with HEXA mutations at codon 499, and five novel RT mutations responsible for infantile acute form."; RL J. Hum. Genet. 48:571-574(2003). RN [51] RP VARIANT [LARGE SCALE ANALYSIS] VAL-436, AND IDENTIFICATION BY MASS RP SPECTROMETRY [LARGE SCALE ANALYSIS]. RX PubMed=21269460; DOI=10.1186/1752-0509-5-17; RA Burkard T.R., Planyavsky M., Kaupe I., Breitwieser F.P., Buerckstuemmer T., RA Bennett K.L., Superti-Furga G., Colinge J.; RT "Initial characterization of the human central proteome."; RL BMC Syst. Biol. 5:17-17(2011). RN [52] RP VARIANTS GM2G1 LYS-114; TRP-170; ASN-322; TYR-322; PRO-393; VAL-462 AND RP ARG-478. RX PubMed=22723944; DOI=10.1371/journal.pone.0039122; RA Mistri M., Tamhankar P.M., Sheth F., Sanghavi D., Kondurkar P., Patil S., RA Idicula-Thomas S., Gupta S., Sheth J.; RT "Identification of novel mutations in HEXA gene in children affected with RT Tay Sachs disease from India."; RL PLoS ONE 7:E39122-E39122(2012). RN [53] RP CHARACTERIZATION OF VARIANTS GM2G1 SER-269 AND LYS-482. RX PubMed=27682588; DOI=10.1091/mbc.e16-01-0012; RA Dersh D., Iwamoto Y., Argon Y.; RT "Tay Sachs disease mutations in HEXA target the alpha chain of RT hexosaminidase A to ER-associated degradation."; RL Mol. Biol. Cell 27:3813-3827(2016). CC -!- FUNCTION: Hydrolyzes the non-reducing end N-acetyl-D-hexosamine and/or CC sulfated N-acetyl-D-hexosamine of glycoconjugates, such as the CC oligosaccharide moieties from proteins and neutral glycolipids, or from CC certain mucopolysaccharides (PubMed:11707436, PubMed:9694901, CC PubMed:8672428, PubMed:8123671). The isozyme S is as active as the CC isozyme A on the anionic bis-sulfated glycans, the chondroitin-6- CC sulfate trisaccharide (C6S-3), and the dermatan sulfate CC pentasaccharide, and the sulfated glycosphingolipid SM2 CC (PubMed:11707436). The isozyme B does not hydrolyze each of these CC substrates, however hydrolyzes efficiently neutral oligosaccharide CC (PubMed:11707436). Only the isozyme A is responsible for the CC degradation of GM2 gangliosides in the presence of GM2A CC (PubMed:9694901, PubMed:8672428, PubMed:8123671). CC {ECO:0000269|PubMed:11707436, ECO:0000269|PubMed:8123671, CC ECO:0000269|PubMed:8672428, ECO:0000269|PubMed:9694901}. 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:11707436, ECO:0000269|PubMed:8123671, CC ECO:0000269|PubMed:8672428, ECO:0000269|PubMed:9694901}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + N-acetyl-beta-D-galactosaminyl-(1->4)-beta-D-3- CC sulfogalactosyl-(1->4)-beta-D-glucosyl-(1<->1')-ceramide = a beta-D- CC 3-sulfogalactosyl-(1->4)-beta-D-glucosyl-(1<->1')-ceramide + N- CC acetyl-beta-D-galactosamine; Xref=Rhea:RHEA:48276, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:28497, ChEBI:CHEBI:90163, ChEBI:CHEBI:90164; CC Evidence={ECO:0000269|PubMed:11707436}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:48277; CC Evidence={ECO:0000305|PubMed:11707436}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a ganglioside GM2 (d18:1(4E)) + H2O = a ganglioside GM3 CC (d18:1(4E)) + N-acetyl-beta-D-galactosamine; Xref=Rhea:RHEA:47940, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:28497, ChEBI:CHEBI:60065, CC ChEBI:CHEBI:71502; Evidence={ECO:0000269|PubMed:8123671, CC ECO:0000269|PubMed:8672428, ECO:0000269|PubMed:9694901}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47941; CC Evidence={ECO:0000305|PubMed:9694901}; CC -!- CATALYTIC ACTIVITY: CC Reaction=a ganglioside GM2 + H2O = a ganglioside GM3 + N-acetyl-beta-D- CC galactosamine; Xref=Rhea:RHEA:47968, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:28497, ChEBI:CHEBI:79210, ChEBI:CHEBI:79218; CC Evidence={ECO:0000269|PubMed:8123671, ECO:0000269|PubMed:8672428, CC ECO:0000269|PubMed:9694901}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:47969; CC Evidence={ECO:0000305|PubMed:9694901}; CC -!- CATALYTIC ACTIVITY: CC Reaction=beta-D-GalNAc-(1->4)-alpha-L-IdoA-(1->3)-beta-D-GalNAc-4- CC sulfate-(1->4)-alpha-L-IdoA-(1->3)-D-GalNAc-4-sulfate + H2O = alpha- CC L-IdoA-(1->3)-beta-D-GalNAc-4-sulfate-(1->4)-alpha-L-IdoA-(1->3)-D- CC GalNAc-4-sulfate + N-acetyl-D-galactosamine; Xref=Rhea:RHEA:64372, CC ChEBI:CHEBI:15377, ChEBI:CHEBI:28037, ChEBI:CHEBI:152565, CC ChEBI:CHEBI:152566; Evidence={ECO:0000269|PubMed:11707436}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64373; CC Evidence={ECO:0000305|PubMed:11707436}; CC -!- CATALYTIC ACTIVITY: CC Reaction=H2O + N-acetyl-beta-D-6-sulfogalactosaminyl-(1->4)-alpha-L- CC iduronyl-(1->3)-N-acetyl-D-6-sulfogalactosamine = alpha-L-iduronyl- CC (1->3)-N-acetyl-D-6-sulfogalactosamine + N-acetyl-D-6- CC sulfogalactosamine; Xref=Rhea:RHEA:64384, ChEBI:CHEBI:15377, CC ChEBI:CHEBI:152567, ChEBI:CHEBI:152568, ChEBI:CHEBI:153064; CC Evidence={ECO:0000269|PubMed:11707436}; CC PhysiologicalDirection=left-to-right; Xref=Rhea:RHEA:64385; CC Evidence={ECO:0000305|PubMed:11707436}; CC -!- ACTIVITY REGULATION: Addition of GM2A stimulates the hydrolysis of CC sulfated glycosphingolipid SM2 and the ganglioside GM2. CC {ECO:0000269|PubMed:11707436}. CC -!- SUBUNIT: There are 3 beta-hexosaminidase isozymes: isozyme A CC (hexosaminidase A) is an heterodimer composed of one subunit alpha and CC one subunit beta (chain A and B); isozyme B (hexosaminidase B) is an CC homodimer of two beta subunits (two chains A and B); isozyme S CC (hexosaminidase S) is a homodimer of two alpha subunits CC (PubMed:16698036). The composition of the dimer (isozyme A versus CC isozyme S) has a significant effect on the substrate specificity of the CC alpha subunit active site (PubMed:8672428). CC {ECO:0000269|PubMed:16698036, ECO:0000269|PubMed:8672428}. CC -!- INTERACTION: CC P06865; P07686: HEXB; NbExp=3; IntAct=EBI-723519, EBI-7133736; CC -!- SUBCELLULAR LOCATION: Lysosome. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=2; CC Name=1; CC IsoId=P06865-1; Sequence=Displayed; CC Name=2; CC IsoId=P06865-2; Sequence=VSP_056657, VSP_056658, VSP_056659; CC -!- PTM: N-linked glycan at Asn-115 consists of Man(3)-GlcNAc(2) CC (PubMed:1533633, PubMed:16698036, PubMed:19159218) (Probable). N-linked CC glycan at Asn-157 consists of either GlcNAc or GlcNAc(2)-Man(7-9). N- CC linked glycan at Asn-295 consists of either GlcNAc, GlcNAc-Fuc, or CC GlcNAc(2)-Man(4) (Probable). {ECO:0000269|PubMed:1533633, CC ECO:0000269|PubMed:16698036, ECO:0000269|PubMed:19159218, CC ECO:0000305|PubMed:11707436}. CC -!- DISEASE: GM2-gangliosidosis 1 (GM2G1) [MIM:272800]: An autosomal CC recessive lysosomal storage disease marked by the accumulation of GM2 CC gangliosides in the neuronal cells. It is characterized by GM2 CC gangliosides accumulation in the absence of HEXA activity, leading to CC neurodegeneration and, in the infantile form, death in early childhood. CC It exists in several forms: infantile (most common and most severe), CC juvenile and adult (late-onset). {ECO:0000269|PubMed:1301189, CC ECO:0000269|PubMed:1301190, ECO:0000269|PubMed:1302612, CC ECO:0000269|PubMed:14566483, ECO:0000269|PubMed:1532289, CC ECO:0000269|PubMed:1837283, ECO:0000269|PubMed:2140574, CC ECO:0000269|PubMed:2144098, ECO:0000269|PubMed:22723944, CC ECO:0000269|PubMed:2522679, ECO:0000269|PubMed:27682588, CC ECO:0000269|PubMed:2970528, ECO:0000269|PubMed:7717398, CC ECO:0000269|PubMed:7837766, ECO:0000269|PubMed:7898712, CC ECO:0000269|PubMed:7951261, ECO:0000269|PubMed:8445615, CC ECO:0000269|PubMed:8490625, ECO:0000269|PubMed:8581357, CC ECO:0000269|PubMed:8730294, ECO:0000269|PubMed:8757036, CC ECO:0000269|PubMed:9150157, ECO:0000269|PubMed:9338583, CC ECO:0000269|PubMed:9375850, ECO:0000269|PubMed:9401008, CC ECO:0000269|PubMed:9603435}. Note=The disease is caused by variants CC affecting the gene represented in this entry. CC -!- SIMILARITY: Belongs to the glycosyl hydrolase 20 family. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; M16424; AAB00965.1; -; Genomic_DNA. DR EMBL; M16411; AAB00965.1; JOINED; Genomic_DNA. DR EMBL; M16412; AAB00965.1; JOINED; Genomic_DNA. DR EMBL; M16413; AAB00965.1; JOINED; Genomic_DNA. DR EMBL; M16414; AAB00965.1; JOINED; Genomic_DNA. DR EMBL; M16415; AAB00965.1; JOINED; Genomic_DNA. DR EMBL; M16416; AAB00965.1; JOINED; Genomic_DNA. DR EMBL; M16417; AAB00965.1; JOINED; Genomic_DNA. DR EMBL; M16418; AAB00965.1; JOINED; Genomic_DNA. DR EMBL; M16419; AAB00965.1; JOINED; Genomic_DNA. DR EMBL; M16420; AAB00965.1; JOINED; Genomic_DNA. DR EMBL; M16421; AAB00965.1; JOINED; Genomic_DNA. DR EMBL; M16422; AAB00965.1; JOINED; Genomic_DNA. DR EMBL; M16423; AAB00965.1; JOINED; Genomic_DNA. DR EMBL; S62076; AAD13932.1; -; Genomic_DNA. DR EMBL; S62047; AAD13932.1; JOINED; Genomic_DNA. DR EMBL; S62049; AAD13932.1; JOINED; Genomic_DNA. DR EMBL; S62051; AAD13932.1; JOINED; Genomic_DNA. DR EMBL; S62053; AAD13932.1; JOINED; Genomic_DNA. DR EMBL; S62055; AAD13932.1; JOINED; Genomic_DNA. DR EMBL; S62057; AAD13932.1; JOINED; Genomic_DNA. DR EMBL; S62059; AAD13932.1; JOINED; Genomic_DNA. DR EMBL; S62061; AAD13932.1; JOINED; Genomic_DNA. DR EMBL; S62063; AAD13932.1; JOINED; Genomic_DNA. DR EMBL; S62066; AAD13932.1; JOINED; Genomic_DNA. DR EMBL; S62068; AAD13932.1; JOINED; Genomic_DNA. DR EMBL; S62070; AAD13932.1; JOINED; Genomic_DNA. DR EMBL; S62072; AAD13932.1; JOINED; Genomic_DNA. DR EMBL; AK296528; BAG59159.1; -; mRNA. DR EMBL; AK222502; BAD96222.1; -; mRNA. DR EMBL; CR627386; CAH10482.1; -; mRNA. DR EMBL; AC009690; -; NOT_ANNOTATED_CDS; Genomic_DNA. DR EMBL; BC018927; AAH18927.1; -; mRNA. DR EMBL; BC084537; AAH84537.1; -; mRNA. DR EMBL; M13520; AAA51827.1; -; mRNA. DR CCDS; CCDS10243.1; -. [P06865-1] DR PIR; A23561; AOHUBA. DR RefSeq; NP_000511.2; NM_000520.5. [P06865-1] DR RefSeq; NP_001305754.1; NM_001318825.1. DR PDB; 2GJX; X-ray; 2.80 A; A/D/E/H=23-529. DR PDB; 2GK1; X-ray; 3.25 A; A/C/E/G=23-529. DR PDBsum; 2GJX; -. DR PDBsum; 2GK1; -. DR AlphaFoldDB; P06865; -. DR SMR; P06865; -. DR BioGRID; 109322; 98. DR ComplexPortal; CPX-502; Beta-hexosaminidase A complex. DR ComplexPortal; CPX-687; Beta-hexosaminidase S complex. DR CORUM; P06865; -. DR IntAct; P06865; 18. DR STRING; 9606.ENSP00000455114; -. DR BindingDB; P06865; -. DR ChEMBL; CHEMBL1250415; -. DR DrugCentral; P06865; -. DR SwissLipids; SLP:000001416; -. [P06865-1] DR CAZy; GH20; Glycoside Hydrolase Family 20. DR GlyConnect; 1038; 8 N-Linked glycans (1 site). DR GlyCosmos; P06865; 3 sites, 7 glycans. DR GlyGen; P06865; 5 sites, 8 N-linked glycans (1 site), 2 O-linked glycans (1 site). DR iPTMnet; P06865; -. DR PhosphoSitePlus; P06865; -. DR SwissPalm; P06865; -. DR BioMuta; HEXA; -. DR DMDM; 311033393; -. DR EPD; P06865; -. DR jPOST; P06865; -. DR MassIVE; P06865; -. DR MaxQB; P06865; -. DR PaxDb; 9606-ENSP00000268097; -. DR PeptideAtlas; P06865; -. DR ProteomicsDB; 4455; -. DR ProteomicsDB; 51937; -. [P06865-1] DR Pumba; P06865; -. DR Antibodypedia; 26658; 537 antibodies from 32 providers. DR DNASU; 3073; -. DR Ensembl; ENST00000268097.10; ENSP00000268097.6; ENSG00000213614.11. [P06865-1] DR GeneID; 3073; -. DR KEGG; hsa:3073; -. DR MANE-Select; ENST00000268097.10; ENSP00000268097.6; NM_000520.6; NP_000511.2. DR UCSC; uc002aun.5; human. [P06865-1] DR AGR; HGNC:4878; -. DR CTD; 3073; -. DR DisGeNET; 3073; -. DR GeneCards; HEXA; -. DR GeneReviews; HEXA; -. DR HGNC; HGNC:4878; HEXA. DR HPA; ENSG00000213614; Low tissue specificity. DR MalaCards; HEXA; -. DR MIM; 272800; phenotype. DR MIM; 606869; gene. DR neXtProt; NX_P06865; -. DR OpenTargets; ENSG00000213614; -. DR Orphanet; 309192; Tay-Sachs disease, adult form. DR Orphanet; 309178; Tay-Sachs disease, infantile form. DR Orphanet; 309185; Tay-Sachs disease, juvenile form. DR PharmGKB; PA29256; -. DR VEuPathDB; HostDB:ENSG00000213614; -. DR eggNOG; KOG2499; Eukaryota. DR GeneTree; ENSGT00390000008107; -. DR InParanoid; P06865; -. DR OMA; KMWPRAA; -. DR OrthoDB; 178991at2759; -. DR PhylomeDB; P06865; -. DR TreeFam; TF313036; -. DR BioCyc; MetaCyc:ENSG00000140495-MONOMER; -. DR BRENDA; 3.2.1.169; 2681. DR PathwayCommons; P06865; -. DR Reactome; R-HSA-2022857; Keratan sulfate degradation. DR Reactome; R-HSA-2024101; CS/DS degradation. DR Reactome; R-HSA-2160916; Hyaluronan uptake and degradation. DR Reactome; R-HSA-3656234; Defective HEXA causes GM2G1. DR Reactome; R-HSA-9840310; Glycosphingolipid catabolism. DR SABIO-RK; P06865; -. DR SignaLink; P06865; -. DR BioGRID-ORCS; 3073; 11 hits in 1159 CRISPR screens. DR ChiTaRS; HEXA; human. DR EvolutionaryTrace; P06865; -. DR GeneWiki; HEXA; -. DR GenomeRNAi; 3073; -. DR Pharos; P06865; Tchem. DR PRO; PR:P06865; -. DR Proteomes; UP000005640; Chromosome 15. DR RNAct; P06865; Protein. DR Bgee; ENSG00000213614; Expressed in type B pancreatic cell and 198 other cell types or tissues. DR ExpressionAtlas; P06865; baseline and differential. DR GO; GO:0042582; C:azurophil granule; IDA:UniProtKB. DR GO; GO:1905379; C:beta-N-acetylhexosaminidase complex; IDA:ComplexPortal. DR GO; GO:0005829; C:cytosol; IDA:HPA. DR GO; GO:0070062; C:extracellular exosome; HDA:UniProtKB. DR GO; GO:0043231; C:intracellular membrane-bounded organelle; IDA:HPA. DR GO; GO:0043202; C:lysosomal lumen; TAS:Reactome. DR GO; GO:0005764; C:lysosome; IBA:GO_Central. DR GO; GO:0016020; C:membrane; HDA:UniProtKB. DR GO; GO:0008375; F:acetylglucosaminyltransferase activity; IDA:UniProtKB. DR GO; GO:0004563; F:beta-N-acetylhexosaminidase activity; IDA:UniProtKB. DR GO; GO:0102148; F:N-acetyl-beta-D-galactosaminidase activity; IEA:UniProtKB-EC. DR GO; GO:0046982; F:protein heterodimerization activity; IDA:MGI. DR GO; GO:0007628; P:adult walking behavior; IEA:Ensembl. DR GO; GO:0048667; P:cell morphogenesis involved in neuron differentiation; IEA:Ensembl. DR GO; GO:0030209; P:dermatan sulfate catabolic process; IEA:Ensembl. DR GO; GO:0006689; P:ganglioside catabolic process; IDA:UniProtKB. DR GO; GO:0006024; P:glycosaminoglycan biosynthetic process; IDA:UniProtKB. DR GO; GO:0030203; P:glycosaminoglycan metabolic process; IDA:ComplexPortal. DR GO; GO:0030214; P:hyaluronan catabolic process; IEA:Ensembl. DR GO; GO:0019915; P:lipid storage; IEA:Ensembl. DR GO; GO:0007040; P:lysosome organization; IEA:Ensembl. DR GO; GO:0051651; P:maintenance of location in cell; IEA:Ensembl. DR GO; GO:0042552; P:myelination; IEA:Ensembl. DR GO; GO:0050885; P:neuromuscular process controlling balance; IEA:Ensembl. DR GO; GO:0050884; P:neuromuscular process controlling posture; IEA:Ensembl. DR GO; GO:0007605; P:sensory perception of sound; IEA:Ensembl. DR GO; GO:0019953; P:sexual reproduction; IEA:Ensembl. DR GO; GO:0001501; P:skeletal system development; IEA:Ensembl. DR CDD; cd06562; GH20_HexA_HexB-like; 1. DR Gene3D; 3.30.379.10; Chitobiase/beta-hexosaminidase domain 2-like; 1. DR Gene3D; 3.20.20.80; Glycosidases; 1. DR InterPro; IPR025705; Beta_hexosaminidase_sua/sub. DR InterPro; IPR015883; Glyco_hydro_20_cat. DR InterPro; IPR017853; Glycoside_hydrolase_SF. DR InterPro; IPR029018; Hex-like_dom2. DR InterPro; IPR029019; HEX_eukaryotic_N. DR PANTHER; PTHR22600; BETA-HEXOSAMINIDASE; 1. DR PANTHER; PTHR22600:SF39; BETA-HEXOSAMINIDASE SUBUNIT ALPHA; 1. DR Pfam; PF00728; Glyco_hydro_20; 1. DR Pfam; PF14845; Glycohydro_20b2; 1. DR PIRSF; PIRSF001093; B-hxosamndse_ab_euk; 1. DR PRINTS; PR00738; GLHYDRLASE20. DR SUPFAM; SSF51445; (Trans)glycosidases; 1. DR SUPFAM; SSF55545; beta-N-acetylhexosaminidase-like domain; 1. DR Genevisible; P06865; HS. PE 1: Evidence at protein level; KW 3D-structure; Alternative splicing; Direct protein sequencing; KW Disease variant; Disulfide bond; Gangliosidosis; Glycoprotein; Glycosidase; KW Hydrolase; Lipid metabolism; Lysosome; Neurodegeneration; KW Reference proteome; Signal; Zymogen. FT SIGNAL 1..22 FT /evidence="ECO:0000269|PubMed:2952641, FT ECO:0000305|PubMed:11707436" FT PROPEP 23..88 FT /evidence="ECO:0000269|PubMed:2965147" FT /id="PRO_0000011993" FT CHAIN 89..529 FT /note="Beta-hexosaminidase subunit alpha" FT /id="PRO_0000011994" FT REGION 423..424 FT /note="Critical for hydrolysis GM2 gangliosides" FT ACT_SITE 323 FT /note="Proton donor" FT /evidence="ECO:0000305|PubMed:16698036" FT CARBOHYD 115 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:1533633, FT ECO:0000269|PubMed:16698036, ECO:0000305|PubMed:11707436" FT CARBOHYD 157 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:1533633, FT ECO:0000269|PubMed:16698036, ECO:0000269|PubMed:19159218, FT ECO:0000305|PubMed:11707436" FT CARBOHYD 295 FT /note="N-linked (GlcNAc...) asparagine" FT /evidence="ECO:0000269|PubMed:1533633, FT ECO:0000269|PubMed:16698036, ECO:0000269|PubMed:19159218, FT ECO:0000305|PubMed:11707436" FT DISULFID 58..104 FT /evidence="ECO:0000269|PubMed:16698036, FT ECO:0000305|PubMed:11707436" FT DISULFID 277..328 FT /evidence="ECO:0000269|PubMed:16698036, FT ECO:0000305|PubMed:11707436" FT DISULFID 505..522 FT /evidence="ECO:0000269|PubMed:16698036, FT ECO:0000305|PubMed:11707436" FT VAR_SEQ 1..192 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_056657" FT VAR_SEQ 359..360 FT /note="LL -> YP (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_056658" FT VAR_SEQ 361..529 FT /note="Missing (in isoform 2)" FT /evidence="ECO:0000303|PubMed:14702039" FT /id="VSP_056659" FT VARIANT 25 FT /note="P -> S (in GM2G1; late infantile)" FT /evidence="ECO:0000269|PubMed:8445615" FT /id="VAR_003202" FT VARIANT 39 FT /note="L -> R (in GM2G1; infantile; dbSNP:rs121907979)" FT /evidence="ECO:0000269|PubMed:9090523" FT /id="VAR_003203" FT VARIANT 114 FT /note="E -> K (in GM2G1; uncertain significance; FT dbSNP:rs748190164)" FT /evidence="ECO:0000269|PubMed:22723944" FT /id="VAR_077497" FT VARIANT 127 FT /note="L -> F (in GM2G1)" FT /evidence="ECO:0000269|PubMed:9150157" FT /id="VAR_022439" FT VARIANT 127 FT /note="L -> R (in GM2G1; infantile; dbSNP:rs121907975)" FT /evidence="ECO:0000269|PubMed:9090523" FT /id="VAR_003204" FT VARIANT 166 FT /note="R -> G (in GM2G1; late infantile)" FT /evidence="ECO:0000269|PubMed:8581357" FT /id="VAR_003205" FT VARIANT 170 FT /note="R -> Q (in GM2G1; infantile; inactive or unstable FT protein; dbSNP:rs121907957)" FT /evidence="ECO:0000269|PubMed:9338583" FT /id="VAR_003206" FT VARIANT 170 FT /note="R -> W (in GM2G1; infantile; dbSNP:rs121907972)" FT /evidence="ECO:0000269|PubMed:1302612, FT ECO:0000269|PubMed:22723944" FT /id="VAR_003207" FT VARIANT 178 FT /note="R -> C (in GM2G1; infantile; inactive protein; FT dbSNP:rs121907953)" FT /evidence="ECO:0000269|PubMed:9090523" FT /id="VAR_003208" FT VARIANT 178 FT /note="R -> H (in GM2G1; infantile; inactive protein; FT dbSNP:rs28941770)" FT /evidence="ECO:0000269|PubMed:8730294, FT ECO:0000269|PubMed:9090523" FT /id="VAR_003209" FT VARIANT 178 FT /note="R -> L (in GM2G1; infantile; dbSNP:rs28941770)" FT /evidence="ECO:0000269|PubMed:9090523" FT /id="VAR_003210" FT VARIANT 180 FT /note="Y -> H (in GM2G1; dbSNP:rs28941771)" FT /evidence="ECO:0000269|PubMed:8757036" FT /id="VAR_003211" FT VARIANT 192 FT /note="V -> L (in GM2G1; infantile; dbSNP:rs387906310)" FT /evidence="ECO:0000269|PubMed:9090523" FT /id="VAR_003212" FT VARIANT 196 FT /note="N -> S (in GM2G1; dbSNP:rs753862880)" FT /evidence="ECO:0000269|PubMed:7717398" FT /id="VAR_003213" FT VARIANT 197 FT /note="K -> T (in GM2G1; dbSNP:rs121907973)" FT /evidence="ECO:0000269|PubMed:9090523" FT /id="VAR_003214" FT VARIANT 200 FT /note="V -> M (in GM2G1; dbSNP:rs1800429)" FT /evidence="ECO:0000269|PubMed:9090523" FT /id="VAR_003215" FT VARIANT 204 FT /note="H -> R (in GM2G1; infantile; dbSNP:rs121907976)" FT /evidence="ECO:0000269|PubMed:9090523" FT /id="VAR_003216" FT VARIANT 210 FT /note="S -> F (in GM2G1; infantile; dbSNP:rs121907961)" FT /evidence="ECO:0000269|PubMed:1837283" FT /id="VAR_003217" FT VARIANT 211 FT /note="F -> S (in GM2G1; infantile; dbSNP:rs121907974)" FT /evidence="ECO:0000269|PubMed:9090523" FT /id="VAR_003218" FT VARIANT 226 FT /note="S -> F (in GM2G1; dbSNP:rs769866128)" FT /evidence="ECO:0000269|PubMed:9150157" FT /id="VAR_022440" FT VARIANT 247 FT /note="R -> W (in HEXA pseudodeficiency; FT dbSNP:rs121907970)" FT /evidence="ECO:0000269|PubMed:1384323" FT /id="VAR_003219" FT VARIANT 249 FT /note="R -> W (in HEXA pseudodeficiency; FT dbSNP:rs138058578)" FT /evidence="ECO:0000269|PubMed:17974005, FT ECO:0000269|PubMed:7902672" FT /id="VAR_003220" FT VARIANT 250 FT /note="G -> D (in GM2G1; juvenile; dbSNP:rs121907959)" FT /evidence="ECO:0000269|PubMed:1301189" FT /id="VAR_003221" FT VARIANT 250 FT /note="G -> S (in GM2G1; dbSNP:rs1057521137)" FT /evidence="ECO:0000269|PubMed:7717398" FT /id="VAR_003222" FT VARIANT 252 FT /note="R -> H (in GM2G1; dbSNP:rs762255098)" FT /evidence="ECO:0000269|PubMed:8730294" FT /id="VAR_003223" FT VARIANT 252 FT /note="R -> L (in GM2G1)" FT /evidence="ECO:0000269|PubMed:14566483" FT /id="VAR_017188" FT VARIANT 258 FT /note="D -> H (in GM2G1; infantile; dbSNP:rs121907971)" FT /evidence="ECO:0000269|PubMed:1302612" FT /id="VAR_003224" FT VARIANT 269 FT /note="G -> D (in GM2G1; dbSNP:rs121907980)" FT /evidence="ECO:0000269|PubMed:9150157" FT /id="VAR_022441" FT VARIANT 269 FT /note="G -> S (in GM2G1; late onset; inhibited subunit FT dissociation; loss of processing to a mature form; FT increased degradation; dbSNP:rs121907954)" FT /evidence="ECO:0000269|PubMed:2522679, FT ECO:0000269|PubMed:27682588" FT /id="VAR_003225" FT VARIANT 279 FT /note="S -> P (in GM2G1; late infantile)" FT /evidence="ECO:0000269|PubMed:9401008" FT /id="VAR_003226" FT VARIANT 293 FT /note="S -> I (in dbSNP:rs1054374)" FT /id="VAR_058477" FT VARIANT 295 FT /note="N -> S (in GM2G1; dbSNP:rs199578185)" FT /evidence="ECO:0000269|PubMed:14566483" FT /id="VAR_017189" FT VARIANT 301 FT /note="M -> R (in GM2G1; infantile; dbSNP:rs121907977)" FT /id="VAR_003227" FT VARIANT 304 FT /note="Missing (in GM2G1; infantile; Moroccan Jewish; FT dbSNP:rs121907960)" FT /evidence="ECO:0000269|PubMed:9338583" FT /id="VAR_003228" FT VARIANT 314 FT /note="D -> V (in GM2G1; dbSNP:rs1555472696)" FT /evidence="ECO:0000269|PubMed:9150157" FT /id="VAR_022442" FT VARIANT 320 FT /note="Missing (in GM2G1; late infantile; FT dbSNP:rs797044434)" FT /evidence="ECO:0000269|PubMed:1532289" FT /id="VAR_003229" FT VARIANT 322 FT /note="D -> N (in GM2G1; dbSNP:rs772180415)" FT /evidence="ECO:0000269|PubMed:22723944" FT /id="VAR_077498" FT VARIANT 322 FT /note="D -> Y (in GM2G1; dbSNP:rs772180415)" FT /evidence="ECO:0000269|PubMed:22723944" FT /id="VAR_077499" FT VARIANT 335 FT /note="I -> F (in GM2G1; dbSNP:rs1555472604)" FT /evidence="ECO:0000269|PubMed:7951261" FT /id="VAR_003230" FT VARIANT 347..352 FT /note="Missing (in GM2G1)" FT /evidence="ECO:0000269|PubMed:7951261" FT /id="VAR_003231" FT VARIANT 391 FT /note="V -> M (in GM2G1; mild)" FT /evidence="ECO:0000269|PubMed:7898712" FT /id="VAR_003232" FT VARIANT 393 FT /note="R -> P (in GM2G1; dbSNP:rs370266293)" FT /evidence="ECO:0000269|PubMed:22723944" FT /id="VAR_077500" FT VARIANT 399 FT /note="N -> D (in dbSNP:rs1800430)" FT /evidence="ECO:0000269|PubMed:1532289" FT /id="VAR_003233" FT VARIANT 420 FT /note="W -> C (in GM2G1; infantile; inactive protein; FT dbSNP:rs121907958)" FT /evidence="ECO:0000269|PubMed:14566483, FT ECO:0000269|PubMed:2144098" FT /id="VAR_003234" FT VARIANT 436 FT /note="I -> V (in dbSNP:rs1800431)" FT /evidence="ECO:0000269|PubMed:1532289, FT ECO:0000269|PubMed:15489334, ECO:0000269|PubMed:17974005, FT ECO:0000269|PubMed:1833974, ECO:0000269|PubMed:2933746, FT ECO:0000269|PubMed:2952641, ECO:0000269|PubMed:3013851, FT ECO:0000269|Ref.5, ECO:0007744|PubMed:21269460" FT /id="VAR_003235" FT VARIANT 454 FT /note="G -> S (in GM2G1; infantile; dbSNP:rs121907978)" FT /evidence="ECO:0000269|PubMed:9090523" FT /id="VAR_003236" FT VARIANT 455 FT /note="G -> R (in GM2G1; late infantile)" FT /evidence="ECO:0000269|PubMed:9375850" FT /id="VAR_003237" FT VARIANT 458 FT /note="C -> Y (in GM2G1; infantile)" FT /evidence="ECO:0000269|PubMed:7837766" FT /id="VAR_003238" FT VARIANT 462 FT /note="E -> V (in GM2G1; dbSNP:rs863225434)" FT /evidence="ECO:0000269|PubMed:22723944" FT /id="VAR_077501" FT VARIANT 474 FT /note="W -> C (in GM2G1; subacute; dbSNP:rs121907981)" FT /evidence="ECO:0000269|PubMed:9603435" FT /id="VAR_003239" FT VARIANT 478 FT /note="G -> R (in GM2G1; dbSNP:rs1057519467)" FT /evidence="ECO:0000269|PubMed:22723944" FT /id="VAR_077502" FT VARIANT 482 FT /note="E -> K (in GM2G1; infantile; loss of processing to a FT mature form; increased degradation; dbSNP:rs121907952)" FT /evidence="ECO:0000269|PubMed:27682588, FT ECO:0000269|PubMed:2970528, ECO:0000269|PubMed:9338583" FT /id="VAR_003240" FT VARIANT 484 FT /note="L -> Q (in GM2G1; infantile)" FT /evidence="ECO:0000269|PubMed:7837766" FT /id="VAR_003241" FT VARIANT 485 FT /note="W -> R (in GM2G1; infantile; dbSNP:rs121907968)" FT /evidence="ECO:0000269|PubMed:1301190" FT /id="VAR_003242" FT VARIANT 499 FT /note="R -> C (in GM2G1; infantile; dbSNP:rs121907966)" FT /evidence="ECO:0000269|PubMed:14566483" FT /id="VAR_003243" FT VARIANT 499 FT /note="R -> H (in GM2G1; juvenile; dbSNP:rs121907956)" FT /evidence="ECO:0000269|PubMed:14566483" FT /id="VAR_003244" FT VARIANT 504 FT /note="R -> C (in GM2G1; infantile; dbSNP:rs28942071)" FT /evidence="ECO:0000269|PubMed:1837283" FT /id="VAR_003245" FT VARIANT 504 FT /note="R -> H (in GM2G1; juvenile; fails to associate with FT the beta-subunit to form the enzymatically active FT heterodimer; dbSNP:rs121907955)" FT /evidence="ECO:0000269|PubMed:2140574" FT /id="VAR_003246" FT MUTAGEN 115 FT /note="N->Q: No change of the catalytic activity associated FT with the alpha-chain. No catalytic activity associated with FT the alpha-chain; when associated with Q-157 and Q-295." FT /evidence="ECO:0000269|PubMed:1533633" FT MUTAGEN 157 FT /note="N->Q: No change of the catalytic activity associated FT with the alpha-chain. No catalytic activity associated with FT the alpha-chain; when associated with Q-115 and Q-295." FT /evidence="ECO:0000269|PubMed:1533633" FT MUTAGEN 295 FT /note="N->Q: No change of the catalytic activity associated FT with the alpha-chain. No catalytic activity associated with FT the alpha-chain; when associated with Q-115 and Q-157." FT /evidence="ECO:0000269|PubMed:1533633" FT CONFLICT 331 FT /note="S -> P (in Ref. 5; BAD96222)" FT /evidence="ECO:0000305" FT STRAND 28..31 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 36..39 FT /evidence="ECO:0007829|PDB:2GJX" FT TURN 41..43 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 45..48 FT /evidence="ECO:0007829|PDB:2GJX" FT HELIX 59..73 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 93..100 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 104..106 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 116..123 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 125..131 FT /evidence="ECO:0007829|PDB:2GJX" FT HELIX 132..145 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 146..148 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 154..157 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 159..163 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 168..175 FT /evidence="ECO:0007829|PDB:2GJX" FT TURN 176..178 FT /evidence="ECO:0007829|PDB:2GJX" FT HELIX 183..195 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 200..204 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 216..218 FT /evidence="ECO:0007829|PDB:2GK1" FT HELIX 220..225 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 226..228 FT /evidence="ECO:0007829|PDB:2GK1" FT TURN 229..231 FT /evidence="ECO:0007829|PDB:2GJX" FT HELIX 236..248 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 252..256 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 260..262 FT /evidence="ECO:0007829|PDB:2GJX" FT TURN 264..269 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 274..290 FT /evidence="ECO:0007829|PDB:2GJX" FT HELIX 295..311 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 314..318 FT /evidence="ECO:0007829|PDB:2GJX" FT HELIX 327..331 FT /evidence="ECO:0007829|PDB:2GJX" FT HELIX 333..341 FT /evidence="ECO:0007829|PDB:2GJX" FT HELIX 349..364 FT /evidence="ECO:0007829|PDB:2GJX" FT TURN 365..367 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 369..373 FT /evidence="ECO:0007829|PDB:2GJX" FT HELIX 374..378 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 388..391 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 394..398 FT /evidence="ECO:0007829|PDB:2GJX" FT HELIX 400..409 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 413..416 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 426..428 FT /evidence="ECO:0007829|PDB:2GJX" FT HELIX 431..436 FT /evidence="ECO:0007829|PDB:2GJX" FT HELIX 446..449 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 452..459 FT /evidence="ECO:0007829|PDB:2GJX" FT TURN 466..468 FT /evidence="ECO:0007829|PDB:2GJX" FT HELIX 469..473 FT /evidence="ECO:0007829|PDB:2GJX" FT HELIX 476..485 FT /evidence="ECO:0007829|PDB:2GJX" FT HELIX 493..509 FT /evidence="ECO:0007829|PDB:2GJX" FT STRAND 517..519 FT /evidence="ECO:0007829|PDB:2GJX" SQ SEQUENCE 529 AA; 60703 MW; DACB3E3992E57A47 CRC64; MTSSRLWFSL LLAAAFAGRA TALWPWPQNF QTSDQRYVLY PNNFQFQYDV SSAAQPGCSV LDEAFQRYRD LLFGSGSWPR PYLTGKRHTL EKNVLVVSVV TPGCNQLPTL ESVENYTLTI NDDQCLLLSE TVWGALRGLE TFSQLVWKSA EGTFFINKTE IEDFPRFPHR GLLLDTSRHY LPLSSILDTL DVMAYNKLNV FHWHLVDDPS FPYESFTFPE LMRKGSYNPV THIYTAQDVK EVIEYARLRG IRVLAEFDTP GHTLSWGPGI PGLLTPCYSG SEPSGTFGPV NPSLNNTYEF MSTFFLEVSS VFPDFYLHLG GDEVDFTCWK SNPEIQDFMR KKGFGEDFKQ LESFYIQTLL DIVSSYGKGY VVWQEVFDNK VKIQPDTIIQ VWREDIPVNY MKELELVTKA GFRALLSAPW YLNRISYGPD WKDFYIVEPL AFEGTPEQKA LVIGGEACMW GEYVDNTNLV PRLWPRAGAV AERLWSNKLT SDLTFAYERL SHFRCELLRR GVQAQPLNVG FCEQEFEQT //