HEXB explained

Beta-hexosaminidase subunit beta is an enzyme that in humans is encoded by the HEXB gene.^{[1] [2] [3]}

Hexosaminidase B is the beta subunit of the lysosomal enzyme beta-hexosaminidase that, together with the cofactor GM2 activator protein, catalyzes the degradation of the ganglioside GM2, and other molecules containing terminal N-acetyl hexosamines. Beta-hexosaminidase is composed of two subunits, alpha and beta, which are encoded by separate genes. Both beta-hexosaminidase alpha and beta subunits are members of family 20 of glycosyl hydrolases. Mutations in the alpha or beta subunit genes lead to an accumulation of GM2 ganglioside in neurons and neurodegenerative disorders termed the GM2 gangliosidoses. Beta subunit gene mutations lead to Sandhoff disease (GM2-gangliosidosis type II).^[3]

Structure

Gene

The HEXB gene lies on the chromosome location of 5q13.3 and consists of 14 exons, spanning 35-40Kb.

Protein

HEXB consists of 556 amino acid residues and weighs 63111Da.

Function

HEXB is one of the two subunits forming β-hexosaminidase which functions as a glycosyl hydrolase that remove β-linked nonreducing-terminal GalNAc or GlcNAc residues in the lysosome.^[4] Inability of HEXB will lead toβ-hexosaminidase defect and result in a group of recessive disorders called GM2 gangliosidoses, characterized by the accumulation of GM2 ganglioside.^[5]

Clinical significance

Genetic defects in HEXB can result in the accumulation of GM2 ganglioside in neural tissues and two of three lysosomal storage diseases collectively known as GM2 gangliosidosis, of which Sandhoff disease (defects in the β subunit) is the best studied one. Patients present with neurosomatic manifestations. Therapeutic effects of Hex subunit gene transduction have been examined on Sandhoff disease model mice.^[6] Intracerebroventricular administration of the modified β-hexosaminidase B to Sandhoff mode mice restored the β-hexosaminidase activity in the brains, and reduced the GM2 ganglioside storage in the parenchyma.^[7]

Interactions

HEXB has been found to interact with HEXA^[8] and ganglioside.

Further reading

• Mahuran DJ . The biochemistry of HEXA and HEXB gene mutations causing GM2 gangliosidosis . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 1096 . 2 . 87–94 . February 1991 . 1825792 . 10.1016/0925-4439(91)90044-A .
• Mahuran DJ . Biochemical consequences of mutations causing the GM2 gangliosidoses . Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease . 1455 . 2–3 . 105–38 . October 1999 . 10571007 . 10.1016/S0925-4439(99)00074-5 .
• Gilbert F, Kucherlapati R, Creagan RP, Murnane MJ, Darlington GJ, Ruddle FH . Tay–Sachs' and Sandhoff's diseases: the assignment of genes for hexosaminidase A and B to individual human chromosomes . Proceedings of the National Academy of Sciences of the United States of America . 72 . 1 . 263–7 . January 1975 . 1054503 . 432284 . 10.1073/pnas.72.1.263 . 1975PNAS...72..263G . free .
• McInnes B, Potier M, Wakamatsu N, Melancon SB, Klavins MH, Tsuji S, Mahuran DJ . An unusual splicing mutation in the HEXB gene is associated with dramatically different phenotypes in patients from different racial backgrounds . The Journal of Clinical Investigation . 90 . 2 . 306–14 . August 1992 . 1386607 . 443103 . 10.1172/JCI115863 .
• Bolhuis PA, Bikker H . Deletion of the 5'-region in one or two alleles of HEXB in 15 out of 30 patients with Sandhoff disease . Human Genetics . 90 . 3 . 328–9 . November 1992 . 1487253 . 10.1007/bf00220096 . 219692 .
• Wakamatsu N, Kobayashi H, Miyatake T, Tsuji S . A novel exon mutation in the human beta-hexosaminidase beta subunit gene affects 3' splice site selection . The Journal of Biological Chemistry . 267 . 4 . 2406–13 . February 1992 . 10.1016/S0021-9258(18)45894-2 . 1531140 . free .
• Banerjee P, Siciliano L, Oliveri D, McCabe NR, Boyers MJ, Horwitz AL, Li SC, Dawson G . Molecular basis of an adult form of beta-hexosaminidase B deficiency with motor neuron disease . Biochemical and Biophysical Research Communications . 181 . 1 . 108–15 . November 1991 . 1720305 . 10.1016/S0006-291X(05)81388-9 .
• Boose JA, Tifft CJ, Proia RL, Myerowitz R . Synthesis of a human lysosomal enzyme, beta-hexosaminidase B, using the baculovirus expression system . Protein Expression and Purification . 1 . 2 . 111–20 . November 1990 . 1967020 . 10.1016/1046-5928(90)90003-H .
• Mahuran DJ . Characterization of human placental beta-hexosaminidase I2. Proteolytic processing intermediates of hexosaminidase A . The Journal of Biological Chemistry . 265 . 12 . 6794–9 . April 1990 . 10.1016/S0021-9258(19)39219-1 . 2139028 . free .
• Neote K, McInnes B, Mahuran DJ, Gravel RA . Structure and distribution of an Alu-type deletion mutation in Sandhoff disease . The Journal of Clinical Investigation . 86 . 5 . 1524–31 . November 1990 . 2147027 . 296899 . 10.1172/JCI114871 .
• Neote K, Brown CA, Mahuran DJ, Gravel RA . Translation initiation in the HEXB gene encoding the beta-subunit of human beta-hexosaminidase . The Journal of Biological Chemistry . 265 . 34 . 20799–806 . December 1990 . 10.1016/S0021-9258(17)45286-0 . 2147427 . free .
• Dlott B, d'Azzo A, Quon DV, Neufeld EF . Two mutations produce intron insertion in mRNA and elongated beta-subunit of human beta-hexosaminidase . The Journal of Biological Chemistry . 265 . 29 . 17921–7 . October 1990 . 10.1016/S0021-9258(18)38251-6 . 2170400 . free .
• Nakano T, Suzuki K . Genetic cause of a juvenile form of Sandhoff disease. Abnormal splicing of beta-hexosaminidase beta chain gene transcript due to a point mutation within intron 12 . The Journal of Biological Chemistry . 264 . 9 . 5155–8 . March 1989 . 10.1016/S0021-9258(18)83712-7 . 2522450 . free .
• Hubbes M, Callahan J, Gravel R, Mahuran D . The amino-terminal sequences in the pro-alpha and -beta polypeptides of human lysosomal beta-hexosaminidase A and B are retained in the mature isozymes . FEBS Letters . 249 . 2 . 316–20 . June 1989 . 2525487 . 10.1016/0014-5793(89)80649-0 . 83872800 . free .
• Bikker H, van den Berg FM, Wolterman RA, de Vijlder JJ, Bolhuis PA . Demonstration of a Sandhoff disease-associated autosomal 50-kb deletion by field inversion gel electrophoresis . Human Genetics . 81 . 3 . 287–8 . February 1989 . 2921040 . 10.1007/BF00279006 . 39411971 .
• Bolhuis PA, Oonk JG, Kamp PE, Ris AJ, Michalski JC, Overdijk B, Reuser AJ . Ganglioside storage, hexosaminidase lability, and urinary oligosaccharides in adult Sandhoff's disease . Neurology . 37 . 1 . 75–81 . January 1987 . 2948136 . 10.1212/wnl.37.1.75 . 20622020 .
• Proia RL . Gene encoding the human beta-hexosaminidase beta chain: extensive homology of intron placement in the alpha- and beta-chain genes . Proceedings of the National Academy of Sciences of the United States of America . 85 . 6 . 1883–7 . March 1988 . 2964638 . 279885 . 10.1073/pnas.85.6.1883 . 1988PNAS...85.1883P . free .
• Mahuran DJ, Neote K, Klavins MH, Leung A, Gravel RA . Proteolytic processing of pro-alpha and pro-beta precursors from human beta-hexosaminidase. Generation of the mature alpha and beta a beta b subunits . The Journal of Biological Chemistry . 263 . 10 . 4612–8 . April 1988 . 10.1016/S0021-9258(18)68826-X . 2965147 . free .

Notes and References

1. O'Dowd BF, Quan F, Willard HF, Lamhonwah AM, Korneluk RG, Lowden JA, Gravel RA, Mahuran DJ . Isolation of cDNA clones coding for the beta subunit of human beta-hexosaminidase . Proceedings of the National Academy of Sciences of the United States of America . 82 . 4 . 1184–8 . February 1985 . 2579389 . 397219 . 10.1073/pnas.82.4.1184 . 1985PNAS...82.1184O . free .
2. Korneluk RG, Mahuran DJ, Neote K, Klavins MH, O'Dowd BF, Tropak M, Willard HF, Anderson MJ, Lowden JA, Gravel RA . Isolation of cDNA clones coding for the alpha-subunit of human beta-hexosaminidase. Extensive homology between the alpha- and beta-subunits and studies on Tay–Sachs disease . The Journal of Biological Chemistry . 261 . 18 . 8407–13 . June 1986 . 10.1016/S0021-9258(19)83927-3 . 3013851 . free .
3. Web site: Entrez Gene: HEXB hexosaminidase B (beta polypeptide).
4. Bateman KS, Cherney MM, Mahuran DJ, Tropak M, James MN . Crystal structure of β-hexosaminidase B in complex with pyrimethamine, a potential pharmacological chaperone . Journal of Medicinal Chemistry . 54 . 5 . 1421–9 . March 2011 . 21265544 . 3201983 . 10.1021/jm101443u .
5. Sonnino S, Chigorno V . Ganglioside molecular species containing C18- and C20-sphingosine in mammalian nervous tissues and neuronal cell cultures . Biochimica et Biophysica Acta (BBA) - Reviews on Biomembranes . 1469 . 2 . 63–77 . September 2000 . 10998569 . 10.1016/s0005-2736(00)00210-8.
6. Itakura T, Kuroki A, Ishibashi Y, Tsuji D, Kawashita E, Higashine Y, Sakuraba H, Yamanaka S, Itoh K . Inefficiency in GM2 ganglioside elimination by human lysosomal beta-hexosaminidase beta-subunit gene transfer to fibroblastic cell line derived from Sandhoff disease model mice . Biological & Pharmaceutical Bulletin . 29 . 8 . 1564–9 . August 2006 . 16880605 . 10.1248/bpb.29.1564. free .
7. Matsuoka K, Tamura T, Tsuji D, Dohzono Y, Kitakaze K, Ohno K, Saito S, Sakuraba H, Itoh K . Therapeutic potential of intracerebroventricular replacement of modified human β-hexosaminidase B for GM2 gangliosidosis . Molecular Therapy . 19 . 6 . 1017–24 . June 2011 . 21487393 . 3129794 . 10.1038/mt.2011.27 .
8. Gort L, de Olano N, Macías-Vidal J, Coll MA . GM2 gangliosidoses in Spain: analysis of the HEXA and HEXB genes in 34 Tay–Sachs and 14 Sandhoff patients . Gene . 506 . 1 . 25–30 . September 2012 . 22789865 . 10.1016/j.gene.2012.06.080 .