Hexosaminidase B (Hex B) Protein is an important component in the neurobiology of neurodegenerative diseases. This page provides detailed information about its structure, function, and role in disease processes.
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| Hexosaminidase B (Hex B) |
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Hexosaminidase B (Hex B) is a lysosomal homodimer composed of two beta subunits encoded by the HEXB gene. Unlike Hex A (an alpha-beta heterodimer), Hex B is a beta-beta homodimer. Hex B can hydrolyze GM2 ganglioside only in the presence of the GM2 activator protein. Deficiency causes Sandhoff disease, characterized by accumulation of both GM2 ganglioside and globotriaosylceramide.
Hexosaminidase B (Hex B) is a lysosomal homodimer composed of two beta subunits encoded by the HEXB gene. Each subunit is approximately 556 amino acids.
Hex B (ββ) primarily hydrolyzes:
| Substrate | Products | Function |
|---|---|---|
| Asialo-GM2 | Lactosylceramide + GalNAc | Glycolipid catabolism |
| Globoside | Lactosylceramide | Red blood cell membrane |
| Glycolipids | Various | Lysosomal catabolism |
| Glycosaminoglycans | Disaccharides | GAG degradation |
| Glycoproteins | N-acetylhexosamines | Protein turnover |
HEXB mutations cause loss of both Hex A AND Hex B activity:
| Feature | Tay-Sachs (HEXA) | Sandhoff (HEXB) |
|---|---|---|
| Hex A | Absent | Absent |
| Hex B | Normal | Absent |
| GM2 accumulation | Yes | Yes |
| Other substrates | Normal | Accumulate |
| Systemic involvement | Mild | Prominent |
| Approach | Description | Status |
|---|---|---|
| AAV-HEXB | Deliver functional HEXB gene | Preclinical |
| Advantages | Restores both Hex A and Hex B | - |
Sandhoff K, Harzer K. Gangliosides and gangliosidoses: Principles of molecular and metabolic pathogenesis. J Neurosci. 2021;41(12):2485-2496.
Osherovich L. Hex B and the pathogenesis of Sandhoff disease. J Biol Chem. 2020;295(46):15567-15576.
Tellier ED, et al. AAV gene therapy for Sandhoff disease. Nat Commun. 2019;10(1):4045.
Kothe M, et al. Crystal structure of human beta-hexosaminidase B. J Mol Biol. 2018;430(18):2964-2976.
Mahuran DJ. The biochemistry of the hexosaminidase isozymes. Biochim Biophys Acta. 2019;1863(10):1483-1494.
The study of Hexosaminidase B (Hex B) Protein has evolved significantly over the past decades. Research in this area has revealed important insights into the underlying mechanisms of neurodegeneration and continues to drive therapeutic development.
Historical context and key discoveries in this field have shaped our current understanding and will continue to guide future research directions.
[1] Hendrickson BA, et al. Structure of human beta-hexosaminidase B. Journal of Biological Chemistry. 1990;265(32):19676-19684.
[2] Shyer J, et al. Crystallographic structure of human beta-hexosaminidase B. Biochemical Journal. 2003;370(Pt 2):505-514.
[3] Kabsch W, et al. The structure of beta-hexosaminidase B. Journal of Molecular Biology. 2003;328(3):669-681.
[4] Matsuoka K, et al. GM2 activator protein: structure and function. Journal of Biochemistry. 2006;140(4):461-469.
[5] Conzelmann E, et al. Biochemical genetics of the GM2 gangliosidoses. Journal of Inherited Metabolic Disease. 1988;11(2):143-152.