Hexosaminidase
β-N-Acetylhexosaminidase | |||||||||
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ExPASy NiceZyme view | | ||||||||
KEGG | KEGG entry | ||||||||
MetaCyc | metabolic pathway | ||||||||
PRIAM | profile | ||||||||
PDB structures | RCSB PDB PDBe PDBsum | ||||||||
Gene Ontology | AmiGO / QuickGO | ||||||||
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Hexosaminidase (
Elevated levels of hexosaminidase in blood and/or urine have been proposed as a biomarker of relapse in the treatment of alcoholism.[5]
Hereditary inability to form functional hexosaminidase enzymes are the cause of lipid storage disorders Tay-Sachs disease and Sandhoff disease.[6]
Isoenzymes and genes
Lysosomal A, B, and S isoenzymes
Functional lysosomal β-hexosaminidase enzymes are dimeric in structure. Three isoenzymes are produced through the combination of α and β subunits to form any one of three active dimers:[7]
hexosaminidase isoenzyme |
subunit composition | function |
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A | α/β heterodimer | only isoenzyme that can hydrolyze GM2 ganglioside in vivo |
B | β/β homodimer | exists in tissues but no known physiological function |
S | α/α homodimer | exists in tissues but no known physiological function |
The α and β subunits are encoded by separate genes,
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Function
Even though the α and β subunits of lysosomal hexosaminidase can both cleave GalNAc residues, only the α subunit is able to hydrolyze GM2 gangliosides because of a key residue, Arg-424, and a loop structure that forms from the amino acid sequence in the alpha subunit. The loop in the α subunit, consisting of Gly-280, Ser-281, Glu-282, and Pro-283 which is absent in the β subunit, serves as an ideal structure for the binding of the GM2 activator protein (GM2AP), and arginine is essential for binding the N-acetyl-neuraminic acid residue of GM2 gangliosides. The GM2 activator protein transports GM2 gangliosides and presents the lipids to hexosaminidase, so a functional hexosaminidase enzyme is able to hydrolyze GM2 gangliosides into GM3 gangliosides by removing the N-acetylgalactosamine (GalNAc) residue from GM2 gangliosides.[10]
Mechanism of action
A Michaelis complex consisting of a
Gene mutations resulting in Tay–Sachs disease
There are numerous mutations that lead to hexosaminidase deficiency including gene deletions, nonsense mutations, and missense mutations. Tay–Sachs disease occurs when hexosaminidase A loses its ability to function. People with Tay–Sachs disease are unable to remove the GalNAc residue from the GM2 ganglioside, and as a result, they end up storing 100 to 1000 times more GM2 gangliosides in the brain than the unaffected person. Over 100 different mutations have been discovered just in infantile cases of Tay–Sachs disease alone.[11]
The most common mutation, which occurs in over 80 percent of Tay–Sachs patients, results from a four base pair addition (TATC) in exon 11 of the Hex A gene. This insertion leads to an early stop
Children born with Tay–Sachs usually die between two and four years of age from aspiration and pneumonia. Tay–Sachs causes cerebral degeneration and blindness. Patients also experience flaccid extremities and seizures. At present there has been no cure or effective treatment of Tay–Sachs disease.[11]
NAG-thiazoline, NGT, acts as mechanism based inhibitor of hexosaminidase A. In patients with Tay–Sachs disease (misfolded hexosaminidase A), NGT acts as a molecular chaperone by binding in the active site of hexosaminidase A which helps create a properly folded hexosaminidase A. The stable dimer conformation of hexosaminidase A has the ability to leave the endoplasmic reticulum and is directed to the lysosome where it can perform the degradation of GM2 gangliosides.[10] The two subunits of hexosaminidase A are shown below:
Cytosolic C and D isozymes
The bifunctional protein NCOAT (nuclear cytoplasmic O-GlcNAcase and acetyltransferase) that is encoded by the
A fourth mammalian hexosaminidase polypeptide which has been designated hexosaminidase D (HEXDC) has recently been identified.[17]
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References
- PMID 2529847.
- PMID 33660.
- PMID 6055190.
- PMID 5506280.
- ^ Allen JP, Sillanaukee P, Strid N, Litten RZ (August 2004). "Biomarkers of Heavy Drinking". National Institute on Alcohol Abuse and Alcoholism. Retrieved 2021-07-11.
- ^ Demczko, Matt. "Tay-Sachs Disease and Sandhoff Disease". MSD Manual.
- PMID 8672428.
- .
- PMID 12662933.
- ^ PMID 16698036.
- ^ ISBN 0-340-80970-1.
- PMID 7887427.
- PMID 16356930.
- PMID 945735.
- PMID 11148210.
- PMID 16882729.
- PMID 19040401.
External links
- GeneReviews/NCBI/NIH/UW entry on hexosaminidase A deficiency, Tay–Sachs disease
- hexosaminidase A at the U.S. National Library of Medicine Medical Subject Headings (MeSH)
- EC 3.2.1.52