hexosaminidase

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glucosaminidase

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出典(authority):フリー百科事典『ウィキペディア（Wikipedia）』「2015/12/03 22:01:11」(JST)

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β-N-acetylhexosaminidase
Hexosaminidase A (Hex A)
Identifiers
EC number	3.2.1.52
CAS number	9012-33-3
Databases
IntEnz	IntEnz view
BRENDA	BRENDA entry
ExPASy	NiceZyme view
KEGG	KEGG entry
MetaCyc	metabolic pathway
PRIAM	profile
PDB structures	RCSB PDB PDBe PDBsum
Gene Ontology	AmiGO / EGO
Search PMC articles PubMed articles NCBI proteins

Hexosaminidase (EC 3.2.1.52, beta-acetylaminodeoxyhexosidase, N-acetyl-beta-D-hexosaminidase, N-acetyl-beta-hexosaminidase, N-acetyl hexosaminidase, beta-hexosaminidase, beta-acetylhexosaminidinase, beta-D-N-acetylhexosaminidase, beta-N-acetyl-D-hexosaminidase, beta-N-acetylglucosaminidase, hexosaminidase A, N-acetylhexosaminidase, beta-D-hexosaminidase) is an enzyme involved in the hydrolysis of terminal N-acetyl-D-hexosamine residues in N-acetyl-β-D-hexosaminides.

Isozymes and genes

Lysosomal A, B, and S isozymes

Functional lysosomal β-hexosaminidase enzymes are dimeric in structure. Three isozymes are produced through the combination of α and β subunits to form any one of three active dimers:

hexosaminidase isozyme	subunit composition	function
A	α/β heterodimer	only isozyme 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, HEXA and HEXB respectively. Beta-hexosaminidase and the cofactor G_M2 activator protein catalyze the degradation of the G_M2 gangliosides and other molecules containing terminal N-acetyl hexosamines. Gene mutations in HEXB often result in Sandhoff disease; whereas, mutations in HEXA decrease the hydrolysis of G_M2 gangliosides, which is the main cause of Tay-Sachs disease.

β-hexosaminidase subunit alpha Identifiers Symbol HEXA Entrez 3073 HUGO 4878 OMIM 606869 RefSeq NM_000520 UniProt P06865 Other data EC number 3.2.1.52 Locus Chr. 15 q24.1

β-hexosaminidase subunit beta Identifiers Symbol HEXB Entrez 3074 HUGO 4879 OMIM 606873 RefSeq NM_000521 UniProt P07686 Other data EC number 3.2.1.52 Locus Chr. 5 q13.3

Function

Even though the alpha and beta subunits of lysosomal hexosaminidase can both cleave GalNAc residues, only the alpha subunit is able to hydrolyze G_M2 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 alpha subunit, consisting of Gly-280, Ser-281, Glu-282, and Pro-283 which is absent in the beta subunit, serves as an ideal structure for the binding of the G_M2 activator protein (G_M2AP), and arginine is essential for binding the N-acetyl-neuraminic acid residue of G_M2 gangliosides. The G_M2 activator protein transports G_M2 gangliosides and presents the lipids to hexosaminidase, so a functional hexosaminidase enzyme is able to hydrolyze G_M2 gangliosides into G_M3 gangliosides by removing the N-acetylgalactosamine (GalNAc) residue from G_M2 gangliosides.

Mechanism of action

A Michaelis complex consisting of a glutamate residue, a GalNAc residue on the G_M2 ganglioside, and an aspartate residue leads to the formation of an oxazolinium ion intermediate. A glutamate residue (alpha Glu-323/beta Glu-355) works as an acid by donating its hydrogen to the glycosidic oxygen atom on the GalNAc residue. An aspartate residue (alpha Asp-322/beta Asp-354) positions the C2-acetamindo group so that it can be attacked by the nucleophile (N-acetamido oxygen atom on carbon 1 of the substrate). The aspartate residue stabilizes the positive charge on the nitrogen atom in the oxazolinium ion intermediate. Following the formation of the oxazolinium ion intermediate, water attacks the electrophillic acetal carbon. Glutamate acts as a base by deprotonating the water leading to the formation of the product complex and the G_M3ganglioside.

Hydrolysis of G_M2 ganglioside to G_M3 ganglioside catalyzed by hexosaminidase A.

The mechanism of the hydrolysis of a G_M2 ganglioside and removal of a GalNAc residue to produce G_M3 ganglioside.

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 G_M2 ganglioside, and as a result, they end up storing 100 to 1000 times more G_M2 gangliosides in the brain than the normal person. Over 100 different mutations have been discovered just in infantile cases of Tay-Sachs disease alone.

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 codon, which causes the Hex A deficiency.

Children born with Tay-Sachs usually die between two to four years of age from aspiration and pneumonia. Tay-Sachs causes cerebral degeneration and blindness. Patients also experience flaccid extremities and seizures. At this point in time, there has been no cure or effective treatment of Tay-Sachs disease.

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 G_M2 gangliosides. The two subunits of hexosaminidase A are shown below:

The alpha subunit active site shown bound to NAG-thiazoline (NGT) in beta-hexosaminidase. PDB: 2GK1​ The light green outline surrounding NGT represents the Van der Waals surface of NGT. The critical amino acids in the active site that are able to hydrogen bond with NGT include Arginine 178 and Glutamate 462.

The beta subunit active site shown bound to NAG-thiazoline (NGT) in beta-hexosaminidase. PDB: 2GK1​ The light blue outline surrounding NGT represents the Van der Waals surface of NGT. The critical amino acids in the active site that are able to hydrogen bond with NGT include Glutamate 491 and Aspartate 452.

Cytosolic C and D isozymes

The bifunctional protein NCOAT (nuclear cytoplasmic O-GlcNAcase and acetyltransferase) that is encoded by the MGEA5 gene possesses both hexosaminidase and histone acetyltransferase activities. NCOAT is also known as hexosaminidase C and has distinct substrate specificities compared to lysosomal hexosaminidase A. A single-nucleotide polymorphism in the human O-GlcNAcase gene is linked to diabetes mellitus type 2.

A fourth mammalian hexosaminidase polypeptide which has been designated hexosaminidase D (HEXDC) has recently been identified.

hexosaminidase C Identifiers Symbol MGEA5 Entrez 10724 HUGO 7056 OMIM 604039 RefSeq NM_012215 UniProt O60502 Other data EC number 3.2.1.52 Locus Chr. 10 q24.1-24.3

hexosaminidase D Identifiers Symbol HEXDC Alt. symbols FLJ23825 Entrez 284004 HUGO 26307 RefSeq NM_173620 UniProt Q8IYN4 Other data EC number 3.2.1.52 Locus Chr. 17 q25.3

References

External links

• GeneReviews/NCBI/NIH/UW entry on hexosaminidase A deficiency, Tay-Sachs disease
• hexosaminidase A at the US National Library of Medicine Medical Subject Headings (MeSH)
• EC 3.2.1.52

UpToDate Contents

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English Journal

• Optimization of Maillard reaction with ribose for enhancing anti-allergy effect of fish protein hydrolysates using response surface methodology.

• Yang SY1, Kim SW1, Kim Y2, Lee SH3, Jeon H2, Lee KW4.
• Food chemistry.Food Chem.2015 Jun 1;176:420-5. doi: 10.1016/j.foodchem.2014.12.090. Epub 2014 Dec 30.
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• PMID 25624251

• Damnacanthal inhibits IgE receptor-mediated activation of mast cells.

• Garcia-Vilas JA1, Medina MA1, Melo FR2, Pejler G3, Garcia-Faroldi G4.
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• Enzymatic properties and subtle differences in the substrate specificity of phylogenetically distinct invertebrate N-glycan processing hexosaminidases.

• Dragosits M1, Yan S2, Razzazi-Fazeli E3, Wilson IB2, Rendic D4.
• Glycobiology.Glycobiology.2015 Apr;25(4):448-64. doi: 10.1093/glycob/cwu132. Epub 2014 Dec 8.
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Japanese Journal

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• Chemical and pharmaceutical bulletin 59(12), 1535-1540, 2011-12
• NAID 40019073232

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• … Phycoerythrin (0.01 mg/mL) and phycoerythrobilin (1 μmol/L) significantly inhibited calcium ionophore (A23187) induced release of β-hexosaminidase from rat basophilic leukemia (RBL-2H3) cells (approximately 50% and 40%, respectively). …
• NAID 120004367774

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★リンクテーブル★

リンク元	「ヘキソサミニダーゼ」「glucosaminidase」
拡張検索	「beta-hexosaminidase alpha chain」「hexosaminidase B」「hexosaminidase A」

「ヘキソサミニダーゼ」

　　[★]

英

[[]]

同

hexosaminidase

関

[[]]

同

hexosaminidase

「glucosaminidase」

　　[★]

グルコサミニダーゼ

関

hexosaminidase

「beta-hexosaminidase alpha chain」

　　[★]

• βヘキソアミダーゼα鎖

「hexosaminidase B」

　　[★]

ヘキソサミニダーゼB

「hexosaminidase A」

　　[★] ヘキソサミニダーゼA