bHEXA hydrolyzes GM2A:GM2 to GM2A:GM3

Stable Identifier
Reaction [transition]
Homo sapiens
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Beta-hexosaminidase A complex (bHEXA) cleaves the terminal N-acetyl galactosamine from GM2 ganglioside to form GM3 ganglioside (Lemieux et al. 2006). There are three forms of hexosaminidase complexes: hexosaminidase A, B and S. The A form is a tetramer of the subunits alpha (HEXA, beta A) and beta (HEXB, beta B) dimers. The B form is a tetramer of two beta subunit dimers, and the S form a tetramer of two HEXA dimers (O'Dowd et al. 1988). Only form A is active toward GM2 ganglioside (Conzelmann & Sandhoff 1979). GM2 activator (GM2A, GM2AP) acts as an essential cofactor to the reaction by mobilizing GM2 from intralysosomal vehicle (ILV) membranes and binding to bHEXA (Kytzia & Sandhoff, 1985; Yadao et al., 1997; Ravasi et al., 2002; Wendeler et al., 2006). Defects in the two complex subunits or GM2A cause lysosomal storage diseases marked by the accumulation of GM2 ganglioside in neuronal cells. Defects in the alpha subunits are the cause of GM2-gangliosidosis type 1 (GM2G1) (MIM:272800), also known as Tay-Sachs disease (Nakano et al. 1988). Defects in the beta subunits are the cause of GM2-gangliosidosis type 2 (GM2G2) (MIM:268800), also known as Sandhoff disease (Banerjee et al. 1991). Defects in GM2A function lead to GM2 gangliosidosis AB (MIM:272750), also known as the Tay-Sachs disease AB variant (Schroeder et al., 1991; Wilkening et al., 2000; reviewed by Sandhoff & Sandhoff, 2018).

Literature References
PubMed ID Title Journal Year
29802621 Emerging concepts of ganglioside metabolism

Sandhoff, R, Sandhoff, K

FEBS Lett 2018
16698036 Crystallographic structure of human beta-hexosaminidase A: interpretation of Tay-Sachs mutations and loss of GM2 ganglioside hydrolysis

Mahuran, DJ, James, MN, Lemieux, MJ, Mark, BL, Withers, SG, Cherney, MM

J Mol Biol 2006
527942 Purification and characterization of an activator protein for the degradation of glycolipids GM2 and GA2 by hexosaminidase A

Sandhoff, K, Conzelmann, E

Hoppe Seylers Z Physiol Chem 1979
1720305 Molecular basis of an adult form of beta-hexosaminidase B deficiency with motor neuron disease

Boyers, MJ, Siciliano, L, Banerjee, P, Oliveri, D, Horwitz, AL, Li, SC, McCabe, NR, Dawson, G

Biochem Biophys Res Commun 1991
12374214 Study of interaction of GM2 activator protein with GM2 using circular dichroism and fluorescence spectroscopy

Vecchio, G, Ravasi, D, Li, YT, Masserini, M, Li, SC

Neurochem Res 2002
3158659 Evidence for two different active sites on human beta-hexosaminidase A. Interaction of GM2 activator protein with beta-hexosaminidase A

Kytzia, HJ, Sandhoff, K

J Biol Chem 1985
9217013 Formation of a ternary complex between GM2 activator protein, GM2 ganglioside and hexosaminidase A

Yadao, F, Hechtman, P, Kaplan, F

Biochim Biophys Acta 1997
2970528 A point mutation in the coding sequence of the beta-hexosaminidase alpha gene results in defective processing of the enzyme protein in an unusual GM2-gangliosidosis variant

Ohno, K, Suzuki, K, Muscillo, M, Hoffman, AJ, Nakano, T

J Neurochem 1988
16478472 The enzyme-binding region of human GM2-activator protein

Lemm, T, Maier, T, Schoeniger, M, Hoffmann, D, Saenger, W, Kolter, T, Wendeler, M, Sandhoff, K, Werth, N, Schwarzmann, G

FEBS J 2006
1915858 A mutation in the gene of a glycolipid-binding protein (GM2 activator) that causes GM2-gangliosidosis variant AB

Suzuki, K, Sandhoff, K, Schröder, M, Schnabel, D

FEBS Lett 1991
2971395 Oligosaccharide structure and amino acid sequence of the major glycopeptides of mature human beta-hexosaminidase

Mahuran, D, Gravel, RA, Cumming, DA, O'Dowd, BF

Biochemistry 1988
Catalyst Activity

beta-N-acetylhexosaminidase activity of bHEXA [lysosomal lumen]

Orthologous Events
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