Reactome | bHEXA hydrolyzes GM2A:GM2 to GM2A:GM3

bHEXA hydrolyzes GM2A:GM2 to GM2A:GM3

Stable Identifier

R-HSA-1605595

Type

Reaction [transition]

Species

Homo sapiens

Compartment

lysosomal lumen

ReviewStatus

5/5

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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