title: Specificity of mouse GM2 activator protein and beta-N-acetylhexosaminidases A and B. Similarities and differences with their human counterparts in the catabolism of GM2.
abstract: Tay-Sachs disease, an inborn lysosomal disease featuring a buildup of GM2 in the brain, is caused by a deficiency of beta-hexosaminidase A (Hex A) or GM2 activator. Of the two human lysosomal Hex isozymes, only Hex A, not Hex B, cleaves GM2 in the presence of GM2 activator. In contrast, mouse Hex B has been reported to be more active than Hex A in cleaving GM2 (Burg, J., Banerjee, A., Conzelmann, E., and Sandhoff, K. (1983) Hoppe Seyler's Z. Physiol. Chem. 364, 821-829). In two independent studies, mice with the targeted disruption of the Hexa gene did not display the severe buildup of brain GM2 or the concomitant abnormal behavioral manifestations seen in human Tay-Sachs patients. The results of these two studies were suggested to be attributed to the reported GM2 degrading activity of mouse Hex B. To clarify the specificity of mouse Hex A and Hex B and to better understand the observed results of the mouse model of Tay-Sachs disease, we have purified mouse liver Hex A and Hex B and also prepared the recombinant mouse GM2 activator. Contrary to the findings of Burg et al., we found that the specificities of mouse Hex A and Hex B toward the catabolism of GM2 were not different from the corresponding human Hex isozymes. Mouse Hex A, but not Hex B, hydrolyzes GM2 in the presence of GM2 activator, whereas GM2 is refractory to mouse Hex B with or without GM2 activator. Importantly, we found that, in contrast to human GM2 activator, mouse GM2 activator could effectively stimulate the hydrolysis of GA2 by mouse Hex A and to a much lesser extent also by Hex B. These results provide clear evidence on the existence of an alternative pathway for GM2 catabolism in mice by converting GM2 to GA2 and subsequently to lactosylceramide. They also provide the explanation for the lack of excessive GM2 accumulation in the Hexa gene-disrupted mice.
authors.affiliation: Department of Biochemistry, Tulane University School of Medicine, New Orleans, Louisiana 70112, USA.
authors.forename: J A
authors.initials: JA
authors.lastname: Yuziuk
authors.forename: C
authors.initials: C
authors.lastname: Bertoni
authors.forename: T
authors.initials: T
authors.lastname: Beccari
authors.forename: A
authors.initials: A
authors.lastname: Orlacchio
authors.forename: Y Y
authors.initials: YY
authors.lastname: Wu
authors.forename: S C
authors.initials: SC
authors.lastname: Li
authors.forename: Y T
authors.initials: YT
authors.lastname: Li
mesh_terms: D000818:Animals; D002850:Chromatography, Gel; D002852:Chromatography, Ion Exchange; D002855:Chromatography, Thin Layer; D004591:Electrophoresis, Polyacrylamide Gel; D049289:G(M2) Activator Protein; D005678:G(M2) Ganglioside / Q000378:metabolism*; D054818:Hexosaminidase A; D054819:Hexosaminidase B; D006801:Humans; D006868:Hydrolysis; D007527:Isoenzymes / Q000302:isolation & purification / Q000378:metabolism*; D007700:Kinetics; D008099:Liver / Q000201:enzymology; D051379:Mice; D011506:Proteins / Q000378:metabolism*; D011994:Recombinant Proteins / Q000378:metabolism; D013379:Substrate Specificity; D001619:beta-N-Acetylhexosaminidases / Q000302:isolation & purification / Q000378:metabolism*
chemical_list: D049289:G(M2) Activator Protein; D007527:Isoenzymes; D011506:Proteins; D011994:Recombinant Proteins; D005678:G(M2) Ganglioside; D054818:Hexosaminidase A; D054819:Hexosaminidase B; D001619:beta-N-Acetylhexosaminidases