source: Molecular genetics and metabolism reports

year: 2021

authors: Sandhoff K

In vivo, the lysosomal degradation of GM2 is catalyzed by HexA and its cofactor GM2AP, a lipid binding and transfer protein. The inherited deficiency of each of them causes a fatal neuronal accumulation of ganglioside GM2 in GM2-gangliosidosis. The GM2-splitting activity of HexA does not only need GM2AP as an essential cofactor, but is furthermore strongly regulated by lipids of the GM2 carrying ILV (Intralysosomal Luminal Vesicle)-membranes and by other metabolites. For instance, the HexA catalyzed GM2 cleavage is heavily inhibited by chondroitin-6-sulfate and other primary storage compounds in some MPS diseases and by sphingomyelin in ASM deficient Niemann- Pick disease.

Still, there is a good correlation between the clinical course of the disease on one hand and the turnover of its natural and radiolabeled GM2 in cultured patient’s fibroblasts on the other hand, as assayed by their residual GM2-cleaving activity in vitro. However, there is no correlation with the hydrolysis of the soluble artificial substrate 4MU-β-GlcNAc which is useful to assay the combined activities of hexosaminidases A, B and S.

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