Hexosaminidase

Hexosaminidase is an enzyme that plays a crucial role in the degradation of glycosaminoglycans (GAGs), which are complex polysaccharides found in the cell membrane and extracellular matrix. This enzyme catalyzes the hydrolysis of terminal N-acetyl-D-hexosamines in hexosaminide sequences in glycosaminoglycans, thus participating in the lysosomal breakdown of glycoproteins, glycolipids, and proteoglycans.

There are two major forms of hexosaminidase: Hexosaminidase A (Hex-A) and Hexosaminidase B (Hex-B), which are distinguished by their subunit compositions. Hex-A is a heterodimer composed of one alpha (α) and one beta (β) subunit (encoded by the HEXA and HEXB genes, respectively), while Hex-B is a homodimer composed of two beta (β) subunits. There is also a third form, Hexosaminidase S, which is less well characterized.

Function

The primary function of hexosaminidase is to degrade glycosaminoglycans in the lysosome, a process essential for the recycling of cellular components. By breaking down glycosaminoglycans, hexosaminidase helps maintain the structural integrity of the cell and prevents the accumulation of undegraded molecules, which can be toxic.

Clinical Significance

Alterations in the activity of hexosaminidase are associated with several genetic disorders, most notably Tay-Sachs disease and Sandhoff disease. Tay-Sachs disease is caused by mutations in the HEXA gene, leading to a deficiency in Hex-A activity. This results in the accumulation of GM2 gangliosides in the brain and other tissues, leading to progressive neurodegeneration and, ultimately, death in early childhood. Sandhoff disease, on the other hand, is caused by mutations in the HEXB gene, resulting in deficiencies in both Hex-A and Hex-B activities. This leads to a similar, but clinically more variable, accumulation of GM2 gangliosides and related glycosphingolipids, causing neurodegeneration and a similar, often severe, clinical course.

Diagnosis and Treatment

Diagnosis of hexosaminidase-related disorders typically involves biochemical assays to measure enzyme activity in leukocytes or fibroblasts, genetic testing to identify mutations in the HEXA and HEXB genes, and prenatal testing for at-risk pregnancies. Treatment options are limited and primarily supportive. Research into enzyme replacement therapy, gene therapy, and substrate reduction therapy offers hope for future treatments.

See Also

• Lysosomal storage disease
• Glycosaminoglycan
• Glycoprotein
• Glycolipid