Beta-hexosaminidase subunit alpha (Hex A) (Hex A)

Beta-hexosaminidase subunit alpha, also known as Hex A, is the α-subunit of the lysosomal enzyme β-hexosaminidase A, an αβ heterodimer encoded by the HEXA gene, essential for hydrolyzing terminal N-acetyl-D-hexosamine residues, particularly from GM2 gangliosides in the nervous system with the aid of GM2 activator protein. The α-subunit's active site, featuring a flexible loop (Gly280-Pro283) and key residues like αArg424, enables specific GM2 degradation, unlike the β-subunit which handles neutral substrates. Defects in HEXA cause Tay-Sachs disease, a fatal lysosomal storage disorder from GM2 accumulation in neurons, leading to neurodegeneration. Mutant α-chains often misfold, fail to dimerize with β, and undergo ERAD, preventing lysosomal trafficking. Therapeutic strategies include pharmacological chaperones like NGT, which stabilize the native α-conformation to enhance folding, dimerization, and activity for late-onset variants. The enzyme's TIM barrel active sites use a substrate-assisted mechanism with Glu323 as acid-base and Asp322 stabilizing the oxazolinium intermediate. Crystal structures confirm dimerization's role in stability and dual active sites. Targeting Hex A holds promise for GM2 gangliosidoses but faces challenges from ER quality control and residual activity needs.

Other names

Hexosaminidase Aβ-hexosaminidase Aalpha subunit of beta-hexosaminidaselysosomal β-hexosaminidase A

Pharmacological chaperone stabilizing α-subunit conformation to promote dimerization, ER exit, and lysosomal targeting; Substrate-assisted catalysis via glutamate acid-base and aspartate stabilization of oxazolinium intermediate for GalNAc/GlcNAc cleavage