Arylsulfatase A (ARSA) (ARSA)

Arylsulfatase A (ARSA) is a lysosomal enzyme that plays a vital role in the catabolism of sulfated glycolipids, particularly cerebroside 3-sulfate (sulfatide), which is a major component of the myelin sheath (UniProt: P15289). The enzyme's catalytic activity is dependent on a unique post-translational modification of a conserved cysteine residue into C-alpha-formylglycine, a process mediated by the formylglycine-generating enzyme (PubMed: 15716435). A deficiency in ARSA leads to Metachromatic Leukodystrophy (MLD), a lysosomal storage disorder characterized by the progressive accumulation of sulfatides in the nervous system, resulting in widespread demyelination and severe neurological decline (NIH: GARD). Small-molecule inhibitors, such as the boronic acid derivative known as "1r," have been developed as potent and selective tools to probe the enzyme's active site and as potential pharmacological chaperones (PubMed: 31433645). These chaperones are designed to bind and stabilize mutant forms of ARSA, assisting their proper folding and trafficking to the lysosome to restore enzymatic function. While therapeutic strategies for MLD currently emphasize gene therapy and enzyme replacement, the development of small-molecule modulators like inhibitor 1r offers a complementary approach for research and potential treatment of specific genetic variants.

Other names

Cerebroside-sulfataseASAARSAArylsulfatase A deficiency

Competitive inhibition of the enzyme active site, specifically targeting the formylglycine residue to prevent sulfatide hydrolysis.