Meta-Biol

• Pathways

Arylsulfatase A (ARSA) hydrolyses a sulfatide (cerebroside 3-sulfate, SM4) to form a cerebroside and sulfate Stinshoff & Jatzkewitz, 1975). Saposin B (PSAP(195-273)) is a promiscuous lipid-binding and transfer protein and an essential cofactor for the lysosomal hydrolysis of sulfatide by ARSA. It binds sulfatides in soluble stoichiometric complexes, which ARSA recognizes as substrates (Fischer & Jatzkewitz, 1975). ARSA is present in the lysosomal lumen and comprises two chains, components B and C, linked by disulfide bonds (Stein et al. 1989, Fujii et al. 1992). The conversion to 3-oxoalanine (formylglycine, FGly) of a cysteine residue is critical for catalytic activity in all eukaryotes (Chruszcz et al. 2003, Lukatela et al. 1998).
Defects in ARSA are a cause of metachromatic leukodystrophy (MLD) (MIM:250100), characterized by lysosomal storage of cerebroside-3-sulfate in neural and non-neural tissues (Gieselmann et al. 1991, Polten et al. 1991). Arylsulfatase A activity is reduced in multiple sulfatase deficiency (MSD) (MIM:272200), a disorder characterized by decreased activity of sulfatases. The defect is due to the lack of post-translational modification of the critical cysteine needed for activity (Schmidt et al. 1995). In metachromatic leukodystrophy due to saposin B deficiency (MLDSAPB, MIM:249290) sulfatide accumulates because of the missing cofactor saposin B (Regis et al., 1999).