L- and S-ASM arise from a common ASM precursor protein.
The ASM-encoding gene SMPD1 gives rise to a common mannosylated precursor protein, pre-pro-ASM, which is cleaved to yield pro-ASM. Differential glycosylation and N-terminal as well as C-terminal processing inside the Golgi then lead to the generation of two distinct ASM forms. Whereas S-ASM is released into the extracellular space via the constitutive secretory pathway and requires Zn2+ ions for activation, L-ASM is shuttled into the lysosomal trafficking pathway via its mannose 6-phosphate groups and encounters Zn2+ ions on its way to the endolysosomal compartment. The details of the exocytotic and endocytotic steps have not been fully elucidated (dotted lines). Data regarding the molecular weight of the mature enzyme with the deglycosylated protein core in brackets are based on the most recently reported data (Edelmann et al., 2011; Jenkins et al., 2011b) and protein molecular weight calculations (protcalc.sourceforge.net) after modifications cited in the text; they may vary from other reports.