FIGURE 14-21 Formation of mannose 6-phosphate (M6P) residues that target soluble enzymes to lysosomes. The M6P residues that direct proteins to lysosomes are generated in the cis-Golgi by two Golgi-resident enzymes. Step 1: An N-acetylglucosamine (GlcNAc) phosphotransferase transfers a phosphorylated GlcNAc group to carbon atom 6 of one or more mannose residues. Because only lysosomal enzymes contain sequences (red) that are recognized and bound by this enzyme, phosphorylated GlcNAc groups are added specifically to lysosomal enzymes. Step 2: After release of the modified protein from the phosphotransferase, a phosphodiesterase removes the GlcNAc group, leaving a phosphorylated mannose residue on the lysosomal enzyme. See A. B. Cantor et al., 1992, J. Biol. Chem. 267:23349, and S. Kornfeld, 1987, FASEB J. 1:462.