The phosphomannosyl recognition marker of acid hydrolases, which mediates their translocation to lysosomes, has been shown to be synthesized in two steps. First, N-acetylglucosamine 1-phosphate is transferred to an acceptor mannose by UDP-N-acety1glucosamine: lysosomal enzyme N-acetylglucosamine-1-phosphotransferase, resulting in a phosphate group in diester linkage between the outer N-acetylglucosamine and the inner mannose. Next, an aN-acetylglucosaminyl phosphodiesterase removes the N-acetylglucosamine, leaving the phosphate in monoester linkage with the underlying mannose residue. This exposed phosphomannosyl residue serves as the essential component of a recognition marker which leads to binding to high-affinity receptors and subsequent translocation to lysosomes. We propose that the first enzyme in this scheme, N-acetylglucosaminylphosphotransferase, catalyses the initial, determining step by which newly synthesized acid hydrolases are distinguished from other newly synthesized glycoproteins and thus are eventually targeted to lysosomes. The absence of this enzyme activity, as in inclusion-cell (I-cell) disease and pseudo-Hurler polydystrophy, precludes the receptor-mediated targeting of newly synthesized acid hydrolases to lysosomes. As a consequence, the enzymes are secreted into the extracellular milieu.

It is now well established that adsorptive pinocytosis of lysosomal enzymes is mediated by phosphomannosyl residues on these enzymes (Kaplan et a1 1977, Sando & Neufeld 1977, Kaplan et a1 1978, Ullrich et a1 1978, Natowicz et a1 1979, Distler et a1 1979, von Figura & Klein 1979, Bach et a1 1979, Fischer et a1 1980a, b, Hasilik & Neufeld 1980a, b, Gonzalez-Noriega et a1 1980). These residues are the essential components of a recognition marker that is necessary for binding to high-affinity receptors on the cell surface and for