Pohl Sandra, Marschner Katrin, Storch Stephan, Braulke Thomas
Department of Biochemistry, Children's Hospital, University Medical Center Hamburg-Eppendorf, D-20246 Hamburg, Germany.
Biol Chem. 2009 Jul;390(7):521-7. doi: 10.1515/BC.2009.076.
Lysosomes contain more than 50 soluble hydrolases that are targeted to lysosomes in a mannose 6-phosphate (Man6P)-dependent manner. The phosphorylation of man- nose residues on high mannose-type oligosaccharides of newly synthesized lysosomal enzymes is catalyzed by two multimeric enzymes, GlcNAc-1-phosphotransferase and GlcNAc-1-phosphodiester-alpha-N-acetylglucosaminidase, allowing the binding to two distinct Man6P receptors in the Golgi apparatus. Inherited defects in the GlcNAc-1-phosphotransferase complex result in missorting and cellular loss of lysosomal enzymes, and the subsequent lysosomal dysfunction causes the lysosomal storage disorders mucolipidosis types II and III. Biosynthetic studies and the availability of Man6P receptor-deficient mouse models have provided new insights into the structural requirements for preferential binding of subsets of lysosomal enzymes to Man6P receptors as well as the identification of alternative targeting pathways.
溶酶体含有50多种可溶性水解酶，这些酶以依赖甘露糖6 - 磷酸（Man6P）的方式靶向溶酶体。新合成的溶酶体酶的高甘露糖型寡糖上的甘露糖残基的磷酸化由两种多聚酶催化，即N - 乙酰葡糖胺 - 1 - 磷酸转移酶和N - 乙酰葡糖胺 - 1 - 磷酸二酯 - α - N - 乙酰葡糖胺酶，这使得它们能够与高尔基体中的两种不同的Man6P受体结合。N - 乙酰葡糖胺 - 1 - 磷酸转移酶复合物的遗传性缺陷导致溶酶体酶分选错误和细胞内丢失，随后的溶酶体功能障碍会引发II型和III型黏脂贮积症等溶酶体贮积病。生物合成研究以及Man6P受体缺陷小鼠模型的可用性，为溶酶体酶亚群与Man6P受体优先结合的结构要求以及替代靶向途径的鉴定提供了新的见解。
