Biochemistry I, Department of Chemistry, Bielefeld University, 33615 Bielefeld, Germany.
Proc Natl Acad Sci U S A. 2012 Jun 26;109(26):10310-5. doi: 10.1073/pnas.1202071109. Epub 2012 Jun 11.
Deficiency of glycosaminoglycan (GAG) degradation causes a subclass of lysosomal storage disorders called mucopolysaccharidoses (MPSs), many of which present with severe neuropathology. Critical steps in the degradation of the GAG heparan sulfate remain enigmatic. Here we show that the lysosomal arylsulfatase G (ARSG) is the long-sought glucosamine-3-O-sulfatase required to complete the degradation of heparan sulfate. Arsg-deficient mice accumulate heparan sulfate in visceral organs and the central nervous system and develop neuronal cell death and behavioral deficits. This accumulated heparan sulfate exhibits unique nonreducing end structures with terminal N-sulfoglucosamine-3-O-sulfate residues, allowing diagnosis of the disorder. Recombinant human ARSG is able to cleave 3-O-sulfate groups from these residues as well as from an authentic 3-O-sulfated N-sulfoglucosamine standard. Our results demonstrate the key role of ARSG in heparan sulfate degradation and strongly suggest that ARSG deficiency represents a unique, as yet unknown form of MPS, which we term MPS IIIE.
糖胺聚糖 (GAG) 降解缺陷会导致一类溶酶体贮积症，称为黏多糖贮积症 (MPSs)，其中许多伴有严重的神经病理学表现。GAG 硫酸乙酰肝素降解的关键步骤仍然是个谜。本文中，我们发现溶酶体芳基硫酸酯酶 G (ARSG) 是缺失的葡萄糖胺-3-O-硫酸酯酶，它是完成硫酸乙酰肝素降解所必需的。Arsg 缺陷小鼠的内脏器官和中枢神经系统中积累硫酸乙酰肝素，并发生神经元细胞死亡和行为缺陷。这些积累的硫酸乙酰肝素表现出独特的非还原末端结构，带有末端 N-磺基葡萄糖胺-3-O-硫酸酯基残基，从而可以诊断这种疾病。重组人 ARSG 能够从这些残基以及真实的 3-O-磺基-N-磺基葡萄糖胺标准物中切割 3-O-硫酸酯基团。我们的结果表明 ARSG 在硫酸乙酰肝素降解中的关键作用，并强烈表明 ARSG 缺陷代表一种独特的、尚未知的 MPS 形式，我们将其称为 MPS IIIE。
