HS (heparan sulfate) is essential for normal embryonic development. This requirement is due to the obligatory role for HS in the signalling pathways of many growth factors and morphogens that bind to sulfated domains in the HS polymer chain. The sulfation patterning of HS is determined by a complex interplay of Golgi-located N- and O-sulfotransferases which sulfate the heparan precursor and cell surface endosulfatases that selectively remove 6-O-sulfates from mature HS chains. In the present study we generated single or double knock-out mice for the two murine endosulfatases mSulf1 and mSulf2. Detailed structural analysis of HS from mSulf1-/- fibroblasts showed a striking increase in 6-O-sulfation, which was not seen in mSulf2-/- HS. Intriguingly, the level of 6-O-sulfation in the double mSulf1-/-/2-/- HS was significantly higher than that observed in the mSulf1-/- counterpart. These data imply that mSulf1 and mSulf2 are functionally co-operative. Unlike their avian orthologues, mammalian Sulf activities are not restricted to the highly sulfated S-domains of HS. Mitogenesis assays with FGF2 (fibroblast growth factor 2) revealed that Sulf activity decreases the activating potential of newly-synthesized HS, suggesting an important role for these enzymes in cell growth regulation in embryonic and adult tissues.
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.
Sequenzhomologien unter den Mitgliedern der Sulfatasefamilie. Dargestellt ist das FGlydeterminierende Motiv. Hervorgehoben sind die Aminosäuren, die in mind. 9 der 13 humanen Sulfatasen konserviert sind. Das markierte Cystein (Pfeil) wird in Formylglycin umgewandelt. *n.u. -nicht untersucht. Sieben Sulfatasen bilden eine Untergruppe und werden als Arylsulfatasen bezeichnet. Die Arylsulfatasen A, B, C, E und F sind in der Lage, synthetische chromogene oder fluorogene Arylsulfate (p-Nitrocatecholsulfat, 4-Methylumbelliferylsulfat und Indoxylsulfat) zu spalten, die in Enzymassays und in der Histochemie Verwendung finden. Die Arylsulfatasen D und G hingegen besitzen keine Sulfataseaktivität gegenüber den o.g. Arylsulfaten, werden aber aufgrund ihrer starken Sequenz-Homologien zu den Arylsulfatasen A und C zur Gruppe der Arylsulfatasen gezählt. Die Arylsulfatase C (Steroidsulfatase) ist die einzige Sulfatase, deren natürliches Substrat ein Arylsulfat darstellt, nämlich Steroidsulfat. Acht Sulfatasen sind lysosomale Enzyme mit einem pH-Optimum um 5 und sind an der Degradation von Glykosaminoglykanen und Sulfolipiden beteiligt (Tab. 1.1). Die Steroidsulfatase, ein integrales Membranprotein des endoplasmatischen Retikulums und der Plasmamembran, katalysiert die Desulfatierung von sulfatierten Steroidhormonen und Cholesterolsulfat. Die Arylsulfatase E ist im Golgi-Apparat lokalisiert und spielt vermutlich eine Rolle im Vitamin-K-Metabolismus (Daniele et al. 1998).
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