Sulfatase activities towards the regulation of cell metabolism and signaling in mammals

Abstract

In higher vertebrates, sulfatases belong to a conserved family of enzymes that are involved in the regulation of cell metabolism and in developmental cell signaling. They cleave the sulfate from sulfate esters contained in hormones, proteins, and complex macromolecules. A highly conserved cysteine in their active site is post-translationally converted into formylglycine by the formylglycine-generating enzyme encoded by SUMF1 (sulfatase modifying factor 1). This post-translational modification activates all sulfatases. Sulfatases are extensively glycosylated proteins and some of them follow trafficking pathways through cells, being secreted and taken up by distant cells. Many proteoglycans, glycoproteins, and glycolipids contain sulfated carbohydrates, which are sulfatase substrates. Indeed, sulfatases operate as decoding factors for a large amount of biological information contained in the structures of the sulfated sugar chains that are covalently linked to proteins and lipids. Modifications to these sulfate groups have pivotal roles in modulating specific signaling pathways and cell metabolism in mammals.

Fig. 1

a Cristal structure of human Arylsulfatase A (ARSA). The drawing shows the N-terminal part that contains the A and C, and the C-terminal region that includes the D domain. b Detailed representation of N-terminal B domain of hARSA that contains the FGly generation consensus sequence CXP(X/S)R in the substrate binding pocket. c ClustalW multiple protein sequence alignments of all the 17 human sulfatases. The FGly generation consensus sequence CXP(X/S)R is conserved in the active site of all sulfatases. Amino acids with the same gray shadingintensities are conserved in all of the analyzed sequences, or share similar chemical characteristics