ABSTRACT

Sulfation State of CarbohydratesSulfated carbohydrates are important determinants of cellular activity, participating in diverse processes such as memory, mental illness, neurodegeneration, embryogenesis, differentiation, stem cell biology, proliferation, inflammation, coagulation, angiogenesis, cancer metastasis, and microbial and viral adherence and invasion (Sasisekharan, 2002; Bomsel and Alfsen, 2003; Haltiwanger and Lowe, 2004; Handel et al., 2005; Tamm et al., 2012; Lencz, 2013; Swarup et al., 2013; Kinunen, 2014). This activity is largely modulated by the sulfation state of the carbohydrate structure, wherein the varying display of sulfate groups along the backbone contributes geometric and ionic recognition elements that mediate binding. In this sense, the presence of a sulfate group on a carbohydrate can be viewed similarly to DNA modifications in chromosome maintenance, or protein phosphorylation in cell signaling, both of which alter ligand-substrate interactions by altering electronic and steric factors. Like most biomolecule modifications, the attachment of sulfate groups is controlled by a complementary set of enzymes, the STs and sulfatases (Chapman et al., 2004; Hanson et al., 2004). The STs catalyze the transfer of a sulfuryl group from the high-energy donor 3′-phosphoadenosine-5′-phosphosulfate (PAPS) to an oxygen or nitrogen of an acceptor substrate; whereas, the sulfatases remove sulfuryl groups by catalytic hydrolysis (Fig. 10.1). The former is referred to as sulfurylation (or sulfonation) and the later desulfurylation (or desulfonation).In this chapter, the structure and mechanism of STs and sulfatases will be presented with focus on human enzymes that modify carbohydrates and how this modification is involved in biological function. There are three main types of sulfated carbohydrates in the human cell, including GAGs, mucins, and sulfoglycolipids, whose sulfation states are controlled by STs and sulfatases at various stages in the cell cycle and at various locations

Figure 10.1 Complementary catalytic reactions controlled by STs and sulfatases. STs transfer a sulfuryl group (boxed) from the abundant, high-energy, sulfuryl donor PAPS to an awaiting oxygen or nitrogen acceptor, producing a sulfated biomolecule and the byproduct, PAP. Sulfatases catalyze the hydrolytic desulfurylation of sulfates (CO-SO3-) and sulfamates (CN-SO3-), generating a desulfurylated substrate and inorganic sulfate. in the cell. Descriptions and representative structures for these categories, along with the key positions of sulfate groups and their associated STs and sulfatases, are shown in Fig. 10.2 Additionally, tables are provided listing the known carbohydrate-modifying human STs (Table 10.1) and sulfatases (Table 10.2). In eukaryotes, carbohydrate-active STs are primarily biosynthetic enzymes that decorate carbohydrates with sulfate in the secretory pathway; while, sulfatases cleave sulfate to remodel GAGs at the cell surface and to perform essential steps in sulfated biomolecule catabolism in the lysosome. In prokaryotes, carbohydrate-modifying STs and sulfatases play important roles in communication, recognition, survival, and pathogenesis.