Sulfation reactions consist in a sulfate being transferred from the cofactor 3'-phosphoadenosine 5'-phosphosulfate (29, Figure 12; PAPS) to the substrate under catalysis by a sulfotransferase. All criteria of conjugation are met in these reactions, since they are enzymatic and the moiety transferred (sulfuric acid or rather sulfate) is of medium MW, ionized and highly hydrophilic, and is carried by a coenzyme.
In PAPS, the sulfate and phosphate moieties are linked by an anhydride bond whose cleavage is exothermic and supplies enthalpy to the catalytic reaction. The nucleophilic hydroxy group (phenols, alcohols, and hydroxylamines, Figure 12a) or primary or secondary amino groups (Figure 12b) in the substrate will react with the leaving SO3— moiety, forming an ester sulfate or a sulfamate (Figure 12).50 Some of these conjugates are unstable under biological conditions and may undergo heterolytic cleavage to form electrophilic intermediates of considerable toxicological significance, as discussed later.
Sulfotransferases involved in the metabolism of small endogenous and exogenous molecules are soluble (cytosolic) enzymes. Following major advances in molecular biology, they are now recognized as being encoded by a gene superfamily of which about 50 mammalian genes are known and whose products are classified into families (> 45% residue identity) and subfamilies (>60% residue identity) according to their degree of homology. Thus, human sulfotransferases include:
• the SULT1A subfamily, which contains the enzymes 1A1, 1A2, and 1A3 (phenol[ = aryl] sulfotransferases, with some correspondence with EC 22.214.171.124);
• the subfamily SULT1B with the enzyme 1B1 (thyroid hormone sulfotransferase);
• the subfamily SULT1C with the enzymes 1C1 and 1C2;
• the subfamily SULT1E with 1E1 (estrogen sulfotransferase, EC 126.96.36.199);
• the subfamily SULT2A with 2A1 (alcohol[ = hydroxysteroid] sulfotransferase, EC 188.8.131.52);
• the subfamily SULT2B with the two transcript variants 2B1a and 2B1b; and
• the family SULF4 with 4A1.51-60
A number of other sulfotransferase activities are recognized by the NC-IUBMB, including steroid sulfotransferase (EC 184.108.40.206) and cortisol sulfotransferase (glucocorticosteroid sulfotransferase; EC 220.127.116.11). An important family is
Figure 12 Structure of the cofactor 3'-phosphoadenosine 5'-phosphosulfate (29; PAPS); generic reactions of N-sulfation
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