Multiplicity and ligand specificity

At least 10 human cytosolic SULT isoforms belonging to three SULT families are known. The human SULT1 family is the most diverse, being comprised of SULT1A1, 1A2, 1A3, 1B1, 1C2, 1C4, and 1E1. In addition, SULT2A1, 2B1, and 4A1 have been described in humans.130 As with the UGTs, family members share at least 45% sequence homology, and subfamily members share at least 60% homology. This nomenclature system has replaced earlier, more confusing designations that usually reflected their substrate specificity, e.g., estradiol sulfotransferase, phenol sulfotransferase (PST), or hydroxysteroid sulfotransferase (HST). In terms of their substrate specificities, most information is available for the SULT1A and 1E isoforms which are recognized to metabolize preferentially a variety of simple phenols, estrogens, and catechols. Selective inhibitors for the various SULT isoforms are not available at present, although some general competitive inhibitors for the PAPS-binding site have been described.131

5.07.4.5.2 Structure

Crystal structures for several SULTs are available. These enzymes are globular proteins with a-helices on both sides of a characteristic 5 stranded b-sheet. Despite their discrete susbtrate specifcities, crystallographic evidence indicates that membrane-bound and cytosolic SULTs share the same overall structural fold.128 The PAPS-binding site is highly conserved between cytosolic and membrane SULTS, but the sulfate-acceptor binding site is very different. Figure 3 depicts the crystal structure of SULT1A1 complexed with an inhibitor as well as PAPS.

Structural and site-directed mutagenesis data support the involvement of His107 as the active site base that activates the incipent nucleophilic substrate, with additional critical roles for Ser137 and Arg47 in the catalytic mechanism of the enzyme.

Figure 3 The crystal structure of human SULT1A1 complexed with estradiol (E2) and the cofactor (a PAP analog). The Ca trace is colored blue (N-terminus) to red (C-terminus). Secondary structure elements are represented as coils for helices and arrows for strands. The bound ligands are shown as space-filling models: PAP, pink; E2, dark gray. (Reproduced from Gamage, N. U.; Tsvetanov, S.; Duggleby, R. G.; McManus, M. E.; Martin, J. L. J. Biol. Chem. 2005, 280, 41482-41486, copyright (2005) with permission from the American Society for Biochemistry & Molecular Biology.133)

Figure 3 The crystal structure of human SULT1A1 complexed with estradiol (E2) and the cofactor (a PAP analog). The Ca trace is colored blue (N-terminus) to red (C-terminus). Secondary structure elements are represented as coils for helices and arrows for strands. The bound ligands are shown as space-filling models: PAP, pink; E2, dark gray. (Reproduced from Gamage, N. U.; Tsvetanov, S.; Duggleby, R. G.; McManus, M. E.; Martin, J. L. J. Biol. Chem. 2005, 280, 41482-41486, copyright (2005) with permission from the American Society for Biochemistry & Molecular Biology.133)

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