While the human SULT2B1 isoforms are considered to be hydroxysteroid sulfotransferases, they are, nevertheless, structurally distinct when compared to SULT2A1 (cf.

Figure 11.1). In comparing the SULT2A1 and SULT2B1 isozymes, the most outstanding distinction between them is the extended amino- and carboxy-terminal ends of the latter proteins. Overall, the SULT2A1 and SULT2B1 proteins are ~37% identical. However, if the extended amino- and carboxy-terminal ends of the SULT2B1 isoforms are excluded, identities increase to ~48%. All previously cloned members of the mammalian cytosolic sulfotransferase superfamily, i.e., estrogen and phenol sulfotransferases as well as the hydroxysteroid sulfotransferases, have sizes that range from 282 to 295 amino acids (Rikke and Roy, 1996; Weinshilboum et al., 1997), whereas human SULT2B1a and SULT2B1b consist of 350 and 365 amino acids, respectively. The extended amino- and carboxy-terminal ends of the SULT2B1 isoforms, notwithstanding, there is a significant structural similarity between the SULT2A1 and SULT2B1 isozymes in their core regions. Most notably, key structural elements important in protein-PAPS interaction as well as the dimerization motif, which are described above under SULT2A1, are conserved in the SULT2B1 isoforms (cf. Figure 11.1).

The human SULT2B1 isoforms, which differ only at their amino-terminal ends, are produced by employment of an alternative exon I along with differential splicing (Her et al., 1998). The functional significance of the extended carboxy-terminal end of the SULT2B1 isoforms is not presently appreciated. One speculation is that this region, which is proline-enriched, might play a role in protein-protein interactions (Javitt et al., 2001). Notably, the terminal 53 amino acids of the relatively long carboxyl ends, which are common to both proteins, can be removed without causing a significant change in the catalytic behavior of either isoform (Figure 11.6). On the other hand, removal of the unique amino termini of the two isoforms yields interesting results. That is, removal of the 23 residues from the amino terminus of SULTT2B1b, which are unique to this isoform (cf. Figure 11.1), results in an almost complete loss of cholesterol sulfotransferase activity (Figure 11.6), whereas removal of the 8 residues from the amino terminus of SULT2B1a, which are unique to this isoform (cf. Figure 11.1), does not alter pregnenolone sulfotransferase activity (Figure 11.6). It is noteworthy that exon IB of the human SULT2B1 gene encodes for only the unique amino-terminal 23 amino acids of SULT2B1b, whereas exon IA encodes for the unique amino-terminal 8 amino acids of SULT2B 1a plus an additional 48 amino acids that are common to both isoforms. Thus, if the gene for human SULT2B1 (cf. Figure 11.2) employs exon IB, cholesterol sulfotransferase is synthesized, whereas if the gene employs exon IA, pregnenolone sulfotransferase is produced (Fuda et al., 2002). This realization strongly suggests that differential expression of the SULT2B1 isoforms has significant biologic implications.

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