The Journal of Steroid Biochemistry and Molecular Biology
Human cytosolic sulfotransferase 2B1: Isoform expression, tissue specificity and subcellular localization☆
Introduction
Conjugation with a sulfonate group is a major pathway involved with the synthesis, inactivation and excretion of steroid hormones in human tissues. The family of cytosolic sulfotransferases (SULTs) catalyzes the transfer of the sulfonate group from 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to a wide variety of compounds containing hydroxyl or amine groups to form sulfates or sulfamates, respectively. One of the major SULT catalyzed reactions involves the sulfonation of hydroxysteroids such as dehydroepiandrosterone (DHEA) or estrogens to form sulfate esters (Fig. 1). The sulfonate group is charged at physiological pHs rendering the steroid sulfates incapable of binding and activating their receptors [1], [2].
Steroid sulfation in humans and higher primates is unique from that in laboratory animals due primarily to the synthesis and secretion of large amounts of adrenal androgens. High levels of adrenal androgens are secreted by the fetal adrenal during development as well as by the reticular layer of the adult adrenal after adrenarche [3], [4]. By far, the most abundant adrenal androgen secreted is DHEA-sulfate [5], [6]. DHEA-sulfate is present at micromolar quantities in the plasma of young adults and decreases slowly with age until the 7th or 8th decade of life [7]. DHEA is important as a source of precursor for the synthesis of androgens and estrogens in peripheral tissues and after the removal of the sulfate moiety by sulfatase activity can be converted into testosterone in the prostate or estrogens in breast tissue. After menopause in women all estrogen synthesis uses DHEA as a precursor [5], [8]. Therefore, the desulfation and conversion of DHEA to either potent androgens or estrogens in hormonally responsive tissues is important in regulation of these tissues. Sulfation of DHEA as well as other androgens and estrogens in these tissues then becomes an important mechanism for controlling the interconversion and activity of these steroids.
Section snippets
Cytosolic SULT family
The human SULT gene family consists of at least twelve genes encoding thirteen different isoforms (Table 1). Five members of the SULT1 or phenol SULT family (SULT1A1, 1A3, 1E1, 1C2, 1C4) sulfate steroids, however these isoforms primarily conjugate the phenolic groups of estrogens and related compounds. SULT1E1 is responsible for the sulfation of β-estradiol at picomolar and nanomolar concentrations and in contrast to the high affinity for β-estradiol conjugates DHEA at relatively high
Cloning and structure of SULT2B1 isoforms
The SULT2B1b gene is located at the same chromosomal loci as the SULT2A1 gene suggesting that even though they are not highly homologous they may have been derived by a gene duplication event [24]. The two isoforms of SULT2B1 are generated from two different transcriptional products of the SULT2B1 gene. Her et al. [21] initially identified the SULT2B1 cDNAs by screening a human placental expressed sequence tag database with a highly conserved amino acid sequence motif “RKGxxGDWKNxFT” present in
Expression of SULT2B1 isoforms
SULT2B1a and SULT2B1b message expression occurs in a number of human tissues including prostate, placenta, respiratory system and skin [21], [25], [26], [27]. Analysis of the expression of the two specific SULT2B1 messages in different human tissues using RT-PCR shows variability especially in SULT2B1a expression [23], [28]. The levels of SULT2B1b specific message are generally several-fold greater than those for SULT2B1a and SULT2B1b message is detectable in more tissue types. Immunoblot
Subcellular localization
The subcellular localization of SULT2B1b is unique among the human SULT isoforms. SULT2B1b has been localized to the cytosol and nuclei of both human cells and tissues [25]. In human term placenta, SULT2B1b is almost totally localized in the nuclei of synchiotrophoblast cells [25]. SULT2B1b activity can be assayed in intact purified placenta nuclei and SULT2B1b protein detected by immunoblotting. In contrast, the localization of SULT2B1b varies in other tissues. SULT2B1b is expressed only in
Comparison of human, rat and murine SULT2B1
The SULT2B1 cDNAs have also been isolated and characterized from rat [37] and mouse [38] tissues. Both rodent genes have similar exon and intron structures to the human gene. In all three species the promoter for the transcription of the SULT2B1a message generates a 5′-addition to the sequence that represents the second exon in the SULT2B1b message resulting in the absence of the first intron observed in the SULT2B1b transcript. The promoter and transcriptional start site for the SULT2B1b
Acknowledgement
This research was supported in part by PHS grant GM38952 to CNF.
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Lecture presentation at the 17th International Symposium of the Journal of Steroid Biochemistry; Molecular Biology, Recent Advances in Steroid Biochemistry and Molecular Biology (Seefeld, Tyrol, Austria, 31 May–3 June 2006).