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The Regulation of Steroid Action by Sulfation and Desulfation.

Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA - Endocr. Rev. (2015)

Bottom Line: Because most steroids can be sulfated, including cholesterol, pregnenolone, dehydroepiandrosterone, and estrone, understanding the function, tissue distribution, and regulation of sulfation and desulfation processes provides significant insights into normal endocrine function.We describe the interplay between sulfatases and sulfotransferases, showing how their expression and regulation influences steroid action.Finally, the recent advances in pharmacologically targeting steroidogenic pathways will be examined.

View Article: PubMed Central - PubMed

Affiliation: Centre for Endocrinology, Diabetes, and Metabolism, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.

ABSTRACT
Steroid sulfation and desulfation are fundamental pathways vital for a functional vertebrate endocrine system. After biosynthesis, hydrophobic steroids are sulfated to expedite circulatory transit. Target cells express transmembrane organic anion-transporting polypeptides that facilitate cellular uptake of sulfated steroids. Once intracellular, sulfatases hydrolyze these steroid sulfate esters to their unconjugated, and usually active, forms. Because most steroids can be sulfated, including cholesterol, pregnenolone, dehydroepiandrosterone, and estrone, understanding the function, tissue distribution, and regulation of sulfation and desulfation processes provides significant insights into normal endocrine function. Not surprisingly, dysregulation of these pathways is associated with numerous pathologies, including steroid-dependent cancers, polycystic ovary syndrome, and X-linked ichthyosis. Here we provide a comprehensive examination of our current knowledge of endocrine-related sulfation and desulfation pathways. We describe the interplay between sulfatases and sulfotransferases, showing how their expression and regulation influences steroid action. Furthermore, we address the role that organic anion-transporting polypeptides play in regulating intracellular steroid concentrations and how their expression patterns influence many pathologies, especially cancer. Finally, the recent advances in pharmacologically targeting steroidogenic pathways will be examined.

No MeSH data available.


Related in: MedlinePlus

Human sulfation pathways are complex. The various parts of human sulfation pathways are schematically depicted. Several sulfate transporters are responsible for cellular sulfate uptake (reviewed in Refs. 59 and 62), followed by the two-step enzymatic sulfate activation by bifunctional PAPS synthases. PAPS is then either used directly by cytoplasmic and nuclear sulfotransferases or shuttled to the Golgi apparatus to serve a multitude of Golgi-residing carbohydrate and protein sulfotransferases. In contrast to the nonsulfated biomolecules, sulfated xenobiotics or steroids need designated organic anion transporters to enter or exit cells. Many different sulfatases exist to cleave sulfate esters again. The otherwise toxic, sulfation by-product PAP needs to be removed by dedicated phosphatases (reviewed in Ref. 65). In this review, we focus on sulfate activation, steroid sulfation, and desulfation as well as the transport of steroid sulfates via organic anion transporters. For all other steps, the reader may refer to the reviews given above.
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Figure 3: Human sulfation pathways are complex. The various parts of human sulfation pathways are schematically depicted. Several sulfate transporters are responsible for cellular sulfate uptake (reviewed in Refs. 59 and 62), followed by the two-step enzymatic sulfate activation by bifunctional PAPS synthases. PAPS is then either used directly by cytoplasmic and nuclear sulfotransferases or shuttled to the Golgi apparatus to serve a multitude of Golgi-residing carbohydrate and protein sulfotransferases. In contrast to the nonsulfated biomolecules, sulfated xenobiotics or steroids need designated organic anion transporters to enter or exit cells. Many different sulfatases exist to cleave sulfate esters again. The otherwise toxic, sulfation by-product PAP needs to be removed by dedicated phosphatases (reviewed in Ref. 65). In this review, we focus on sulfate activation, steroid sulfation, and desulfation as well as the transport of steroid sulfates via organic anion transporters. For all other steps, the reader may refer to the reviews given above.

Mentions: Enzymatic sulfate activation by PAPS synthase is essential due to the inert nature of the sulfate ion; this activation occurs via consecutive enzymatic steps (Figure 3) (70, 71). First, the AMP moiety of ATP is transferred to sulfate catalyzed by the ATP sulfurylase activity of PAPS synthase, yielding adenosine-5′-phosphosulfate (APS). Formation of this unusual phospho-sulfo-bond is highly endergonic, so that subsequent cleavage of the release pyrophosphate by ubiquitous pyrophosphatases and an additional phosphorylation step are needed to draw the reaction to completion. This phosphorylation of APS at its ribose 3′-hydroxyl group is carried out by the APS kinase domain of PAPS synthase, resulting in 3′-phospho-APS (PAPS) (70). PAPS is the universal sulfate donor required by all human sulfotransferases, and in humans and most vertebrates it is exclusively produced by two bifunctional PAPS synthases, PAPSS1 and PAPSS2 (72). Active sulfate in the form of PAPS is used by sulfotransferases for sulfation of a multitude of hydroxyl and amino groups in a diverse array of biomolecules, including steroids. The by-product of this reaction, the bis-phospho-nucleotide 3′-phospho-adenosine-5′-phosphate (PAP), is then degraded by dedicated phosphatases (73, 74) (see Section III. C.).


The Regulation of Steroid Action by Sulfation and Desulfation.

Mueller JW, Gilligan LC, Idkowiak J, Arlt W, Foster PA - Endocr. Rev. (2015)

Human sulfation pathways are complex. The various parts of human sulfation pathways are schematically depicted. Several sulfate transporters are responsible for cellular sulfate uptake (reviewed in Refs. 59 and 62), followed by the two-step enzymatic sulfate activation by bifunctional PAPS synthases. PAPS is then either used directly by cytoplasmic and nuclear sulfotransferases or shuttled to the Golgi apparatus to serve a multitude of Golgi-residing carbohydrate and protein sulfotransferases. In contrast to the nonsulfated biomolecules, sulfated xenobiotics or steroids need designated organic anion transporters to enter or exit cells. Many different sulfatases exist to cleave sulfate esters again. The otherwise toxic, sulfation by-product PAP needs to be removed by dedicated phosphatases (reviewed in Ref. 65). In this review, we focus on sulfate activation, steroid sulfation, and desulfation as well as the transport of steroid sulfates via organic anion transporters. For all other steps, the reader may refer to the reviews given above.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4591525&req=5

Figure 3: Human sulfation pathways are complex. The various parts of human sulfation pathways are schematically depicted. Several sulfate transporters are responsible for cellular sulfate uptake (reviewed in Refs. 59 and 62), followed by the two-step enzymatic sulfate activation by bifunctional PAPS synthases. PAPS is then either used directly by cytoplasmic and nuclear sulfotransferases or shuttled to the Golgi apparatus to serve a multitude of Golgi-residing carbohydrate and protein sulfotransferases. In contrast to the nonsulfated biomolecules, sulfated xenobiotics or steroids need designated organic anion transporters to enter or exit cells. Many different sulfatases exist to cleave sulfate esters again. The otherwise toxic, sulfation by-product PAP needs to be removed by dedicated phosphatases (reviewed in Ref. 65). In this review, we focus on sulfate activation, steroid sulfation, and desulfation as well as the transport of steroid sulfates via organic anion transporters. For all other steps, the reader may refer to the reviews given above.
Mentions: Enzymatic sulfate activation by PAPS synthase is essential due to the inert nature of the sulfate ion; this activation occurs via consecutive enzymatic steps (Figure 3) (70, 71). First, the AMP moiety of ATP is transferred to sulfate catalyzed by the ATP sulfurylase activity of PAPS synthase, yielding adenosine-5′-phosphosulfate (APS). Formation of this unusual phospho-sulfo-bond is highly endergonic, so that subsequent cleavage of the release pyrophosphate by ubiquitous pyrophosphatases and an additional phosphorylation step are needed to draw the reaction to completion. This phosphorylation of APS at its ribose 3′-hydroxyl group is carried out by the APS kinase domain of PAPS synthase, resulting in 3′-phospho-APS (PAPS) (70). PAPS is the universal sulfate donor required by all human sulfotransferases, and in humans and most vertebrates it is exclusively produced by two bifunctional PAPS synthases, PAPSS1 and PAPSS2 (72). Active sulfate in the form of PAPS is used by sulfotransferases for sulfation of a multitude of hydroxyl and amino groups in a diverse array of biomolecules, including steroids. The by-product of this reaction, the bis-phospho-nucleotide 3′-phospho-adenosine-5′-phosphate (PAP), is then degraded by dedicated phosphatases (73, 74) (see Section III. C.).

Bottom Line: Because most steroids can be sulfated, including cholesterol, pregnenolone, dehydroepiandrosterone, and estrone, understanding the function, tissue distribution, and regulation of sulfation and desulfation processes provides significant insights into normal endocrine function.We describe the interplay between sulfatases and sulfotransferases, showing how their expression and regulation influences steroid action.Finally, the recent advances in pharmacologically targeting steroidogenic pathways will be examined.

View Article: PubMed Central - PubMed

Affiliation: Centre for Endocrinology, Diabetes, and Metabolism, Institute of Metabolism and Systems Research, University of Birmingham, Birmingham B15 2TT, United Kingdom.

ABSTRACT
Steroid sulfation and desulfation are fundamental pathways vital for a functional vertebrate endocrine system. After biosynthesis, hydrophobic steroids are sulfated to expedite circulatory transit. Target cells express transmembrane organic anion-transporting polypeptides that facilitate cellular uptake of sulfated steroids. Once intracellular, sulfatases hydrolyze these steroid sulfate esters to their unconjugated, and usually active, forms. Because most steroids can be sulfated, including cholesterol, pregnenolone, dehydroepiandrosterone, and estrone, understanding the function, tissue distribution, and regulation of sulfation and desulfation processes provides significant insights into normal endocrine function. Not surprisingly, dysregulation of these pathways is associated with numerous pathologies, including steroid-dependent cancers, polycystic ovary syndrome, and X-linked ichthyosis. Here we provide a comprehensive examination of our current knowledge of endocrine-related sulfation and desulfation pathways. We describe the interplay between sulfatases and sulfotransferases, showing how their expression and regulation influences steroid action. Furthermore, we address the role that organic anion-transporting polypeptides play in regulating intracellular steroid concentrations and how their expression patterns influence many pathologies, especially cancer. Finally, the recent advances in pharmacologically targeting steroidogenic pathways will be examined.

No MeSH data available.


Related in: MedlinePlus