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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

SUMF1 and FGE. SUMF1 encodes for the enzyme FGE, which catalyzes the conversion of cysteine to FGly found at the FGE-recognition site LCTPSR on STS. This reaction results in increased steroid desulfation by elevated STS activity.
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Figure 2: SUMF1 and FGE. SUMF1 encodes for the enzyme FGE, which catalyzes the conversion of cysteine to FGly found at the FGE-recognition site LCTPSR on STS. This reaction results in increased steroid desulfation by elevated STS activity.

Mentions: The molecular mechanisms underlying STS catalytic activity are highly conserved among different human sulfatase enzymes (16, 35). A cysteine residue resides in the catalytic center of all sulfatases, which is post-translationally modified to form a FGly residue (Figure 2). FGly is catalytically active and “attacks” the sulfate moiety of substrates; it is essential to bind the substrate and also to hydrolyze the sulfate ester bond (36, 37).


The Regulation of Steroid Action by Sulfation and Desulfation.

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

SUMF1 and FGE. SUMF1 encodes for the enzyme FGE, which catalyzes the conversion of cysteine to FGly found at the FGE-recognition site LCTPSR on STS. This reaction results in increased steroid desulfation by elevated STS activity.
© Copyright Policy - open-access
Related In: Results  -  Collection

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

Figure 2: SUMF1 and FGE. SUMF1 encodes for the enzyme FGE, which catalyzes the conversion of cysteine to FGly found at the FGE-recognition site LCTPSR on STS. This reaction results in increased steroid desulfation by elevated STS activity.
Mentions: The molecular mechanisms underlying STS catalytic activity are highly conserved among different human sulfatase enzymes (16, 35). A cysteine residue resides in the catalytic center of all sulfatases, which is post-translationally modified to form a FGly residue (Figure 2). FGly is catalytically active and “attacks” the sulfate moiety of substrates; it is essential to bind the substrate and also to hydrolyze the sulfate ester bond (36, 37).

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