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      SULFATION PATHWAYS: Insights into steroid sulfation and desulfation pathways

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      Journal: Journal of Molecular Endocrinology
      Publisher: Bioscientifica

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          Abstract

          Sulfation and desulfation pathways represent highly dynamic ways of shuttling, repressing and re-activating steroid hormones, thus controlling their immense biological potency at the very heart of endocrinology. This theme currently experiences growing research interest from various sides, including, but not limited to, novel insights about phospho-adenosine-5′-phosphosulfate synthase and sulfotransferase function and regulation, novel analytics for steroid conjugate detection and quantification. Within this review, we will also define how sulfation pathways are ripe for drug development strategies, which have translational potential to treat a number of conditions, including chronic inflammatory diseases and steroid-dependent cancers.

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          The Regulation of Steroid Action by Sulfation and Desulfation

          Jonathan Mueller, Lorna Gilligan, Jan Idkowiak … (2015)
          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.
          Article 0 comments Cited 143 times – based on 0 reviews     Review now
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            Molecular pathways: Estrogen pathway in colorectal cancer.

            Christian Lenz, Melissa LaBonte, Afsaneh Barzi … (2013)
            Worldwide, colorectal cancer has a higher incidence rate in men than in women, suggesting a protective role for sex hormones in the development of the disease. Preclinical data support a role for estrogen and its receptors in the initiation and progression of colorectal cancer and establishes that protective effects of estrogen are exerted through ERβ. Hormone replacement therapy (HRT) in postmenopausal women as well as consumption of soy reduces the incidence of colorectal cancer. In the Women's Health Initiative trial, use of HRT in postmenopausal women reduced the risk of colon cancer by 56% [95% confidence interval (CI), 0.38-0.81; P = 0.003]. A recent meta-analysis showed that in women, consumption of soy reduced the risk of colon cancer by 21% (95% CI, 0.03-0.35; P = 0.026). In this review, using the preclinical data, we translate the findings in the clinical trials and observational studies to define the role of estrogen in the prevention of colorectal cancer. We hypothesize that sometime during the tumorigenesis process ERβ expression in colonocytes is lost and the estrogen ligand, HRT, or soy products, exerts its effects through preventing this loss. Thus, in the adenoma-to-carcinoma continuum, timing of HRT is a significant determinant of the observed benefit from this intervention. We further argue that the protective effects of estrogen are limited to certain molecular subtypes. Successful development of estrogen modulators for prevention of colorectal cancer depends on identification of susceptible colorectal cancer population(s). Thus, research to better understand the estrogen pathway is fundamental for clinical delivery of these agents.
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              Crystal structures of a GABAA-receptor chimera reveal new endogenous neurosteroid-binding sites

              Duncan Laverty, Philip Thomas, Trevor Smart … (2017)
              γ-aminobutyric acid receptors (GABA A Rs) are vital for controlling excitability in the brain. This is emphasized by the numerous neuropsychiatric disorders that result following receptor dysfunction. A critical component of most native GABA A Rs is the α subunit. Its transmembrane domain is the target for many modulators, including endogenous brain neurosteroids that impact on anxiety, stress and depression, and for therapeutic drugs such as general anaesthetics. To understand the basis for modulating GABA A R function, high-resolution structures are required. Here we present the first atomic structures of a GABA A R chimera at 2.8Å resolution, including those bound with potentiating and inhibitory neurosteroids. These define new allosteric binding sites for these modulators that are associated with the α-subunit transmembrane domain. Our findings will enable neurosteroids to be exploited for therapeutic drug design to regulate GABA A Rs in neurological disorders.
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                Author and article information

                Journal
                Title: Journal of Molecular Endocrinology
                Publisher: Bioscientifica
                ISSN (Print): 0952-5041
                ISSN (Electronic): 1479-6813
                Publication date Created: August 2018
                Publication date Created: August 2018
                Publication date (Print): August 2018
                Publication date (Print): August 2018
                Volume: 61
                Issue: 2
                Pages: T271-T283
                Article
                DOI: 10.1530/JME-18-0086
                PubMed ID: 29764919
                SO-VID: 188c4675-85f1-417b-8eba-10adadb43bb5
                Copyright © © 2018
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