The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases

Rižner, Tea Lanišnik

doi:10.3389/fphar.2016.00030

Cited by 89 publications

(63 citation statements)

References 146 publications

(231 reference statements)

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“…The two mothers with WT/R329X and WT/W462Cfs*3 reported clinical features consistent with a phenotype of polycystic ovary syndrome, specifically chronic anovulation requiring ovulation induction (159). These alleles are far more common in the general population than the compound-heterozygous cases and may contribute significantly to the patient cohort with reduced sulfation capacity and associated health risks (160). Mutations in sulfotransferase genes additionally underlie a number of clinical conditions.…”

Section: Human Genetic Variation and Clinical Outcomesmentioning

confidence: 99%

Sulfation pathways from red to green

Günal

Hardman

Kopriva

et al. 2019

Journal of Biological Chemistry

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Edited by Joseph M. JezSulfur is present in the amino acids cysteine and methionine and in a large range of essential coenzymes and cofactors and is therefore essential for all organisms. It is also a constituent of sulfate esters in proteins, carbohydrates, and numerous cellular metabolites. The sulfation and desulfation reactions modifying a variety of different substrates are commonly known as sulfation pathways. Although relatively little is known about the function of most sulfated metabolites, the synthesis of activated sulfate used in sulfation pathways is essential in both animal and plant kingdoms. In humans, mutations in the genes encoding the sulfation pathway enzymes underlie a number of developmental aberrations, and in flies and worms, their loss-of-function is fatal. In plants, a lower capacity for synthesizing activated sulfate for sulfation reactions results in dwarfism, and a complete loss of activated sulfate synthesis is also lethal. Here, we review the similarities and differences in sulfation pathways and associated processes in animals and plants, and we point out how they diverge from bacteria and yeast. We highlight the open questions concerning localization, regulation, and importance of sulfation pathways in both kingdoms and the ways in which findings from these "red" and "green" experimental systems may help reciprocally address questions specific to each of the systems.Sulfur (S) is an essential nutrient for all life forms. It is present in a plethora of metabolites of primary and secondary metabolism, most prominently in the amino acids cysteine and methionine, and cofactors such as iron-sulfur clusters, lipoic acid, and CoA. In the majority of these metabolites, sulfur is present in its reduced form of organic thiols; however, some compounds contain S in its oxidized form of sulfate (1, 2). Sulfate is transferred to suitable substrates onto hydroxyl or amino groups by sulfotransferases (3,4). These biological sulfation reactions as well as desulfation catalyzed by sulfatases are often denoted as sulfation pathways (Fig. 1) (5, 6).The activated sulfate for the sulfation pathways, 3Ј-phosphoadenosine 5-phosphosulfate (PAPS), 3 is formed from sulfate by two ATP-dependent steps: adenylation, i.e. the transfer of the AMP moiety of ATP to sulfate to form adenosine 5Ј-phosphosulfate (APS) by ATP sulfurylase (ATPS), and the phosphorylation of APS at its 3Ј-OH group by APS kinase. The two enzymes are either fused into a single enzyme PAPS synthase (PAPSS) in the animal kingdom or occur as independent proteins in the green lineage (7). The by-product of PAPS-dependent sulfation reactions, 3Ј-phosphoadenosine 5-phosphate (PAP), is finally dephosphorylated to AMP by 3Ј-nucleotidases. This reaction to remove PAP is important beyond the sulfation pathways, as PAP accumulation has many additional physiological effects (8,9). Sulfate activation to APS or PAPS is a prerequisite not only for sulfation pathways but also for primary sulfate assimilation in plants, algae, bacteria, and fungi (2). Parti...

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Section: Human Genetic Variation and Clinical Outcomesmentioning

confidence: 99%

Sulfation pathways from red to green

Günal

Hardman

Kopriva

et al. 2019

Journal of Biological Chemistry

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“…X-linked ichthyosis, a disease characterized by the scaling of the skin, has been associated with STS gene deletion or the presence of non-functional point mutants [75]. Higher STS activity has been observed in gynecological diseases such as endometrial cancer and ovarian cancer [76]. …”

Section: Structural Basis Of Extramembrane Lipid Modificationmentioning

confidence: 99%

Structural basis for catalysis at the membrane-water interface

Dufrisne

Petrou

Clarke

et al. 2017

Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biolog

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The membrane-water interface forms a uniquely heterogeneous and geometrically constrained environment for enzymatic catalysis. Integral membrane enzymes sample three environments – the uniformly hydrophobic interior of the membrane, the aqueous extramembrane region, and the fuzzy, amphipathic interfacial region formed by the tightly packed headgroups of the components of the lipid bilayer. Depending on the nature of the substrates and the location of the site of chemical modification, catalysis may occur in each of these environments. The availability of structural information for alpha-helical enzyme families from each of these classes, as well as several beta-barrel enzymes from the bacterial outer membrane, has allowed us to review here the different ways in which each enzyme fold has adapted to the nature of the substrates, products, and the unique environment of the membrane. Our focus here is on enzymes that process lipidic substrates.

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“…Whilst there are numerous pathological features associated with the 43 genes, the following sections focus on predominant features, including neurological dysfunction, skeletal dysplasias, reduced fecundity and reproduction, and cardiovascular pathologies. The potential involvement of several sulfate maintenance genes in cancer has also gained attention from the scientific community in recent years, and those findings have been reviewed elsewhere (Dawson et al, 2010a;Dawson, 2012;Daniels and Kadlubar, 2013;Rižner, 2016).…”

Section: A C C E P T E D Accepted Manuscriptmentioning

confidence: 99%

Genetics and pathophysiology of mammalian sulfate biology

Langford

Hurrion

Dawson

2017

Journal of Genetics and Genomics

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Nutrient sulfate is essential for numerous physiological functions in mammalian growth and development. Accordingly, disruptions to any of the molecular processes that maintain the required biological ratio of sulfonated and unconjugated substrates are likely to have detrimental consequences for mammalian physiology. Molecular processes of sulfate biology can be broadly grouped into four categories: firstly, intracellular sulfate levels are maintained by intermediary metabolism and sulfate transporters that mediate the transfer of sulfate across the plasma membrane; secondly, sulfate is converted to 3'-phosphoadenosine 5'-phosphosulfate (PAPS), which is the universal sulfonate donor for all sulfonation reactions; thirdly, sulfotransferases mediate the intracellular sulfonation of endogenous and exogenous substrates; fourthly, sulfate is removed from substrates via sulfatases. From the literature, we curated 91 human genes that encode all known sulfate transporters, enzymes in pathways of sulfate generation, PAPS synthetases and transporters, sulfotransferases and sulfatases, with a focus on genes that are linked to human and animal pathophysiology. The predominant clinical features linked to these genes include neurological dysfunction, skeletal dysplasias, reduced fecundity and reproduction, and cardiovascular pathologies. Collectively, this review provides reference information for genetic investigations of perturbed mammalian sulfate biology.

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The Important Roles of Steroid Sulfatase and Sulfotransferases in Gynecological Diseases

Cited by 89 publications

References 146 publications

Sulfation pathways from red to green

Sulfation pathways from red to green

Structural basis for catalysis at the membrane-water interface

Genetics and pathophysiology of mammalian sulfate biology

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