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Molecular Biology Reports Jun 2020Human estrogen sulfotransferase (SULT1E1) and nuclear factor erythroid 2-related factor 2 (Nrf-2) expression influences each other in advanced human breast... (Review)
Review
Human estrogen sulfotransferase (SULT1E1) and nuclear factor erythroid 2-related factor 2 (Nrf-2) expression influences each other in advanced human breast carcinogenesis. The difference in the metabolism of estradiol (E2) in pre- and post-menopausal women remains to be connected with post-menopausal breast cancer. A synergism between ROS production and E2 generation has been demonstrated. No definite mechanism for simultaneous functions of Nrf2, oxidative stress E2 regulating enzymes (SULT1E1) has been yet clarified. Our present review demonstrates that ROS dependent regulation of Nrf-2 is one of the most important determinants of E2 regulation by altering SULT1E1 expression. This study also focuses the idea that estrogen receptor cased subtypes of cancer may have different molecular environments which has an impact on the therapeutic efficacy.
Topics: Breast Neoplasms; Cell Line, Tumor; Estradiol; Estrogens; Female; Humans; NF-E2-Related Factor 2; Oxidative Stress; Sulfotransferases; Transcription Factors
PubMed: 32449069
DOI: 10.1007/s11033-020-05518-z -
Cytogenetic and Genome Research 2008Pharmacogenetics is the study of the role of inheritance in variation to drug response. Drug response phenotypes can vary from adverse drug reactions at one end of the... (Review)
Review
Pharmacogenetics is the study of the role of inheritance in variation to drug response. Drug response phenotypes can vary from adverse drug reactions at one end of the spectrum to equally serious lack of the desired effect of drug therapy at the other. Many of the current important examples of pharmacogenetics involve inherited variation in drug metabolism. Sulfate conjugation catalyzed by cytosolic sulfotransferase (SULT) enzymes, particularly SULT1A1, is a major pathway for drug metabolism in humans. Pharmacogenetic studies of SULT1A1 began over a quarter of a century ago and have advanced from biochemical genetic experiments to include cDNA and gene cloning, gene resequencing, and functional studies of the effects of single nucleotide polymorphisms (SNPs). SNP genotyping, in turn, led to the discovery of functionally important copy number variations (CNVs) in the SULT1A1 gene. This review will briefly describe the evolution of our understanding of SULT1A1 pharmacogenetics and CNV, as well as challenges involved in utilizing both SNP and CNV data in an attempt to predict SULT1A1 function. SULT1A1 represents one example of the potential importance of CNV for the evolving disciplines of pharmacogenetics and pharmacogenomics.
Topics: Chromosomes, Human; Gene Dosage; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide; Sulfotransferases
PubMed: 19287157
DOI: 10.1159/000184710 -
Learning & Memory (Cold Spring Harbor,... Jun 2022A critical role of protein modifications such as phosphorylation and acetylation in synaptic plasticity and memory is well documented. Tyrosine sulfation plays important...
A critical role of protein modifications such as phosphorylation and acetylation in synaptic plasticity and memory is well documented. Tyrosine sulfation plays important roles in several biological processes. However, its role in synaptic plasticity and memory is not well understood. Here, we show that sulfation contributes to long-term potentiation (LTP) in the hippocampal slices. In addition, inhibition of sulfation impairs long-term memory in a spatial memory task without affecting acquisition or short-term memory. Furthermore, LTP-inducing stimulus enhances protein tyrosine sulfation. These results suggest an important role for tyrosine sulfation in LTP and memory.
Topics: Hippocampus; Long-Term Potentiation; Memory, Long-Term; Neuronal Plasticity; Sulfotransferases; Tyrosine
PubMed: 35589338
DOI: 10.1101/lm.053538.121 -
Drug Metabolism and Disposition: the... Sep 2013Sulfotransferase (SULT) function has been well studied in healthy human subjects by quantifying mRNA and protein expression and determining enzyme activity with probe...
Sulfotransferase (SULT) function has been well studied in healthy human subjects by quantifying mRNA and protein expression and determining enzyme activity with probe substrates. However, it is not well known if sulfotransferase activity changes in metabolic and liver disease, such as diabetes, steatosis, or cirrhosis. Sulfotransferases have significant roles in the regulation of hormones and excretion of xenobiotics. In the present study of normal subjects with nonfatty livers and patients with steatosis, diabetic cirrhosis, and alcoholic cirrhosis, we sought to determine SULT1A1, SULT2A1, SULT1E1, and SULT1A3 activity and mRNA and protein expression in human liver tissue. In general, sulfotransferase activity decreased significantly with severity of liver disease from steatosis to cirrhosis. Specifically, SULT1A1 and SULT1A3 activities were lower in disease states relative to nonfatty tissues. Alcoholic cirrhotic tissues further contained lower SULT1A1 and 1A3 activities than those affected by either of the two other disease states. SULT2A1, on the other hand, was only reduced in alcoholic cirrhotic tissues. SULT1E1 was reduced both in diabetic cirrhosis and in alcoholic cirrhosis tissues, relative to nonfatty liver tissues. In conclusion, the reduced levels of sulfotransferase expression and activity in diseased versus nondiseased liver tissue may alter the metabolism and disposition of xenobiotics and affect homeostasis of endobiotic sulfotransferase substrates.
Topics: Adult; Down-Regulation; Female; Humans; Isoenzymes; Liver Diseases; Male; Middle Aged; Sulfotransferases
PubMed: 23775849
DOI: 10.1124/dmd.113.050930 -
The Journal of Biological Chemistry 2021Polychlorinated bisphenols (PCBs) continue to contaminate food chains globally where they concentrate in tissues and disrupt the endocrine systems of species throughout...
Polychlorinated bisphenols (PCBs) continue to contaminate food chains globally where they concentrate in tissues and disrupt the endocrine systems of species throughout the ecosphere. Hydroxylated PCBs (OH-PCBs) are major PCB metabolites and high-affinity inhibitors of human estrogen sulfotransferase (SULT1E1), which sulfonates estrogens and thus prevents them from binding to and activating their receptors. OH-PCB inhibition of SULT1E1 is believed to contribute significantly to PCB-based endocrine disruption. Here, for the first time, the molecular basis of OH-PCB inhibition of SULT1E1 is revealed in a structure of SULT1E1 in complex with OH-PCB1 (4'-OH-2,6-dichlorobiphenol) and its substrates, estradiol (E2), and PAP (3'-phosphoadenosine-5-phosphosulfate). OH-PCB1 prevents catalysis by intercalating between E2 and catalytic residues and establishes a new E2-binding site whose E2 affinity and positioning are greater than and competitive with those of the reactive-binding pocket. Such complexes have not been observed previously and offer a novel template for the design of high-affinity inhibitors. Mutating residues in direct contact with OH-PCB weaken its affinity without compromising the enzyme's catalytic parameters. These OH-PCB resistant mutants were used in stable transfectant studies to demonstrate that OH-PCBs regulate estrogen receptors in cultured human cell lines by binding the OH-PCB binding pocket of SULT1E1.
Topics: Enzyme Inhibitors; Estrogens; Humans; Hydroxylation; Models, Molecular; Polychlorinated Biphenyls; Receptors, Estrogen; Sulfotransferases
PubMed: 33524392
DOI: 10.1016/j.jbc.2021.100353 -
The Biochemical Journal Oct 2018Sulfation is a common modification of extracelluar glycans and tyrosine residues on proteins, which is important in many signalling pathways and interactions. Existing... (Review)
Review
Sulfation is a common modification of extracelluar glycans and tyrosine residues on proteins, which is important in many signalling pathways and interactions. Existing methods for studying sulfotransferases, the enzymes that catalyse sulfation, are cumbersome and low-throughput. Recent studies published in the have repurposed established biochemical assays from the kinase field and applied them to the characterisation of sulfotransferases. Biochemical screening of a library of kinase inhibitors revealed that compounds that target RAF kinases may also be repurposed to inhibit sulfotransferases. Together with the available structures of sulfotransferases, these studies open the door to the development of chemical tools to probe the biological functions of these important enzymes.
Topics: Animals; Carbohydrates; Humans; Nuclear Magnetic Resonance, Biomolecular; Sulfotransferases; Tyrosine
PubMed: 30291171
DOI: 10.1042/BCJ20180480 -
Bioscience, Biotechnology, and... Jan 2017The cytosolic sulfotransferases (SULTs) are Phase II detoxifying enzymes that mediate the sulfate conjugation of numerous xenobiotic molecules. While the research on the... (Review)
Review
The cytosolic sulfotransferases (SULTs) are Phase II detoxifying enzymes that mediate the sulfate conjugation of numerous xenobiotic molecules. While the research on the SULTs has lagged behind the research on Phase I cytochrome P-450 enzymes and other Phase II conjugating enzymes, it has gained more momentum in recent years. This review aims to summarize information obtained in several fronts of the research on the SULTs, including the range of the SULTs in different life forms, concerted actions of the SULTs and other Phase II enzymes, insights into the structure-function relationships of the SULTs, regulation of SULT expression and activity, developmental expression of SULTs, as well as the use of a zebrafish model for studying the developmental pharmacology/toxicology.
Topics: Animals; Cytosol; Gene Expression Regulation, Enzymologic; Humans; Structure-Activity Relationship; Sulfates; Sulfotransferases; Zebrafish
PubMed: 27649811
DOI: 10.1080/09168451.2016.1222266 -
BMC Biology Jul 2023Chronic kidney disease (CKD) accelerates atherosclerosis, but the mechanisms remain unclear. Tyrosine sulfation has been recognized as a key post-translational...
BACKGROUND
Chronic kidney disease (CKD) accelerates atherosclerosis, but the mechanisms remain unclear. Tyrosine sulfation has been recognized as a key post-translational modification (PTM) in regulation of various cellular processes, and the sulfated adhesion molecules and chemokine receptors have been shown to participate in the pathogenesis of atherosclerosis via enhancement of monocyte/macrophage function. The levels of inorganic sulfate, the essential substrate for the sulfation reaction, are dramatically increased in patients with CKD, which indicates a change of sulfation status in CKD patients. Thus, in the present study, we detected the sulfation status in CKD patients and probed into the impact of sulfation on CKD-related atherosclerosis by targeting tyrosine sulfation function.
RESULTS
PBMCs from individuals with CKD showed higher amounts of total sulfotyrosine and tyrosylprotein sulfotransferase (TPST) type 1 and 2 protein levels. The plasma level of O-sulfotyrosine, the metabolic end product of tyrosine sulfation, increased significantly in CKD patients. Statistically, O-sulfotyrosine and the coronary atherosclerosis severity SYNTAX score positively correlated. Mechanically, more sulfate-positive nucleated cells in peripheral blood and more abundant infiltration of sulfated macrophages in deteriorated vascular plaques in CKD ApoE null mice were noted. Knockout of TPST1 and TPST2 decreased atherosclerosis and peritoneal macrophage adherence and migration in CKD condition. The sulfation of the chemokine receptors, CCR2 and CCR5, was increased in PBMCs from CKD patients.
CONCLUSIONS
CKD is associated with increased sulfation status. Increased sulfation contributes to monocyte/macrophage activation and might be involved in CKD-related atherosclerosis. Inhibition of sulfation may suppress CKD-related atherosclerosis and is worthy of further study.
Topics: Mice; Animals; Sulfotransferases; Proteins; Tyrosine; Mice, Knockout; Receptors, Chemokine; Atherosclerosis; Protein Processing, Post-Translational
PubMed: 37424015
DOI: 10.1186/s12915-023-01641-y -
Glycobiology Aug 2014O-linked β-N-acetylglucosamine (O-GlcNAc) glycosylation, the covalent attachment of N-acetylglucosamine to serine and threonine residues of proteins, is a...
O-linked β-N-acetylglucosamine (O-GlcNAc) glycosylation, the covalent attachment of N-acetylglucosamine to serine and threonine residues of proteins, is a post-translational modification that shares many features with protein phosphorylation. O-GlcNAc is essential for cell survival and plays important role in many biological processes (e.g. transcription, translation, cell division) and human diseases (e.g. diabetes, Alzheimer's disease, cancer). However, detection of O-GlcNAc is challenging. Here, a method for O-GlcNAc detection using in vitro sulfation with two N-acetylglucosamine (GlcNAc)-specific sulfotransferases, carbohydrate sulfotransferase 2 and carbohydrate sulfotransferase 4, and the radioisotope (35)S is described. Sulfation on free GlcNAc is first demonstrated, and then on O-GlcNAc residues of peptides as well as nuclear and cytoplasmic proteins. It is also demonstrated that the sulfation on O-GlcNAc is sensitive to OGT and O-β-N-acetylglucosaminidase treatment. The labeled samples are separated on sodium dodecyl sulfate-polyacrylamide gel electrophoresis and visualized by autoradiography. Overall, the method is sensitive, specific and convenient.
Topics: Acetylglucosamine; Acetylglucosaminidase; Glycosylation; HEK293 Cells; Humans; Sulfates; Sulfotransferases; Carbohydrate Sulfotransferases
PubMed: 24799377
DOI: 10.1093/glycob/cwu037 -
The Journal of Biological Chemistry Sep 1999HNK-1 glycan, sulfo-->3GlcAbeta1-->3Galbeta1-->4GlcNAc-->R, is uniquely enriched in neural cells and natural killer cells and is thought to play important roles in...
HNK-1 glycan, sulfo-->3GlcAbeta1-->3Galbeta1-->4GlcNAc-->R, is uniquely enriched in neural cells and natural killer cells and is thought to play important roles in cell-cell interaction. HNK-1 glycan synthesis is dependent on HNK-1 sulfotransferase (HNK-1ST), and cDNAs encoding human and rat HNK-1ST have been recently cloned. HNK-1ST belongs to the sulfotransferase gene family, which shares two homologous sequences in their catalytic domains. In the present study, we have individually mutated amino acid residues in these conserved sequences and determined how such mutations affect the binding to the donor substrate, adenosine 3'-phosphate 5'-phosphosulfate, and an acceptor. Mutations of Lys(128), Arg(189), Asp(190), Pro(191), and Ser(197) to Ala all abolished the enzymatic activity. When Lys(128) and Asp(190) were conservatively mutated to Arg and Glu, respectively, however, the mutated enzymes still maintained residual activity, and both mutant enzymes still bound to adenosine 3',5'-diphosphate-agarose. K128R and D190E mutant enzymes, on the other hand, exhibited reduced affinity to the acceptor as demonstrated by kinetic studies. These findings, together with those on the crystal structure of estrogen sulfotransferase and heparan sulfate N-deacetylase/sulfotransferase, suggest that Lys(128) may be close to the 3-hydroxyl group of beta-glucuronic acid in a HNK-1 acceptor. In contrast, the effect by mutation at Asp(190) may be due to conformational change because this amino acid and Pro(191) reside in a transition of the secondary structure of the enzyme. These results indicate that conserved amino acid residues in HNK-1ST play roles in maintaining a functional conformation and are directly involved in binding to donor and acceptor substrates.
Topics: Amino Acid Sequence; Animals; Binding Sites; Enzyme Activation; Humans; Molecular Sequence Data; Mutagenesis, Site-Directed; Rats; Sequence Alignment; Structure-Activity Relationship; Substrate Specificity; Sulfotransferases
PubMed: 10464296
DOI: 10.1074/jbc.274.36.25608