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Biochemistry May 2022Among human cytosolic sulfotransferases, SULT2B1b is highly specific for oxysterols─oxidized cholesterol derivatives, including nuclear-receptor ligands causally...
Among human cytosolic sulfotransferases, SULT2B1b is highly specific for oxysterols─oxidized cholesterol derivatives, including nuclear-receptor ligands causally linked to skin and neurodegerative diseases, cancer and atherosclerosis. Sulfonation of signaling oxysterols redirects their receptor-binding functions, and controlling these functions is expected to prove valuable in disease prevention and treatment. SULT2B1b is distinct among the human SULT2 isoforms by virtue of its atypically long N-terminus, which extends 15 residues beyond the next longest N-terminus in the family. Here, in silico studies are used to predict that the N-terminal extension forms an allosteric pocket and to identify potential allosteres. One such allostere, quercetin, is used to confirm the existence of the pocket and to demonstrate that allostere binding inhibits turnover. The structure of the pocket is obtained by positioning quercetin on the enzyme, using spin-label-triangulation NMR, followed by NMR distance-constrained molecular dynamics docking. The model is confirmed using a combination of site-directed mutagenesis and initial-rate studies. Stopped-flow ligand-binding studies demonstrate that inhibition is achieved by stabilizing the closed form of the enzyme active-site cap, which encapsulates the nucleotide, slowing its release. Finally, endogenous oxysterols are shown to bind to the site in a highly selective fashion─one of the two immediate biosynthetic precursors of cholesterol (7-dehydrocholesterol) is an inhibitor, while the other (24-dehydrocholesterol) is not. These findings provide insights into the allosteric dialogue in which SULT2B1b participates in and establishes a template against which to develop isoform-specific inhibitors to control SULT2B1b biology.
Topics: Allosteric Site; Cholesterol; Humans; Oxysterols; Quercetin; Sulfotransferases
PubMed: 35523209
DOI: 10.1021/acs.biochem.1c00740 -
Estrogen sulfotransferase in the metabolism of estrogenic drugs and in the pathogenesis of diseases.Expert Opinion on Drug Metabolism &... Apr 2019Biotransformation is important in the metabolism of endobiotics and xenobiotics. This process comprises the activity of phase I and phase II enzymes. Estrogen...
Biotransformation is important in the metabolism of endobiotics and xenobiotics. This process comprises the activity of phase I and phase II enzymes. Estrogen sulfotransferase (SULT1E1 or EST) is a phase II conjugating enzyme that belongs to the family of cytosolic sulfotransferases. The expression of SULT1E1 can be detected in many tissues, including the liver. SULT1E1 catalyzes the transfer of a sulfate group from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to any available hydroxyl group in estrogenic molecules. The substrates of SULT1E1 include the endogenous and synthetic estrogens. Upon SULT1E1-mediated sulfation, the hydrosolubility of estrogens increases, preventing the binding between the sulfated estrogens and the estrogen receptor (ER). This sulfated state of the estrogens is not irreversible, as the steroid sulfatase (STS) can convert sulfoconjugated estrogens to free estrogens. The expression of SULT1E1 is inducible by several diseases that involve tissue inflammation, such as type 2 diabetes, sepsis, and ischemia-reperfusion injury. Areas covered: This systematic literature review aims to summarize the role of SULT1E1 in the metabolism of estrogenic drugs and xenobiotics, and the role of SULT1E1 in the pathogenesis of several diseases, including cancer, metabolic disease, sepsis, liver injury, and cystic fibrosis. Meanwhile, ablation or pharmacological inhibition of SULT1E1 can affect the outcomes of the aforementioned diseases. Expert opinion: In addition to its role in metabolizing estrogenic drugs, SULT1E1 is unexpectedly being unveiled as a mediator for the disease effect on estrogen metabolism and homeostasis. Meanwhile, because the expression and activity of SULT1E1 can affect the outcome of diseases, the same sulfotransferase and the reversing enzymes STS can be potential therapeutic targets to prevent or manage diseases. Accumulating evidence suggest that the physiological and pathophysiological effects of SULT1E1 can be estrogen-independent and it is necessary to elucidate what other possible substrates may be recognized by the enzyme. Moreover, human studies are paramount to confirm the human relevance of the animal studies.
Topics: Animals; Cytosol; Estrogens; Gene Expression Regulation, Enzymologic; Humans; Liver; Sulfotransferases; Xenobiotics
PubMed: 30822161
DOI: 10.1080/17425255.2019.1588884 -
PLoS Pathogens Sep 2023Select prion diseases are characterized by widespread cerebral plaque-like deposits of amyloid fibrils enriched in heparan sulfate (HS), a abundant extracellular matrix...
Select prion diseases are characterized by widespread cerebral plaque-like deposits of amyloid fibrils enriched in heparan sulfate (HS), a abundant extracellular matrix component. HS facilitates fibril formation in vitro, yet how HS impacts fibrillar plaque growth within the brain is unclear. Here we found that prion-bound HS chains are highly sulfated, and that the sulfation is essential for accelerating prion conversion in vitro. Using conditional knockout mice to deplete the HS sulfation enzyme, Ndst1 (N-deacetylase / N-sulfotransferase) from neurons or astrocytes, we investigated how reducing HS sulfation impacts survival and prion aggregate distribution during a prion infection. Neuronal Ndst1-depleted mice survived longer and showed fewer and smaller parenchymal plaques, shorter fibrils, and increased vascular amyloid, consistent with enhanced aggregate transit toward perivascular drainage channels. The prolonged survival was strain-dependent, affecting mice infected with extracellular, plaque-forming, but not membrane bound, prions. Live PET imaging revealed rapid clearance of recombinant prion protein monomers into the CSF of neuronal Ndst1- deficient mice, neuronal, further suggesting that HS sulfate groups hinder transit of extracellular prion protein monomers. Our results directly show how a host cofactor slows the spread of prion protein through the extracellular space and identify an enzyme to target to facilitate aggregate clearance.
Topics: Animals; Mice; Heparitin Sulfate; Mice, Knockout; Neurons; Prion Diseases; Prion Proteins; Prions; Sulfotransferases
PubMed: 37747931
DOI: 10.1371/journal.ppat.1011487 -
Expert Opinion on Drug Metabolism &... Jul 2021Cytosolic sulfotransferases (SULTs)-mediated sulfation is critically involved in the metabolism of key endogenous compounds, such as catecholamines and thyroid/steroid... (Review)
Review
INTRODUCTION
Cytosolic sulfotransferases (SULTs)-mediated sulfation is critically involved in the metabolism of key endogenous compounds, such as catecholamines and thyroid/steroid hormones, as well as a variety of drugs and other xenobiotics. Studies performed in the past three decades have yielded a good understanding about the enzymology of the SULTs and their structural biology, phylogenetic relationships, tissue/organ-specific/developmental expression, as well as the regulation of the gene expression. An emerging area is related to the functional impact of the genetic polymorphisms.
AREAS COVERED
The current review aims to summarize our current knowledge about the above-mentioned aspects of the SULT research. An emphasis is on the information concerning the effects of the polymorphisms of the genes on the functional activity of the SULT allozymes and the associated physiological, pharmacological, and clinical implications.
EXPERT OPINION
Elucidation of how SNPs may influence the drug-sulfating activity of SULT allozymes will help understand the differential drug metabolism and eventually aid in formulating personalized drug regimens. Moreover, the information concerning the differential sulfating activities of SULT allozymes toward endogenous compounds may allow for the development of strategies for mitigating anomalies in the metabolism of these endogenous compounds in individuals with certain genotypes.
Topics: Animals; Cytosol; Gene Expression Regulation, Enzymologic; Genotype; Humans; Pharmaceutical Preparations; Polymorphism, Single Nucleotide; Sulfates; Sulfotransferases
PubMed: 34107842
DOI: 10.1080/17425255.2021.1940952 -
Drug Metabolism Reviews Nov 2013Combined structure, function and molecular dynamics studies of human cytosolic sulfotransferases (SULT1A1 and 2A1) have revealed that these enzymes contain a ≈... (Review)
Review
Combined structure, function and molecular dynamics studies of human cytosolic sulfotransferases (SULT1A1 and 2A1) have revealed that these enzymes contain a ≈ 30-residue active-site cap whose structure responds to substrates and mediates their interactions. The binding of 3'-phosphoadenosine 5'-phosphosulfate (PAPS) gates access to the active site by a remodeling of the cap that constricts the pore through which acceptors must pass to enter the active site. While the PAPS-bound enzyme spends the majority (≈ 95%) of its time in the constricted state, the pore isomerizes between the open and closed states when the nucleotide (PAPS) is bound. The dimensions of the open and closed pores place widely different steric constraints on substrate selectivity. Nature appears to have crafted these enzymes with two specificity settings - a closed-pore setting that admits a set of closely related structures, and an open setting that allows a far wider spectrum of acceptor geometries. The specificities of these settings seem well matched to the metabolic demands for homeostatic and defensive SULT functions. The departure of nucleotide requires that the cap open. This isomerization dependent release can explain both the product bursts and substrate inhibition seen in many SULTs. Here, the experimental underpinnings of the cap-mechanism are reviewed, and the advantages of such a mechanism are considered in the context of the cellular and metabolic environment in which these enzymes operate.
Topics: Animals; Binding Sites; Cytosol; Humans; Molecular Dynamics Simulation; Protein Binding; Substrate Specificity; Sulfotransferases
PubMed: 24025091
DOI: 10.3109/03602532.2013.835625 -
Trends in Pharmacological Sciences Jul 1991Sulfoconjugation of drugs and small xenobiotic and endogenous compounds in human tissues is primarily catalysed by cytosolic forms of sulfotransferase. In most... (Review)
Review
Sulfoconjugation of drugs and small xenobiotic and endogenous compounds in human tissues is primarily catalysed by cytosolic forms of sulfotransferase. In most instances, sulfate conjugation is associated with a decrease in the biological activity and an increase in the excretion of the sulfated compounds. However, sulfation may also be involved in the bioactivation of both therapeutic drugs and carcinogens. Two isoenzymes of phenol sulfotransferase and one steroid/bile acid sulfotransferase have been isolated from human liver cytosol. Biochemical and immunological characterization of these proteins has provided insights into their structural similarities, tissue localization and possible biological functions.
Topics: Animals; Cytosol; Humans; Liver; Sulfates; Sulfotransferases
PubMed: 1949190
DOI: 10.1016/0165-6147(91)90566-b -
IUBMB Life Oct 2007Nitration of tyrosine, in both protein-bound form and free amino acid form, can readily occur in cells under oxidative/nitrative stress. In addition to serving as a... (Review)
Review
Nitration of tyrosine, in both protein-bound form and free amino acid form, can readily occur in cells under oxidative/nitrative stress. In addition to serving as a biomarker of oxidative/nitrative stress, elevated levels of nitrotyrosine have been shown to cause DNA damage or trigger apoptosis. An important issue is whether the human body is equipped with mechanisms to counteract the potentially harmful effects of nitrotyrosine. Sulfate conjugation, as mediated by the cytosolic sulfotransferases (SULTs), is widely used for the biotransformation and disposal of a variety of drugs and other xenobiotics, as well as endogenous thyroid/steroid hormones and catecholamine neurotransmitters. Recent studies have revealed that the sulfation of nitrotyrosine occurs in cells under oxidative/nitrative stress, and have pinpointed the SULT1A3 as the responsible SULT enzyme. In this review, we summarized the available information concerning the biochemistry of nitrotyrosine sulfation and the effects of genetic polymorphisms on the nitrotyrosine sulfating activity of SULT1A3. Functional implications of the sulfation of nitrotyrosine are discussed.
Topics: Animals; Arylsulfotransferase; Humans; Sulfates; Sulfotransferases; Tyrosine
PubMed: 17891604
DOI: 10.1080/15216540701589320 -
Bioorganic Chemistry Nov 2022Sulfation is a common modification of glycans and glycoproteins. Sulfated N-glycans have been identified in various glycoproteins and implicated for biological...
Sulfation is a common modification of glycans and glycoproteins. Sulfated N-glycans have been identified in various glycoproteins and implicated for biological functions, but in vitro synthesis of structurally well-defined full length sulfated N-glycans remains to be described. We report here the first in vitro enzymatic sulfation of biantennary complex type N-glycans by recombinant human CHST2 (GlcNAc-6-O-sulfotransferase 1, GlcNAc6ST-1). We found that the sulfotransferase showed high antennary preference and could selectively sulfate the GlcNAc moiety located on the Manα1,3Man arm of the biantennary N-glycan. The glycan chain was further elongated by bacterial β1,4 galactosyltransferase from Neiserria meningitidis and human β1,4 galactosyltransferase IV(B4GALT4), which led to the formation of different sulfated N-glycans. Using rituximab as a model IgG antibody, we further demonstrated that the sulfated N-glycans could be efficiently transferred to an intact antibody by using a chemoenzymatic Fc glycan remodeling method, providing homogeneous sulfated glycoforms of antibodies. Preliminary binding analysis indicated that sulfation did not affect the apparent affinity of the antibody for FcγIIIa receptor.
Topics: Galactosyltransferases; Glycoproteins; Humans; Immunoglobulin G; Polysaccharides; Sulfates; Sulfotransferases; Carbohydrate Sulfotransferases
PubMed: 35939855
DOI: 10.1016/j.bioorg.2022.106070 -
Drug Metabolism Reviews Nov 2013Pregnane X receptor (PXR) and constitutive active/androstane receptor (CAR), members of the nuclear receptor superfamily, are two major xeno-sensing transcription... (Review)
Review
Pregnane X receptor (PXR) and constitutive active/androstane receptor (CAR), members of the nuclear receptor superfamily, are two major xeno-sensing transcription factors. They can be activated by a broad range of lipophilic xenobiotics including therapeutics drugs. In addition to xenobiotics, endogenous compounds such as steroid hormones and bile acids can also activate PXR and/or CAR. These nuclear receptors regulate genes that encode enzymes and transporters that metabolize and excrete both xenobiotics and endobiotics. Sulfotransferases (SULTs) are a group of these enzymes and sulfate xenobiotics for detoxification. In general, inactivation by sulfation constitutes the mechanism to maintain homeostasis of endobiotics. Thus, deciphering the molecular mechanism by which PXR and CAR regulate SULT genes is critical for understanding the roles of SULTs in the alterations of physiological and pathophysiological processes caused by drug treatment or environmental exposures.
Topics: Animals; Bile Acids and Salts; Gene Expression Regulation, Enzymologic; Homeostasis; Hormones; Humans; Receptors, Cytoplasmic and Nuclear; Steroids; Sulfotransferases; Xenobiotics
PubMed: 24025090
DOI: 10.3109/03602532.2013.835630 -
Journal of Experimental Botany Jul 2021Tyrosine-sulfated peptides are key regulators of plant growth and development. The disulfated pentapeptide phytosulfokine (PSK) mediates growth via leucine-rich repeat...
Tyrosine-sulfated peptides are key regulators of plant growth and development. The disulfated pentapeptide phytosulfokine (PSK) mediates growth via leucine-rich repeat receptor-like kinases, PSKR1 and PSKR2. PSK receptors (PSKRs) are part of a response module at the plasma membrane that mediates short-term growth responses, but downstream signaling of transcriptional regulation remains unexplored. In Arabidopsis, tyrosine sulfation is catalyzed by a single-copy gene (TPST; encoding tyrosylprotein sulfotransferase). We performed a microarray-based transcriptome analysis in the tpst-1 mutant background that lacks sulfated peptides to identify PSK-regulated genes and genes that are regulated by other sulfated peptides. Of the 169 PSK-regulated genes, several had functions in root growth and development, in agreement with shorter roots and a higher lateral root density in tpst-1. Further, tpst-1 roots developed higher numbers of root hairs, and PSK induced expression of WEREWOLF (WER), its paralog MYB DOMAIN PROTEIN 23 (MYB23), and At1g66800 that maintain non-hair cell fate. The tpst-1 pskr1-3 pskr2-1 mutant showed even shorter roots, and higher lateral root and root hair density than tpst-1, revealing unexpected synergistic effects of ligand and PSKR deficiencies. While residual activities may exist, overexpression of PSKR1 in the tpst-1 background induced root growth, suggesting that PSKR1 may be active in the absence of sulfated ligands.
Topics: Arabidopsis; Arabidopsis Proteins; Receptors, Cell Surface; Signal Transduction; Sulfotransferases
PubMed: 34028532
DOI: 10.1093/jxb/erab233