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Pharmacological Reviews May 2023The primary function of human sulfotransferase 2B1b (SULT2B1b) is to sulfonate cholesterol and closely related sterols. SULT2B1b sterols perform a number of essential... (Review)
Review
The primary function of human sulfotransferase 2B1b (SULT2B1b) is to sulfonate cholesterol and closely related sterols. SULT2B1b sterols perform a number of essential cellular functions. Many are signaling molecules whose activities are redefined by sulfonation-allosteric properties are switched "on" or "off," agonists are transformed into antagonists, and vice versa. Sterol sulfonation is tightly coupled to cholesterol homeostasis, and sulfonation imbalances are causally linked to cholesterol-related diseases including certain cancers, Alzheimer disease, and recessive X-linked ichthyosis-an orphan skin disease. Numerous studies link SULT2B1b activity to disease-relevant molecular processes. Here, these multifaceted processes are integrated into metabolic maps that highlight their interdependence and how their actions are regulated and coordinated by SULT2B1b oxysterol sulfonation. The maps help explain why SULT2B1b inhibition arrests the growth of certain cancers and make the novel prediction that SULT2B1b inhibition will suppress production of amyloid (A) plaques and tau fibrils while simultaneously stimulating A plaque phagocytosis. SULT2B1b harbors a sterol-selective allosteric site whose structure is discussed as a template for creating inhibitors to regulate SULT2B1b and its associated biology. SIGNIFICANCE STATEMENT: Human sulfotransferase 2B1b (SULT2B1b) produces sterol-sulfate signaling molecules that maintain the homeostasis of otherwise pro-disease processes in cancer, Alzheimer disease, and X-linked ichthyosis-an orphan skin disease. The functions of sterol sulfates in each disease are considered and codified into metabolic maps that explain the interdependencies of the sterol-regulated networks and their coordinate regulation by SULT2B1b. The structure of the SULT2B1b sterol-sensing allosteric site is discussed as a means of controlling sterol sulfate biology.
Topics: Humans; Sterols; Alzheimer Disease; Amyloid beta-Peptides; Sulfotransferases; Sulfates; Ichthyosis
PubMed: 36549865
DOI: 10.1124/pharmrev.122.000679 -
PloS One 2022The luciferin sulfokinase (coelenterazine sulfotransferase) of Renilla was previously reported to activate the storage form, luciferyl sulfate (coelenterazine sulfate)...
The luciferin sulfokinase (coelenterazine sulfotransferase) of Renilla was previously reported to activate the storage form, luciferyl sulfate (coelenterazine sulfate) to luciferin (coelenterazine), the substrate for the luciferase bioluminescence reaction. The gene coding for the coelenterazine sulfotransferase has not been identified. Here we used a combined proteomic/transcriptomic approach to identify and clone the sulfotransferase cDNA. Multiple isoforms of coelenterazine sulfotransferase were identified from the anthozoan Renilla muelleri by intersecting its transcriptome with the LC-MS/MS derived peptide sequences of coelenterazine sulfotransferase purified from Renilla. Two of the isoforms were expressed in E. coli, purified, and partially characterized. The encoded enzymes display sulfotransferase activity that is comparable to that of the native sulfotransferase isolated from Renilla reniformis that was reported in 1970. The bioluminescent assay for sensitive detection of 3'-phosphoadenosine 5'-phosphate (PAP) using the recombinant sulfotransferase is demonstrated.
Topics: Animals; Arylsulfotransferase; Chromatography, Liquid; DNA, Complementary; Escherichia coli; Imidazoles; Luciferases; Luminescent Measurements; Proteomics; Pyrazines; Renilla; Sulfates; Sulfotransferases; Tandem Mass Spectrometry
PubMed: 36251663
DOI: 10.1371/journal.pone.0276315 -
Cell Chemical Biology May 2016In humans, the cytosolic sulfotransferases (SULTs) catalyze regiospecific transfer of the sulfuryl moiety (-SO3) from 3'-phosphoadenosine 5'-phosphosulfate to thousands...
In humans, the cytosolic sulfotransferases (SULTs) catalyze regiospecific transfer of the sulfuryl moiety (-SO3) from 3'-phosphoadenosine 5'-phosphosulfate to thousands of metabolites, including numerous signaling small molecules, and thus regulates their activities and half-lives. Imbalances in the in vivo set points of these reactions leads to disease. Here, with the goal of controlling sulfonation in vivo, molecular ligand-recognition principles in the SULT and nuclear receptor families are integrated in creating a strategy that can prevent sulfonation of a compound without significantly altering its receptor affinity, or inhibiting SULTS. The strategy is validated by using it to control the sulfonation and estrogen receptor (ER) activating activity of raloxifene (a US Food and Drug Administration-approved selective estrogen receptor modulator) and its derivatives. Preventing sulfonation is shown to enhance ER-activation efficacy 10(4)-fold in studies using Ishikawa cells. The strategy offers the opportunity to control sulfuryl transfer on a compound-by-compound basis, to enhance the efficacy of sulfonated drugs, and to explore the biology of sulfuryl transfer with unprecedented precision.
Topics: Cell Line, Tumor; Humans; Models, Molecular; Receptors, Estrogen; Sulfotransferases; Sulfur Oxides
PubMed: 27203377
DOI: 10.1016/j.chembiol.2016.04.009 -
Drug Metabolism and Disposition: the... Jul 2022Sulfotransferases are ubiquitous enzymes that transfer a sulfo group from the universal cofactor donor 3'-phosphoadenosine 5'-phosphosulfate to a broad range of acceptor... (Review)
Review
Sulfotransferases are ubiquitous enzymes that transfer a sulfo group from the universal cofactor donor 3'-phosphoadenosine 5'-phosphosulfate to a broad range of acceptor substrates. In humans, the cytosolic sulfotransferases are involved in the sulfation of endogenous compounds such as steroids, neurotransmitters, hormones, and bile acids as well as xenobiotics including drugs, toxins, and environmental chemicals. The Golgi associated membrane-bound sulfotransferases are involved in post-translational modification of macromolecules from glycosaminoglycans to proteins. The sulfation of small molecules can have profound biologic effects on the functionality of the acceptor, including activation, deactivation, or enhanced metabolism and elimination. Sulfation of macromolecules has been shown to regulate a number of physiologic and pathophysiological pathways by enhancing binding affinity to regulatory proteins or binding partners. Over the last 25 years, crystal structures of these enzymes have provided a wealth of information on the mechanisms of this process and the specificity of these enzymes. This review will focus on the general commonalities of the sulfotransferases, from enzyme structure to catalytic mechanism as well as providing examples into how structural information is being used to either design drugs that inhibit sulfotransferases or to modify the enzymes to improve drug synthesis. SIGNIFICANCE STATEMENT: This manuscript honors Dr. Masahiko Negishi's contribution to the understanding of sulfotransferase mechanism, specificity, and roles in biology by analyzing the crystal structures that have been solved over the last 25 years.
Topics: Glycomics; Humans; Inactivation, Metabolic; Phosphoadenosine Phosphosulfate; Steroids; Sulfotransferases
PubMed: 35197313
DOI: 10.1124/dmd.121.000478 -
The Journal of Histochemistry and... Jan 2021The biosynthesis of heparan sulfate (HS) proteoglycans occurs in the Golgi compartment of cells and will determine the sulfation pattern of HS chains, which in turn will... (Review)
Review
The biosynthesis of heparan sulfate (HS) proteoglycans occurs in the Golgi compartment of cells and will determine the sulfation pattern of HS chains, which in turn will have a large impact on the biological activity of the proteoglycans. Earlier studies in mice have demonstrated the importance of HS for embryonic development. In this review, the enzymes participating in zebrafish HS biosynthesis, along with a description of enzyme mutants available for functional studies, are presented. The consequences of the zebrafish genome duplication and maternal transcript contribution are briefly discussed as are the possibilities of CRISPR/Cas9 methodologies to use the zebrafish model system for studies of biosynthesis as well as proteoglycan biology.
Topics: Animals; Biosynthetic Pathways; CRISPR-Cas Systems; Glycosyltransferases; Heparitin Sulfate; Mutation; Sulfotransferases; Zebrafish; Zebrafish Proteins
PubMed: 33216642
DOI: 10.1369/0022155420973980 -
American Journal of Physiology. Cell... Jun 2022Heparan sulfate is a widely expressed polysaccharide in the extracellular matrix and on the cell surface. 3--sulfated heparan sulfate represents only a small percentage... (Review)
Review
Heparan sulfate is a widely expressed polysaccharide in the extracellular matrix and on the cell surface. 3--sulfated heparan sulfate represents only a small percentage of heparan sulfate from biological sources. However, this subpopulation is closely associated with biological functions of heparan sulfate. The 3--sulfated heparan sulfate is biosynthesized by heparan sulfate 3--sulfotransferase, which exists in seven different isoforms. This review article summarizes the recent progress in the substrate specificity studies of different 3--sulfotransferase isoforms involving the use of homogeneous oligosaccharide substrates and crystal structural analysis. The article also reviews a newly developed liquid chromatography-tandem mass spectrometry (LC-MS/MS)-based method to analyze the level of 3--sulfated heparan sulfate with high sensitivity and quantitative capability. This newly emerged technology will provide new tools to study the structure and function relationship of heparan sulfate.
Topics: Chromatography, Liquid; Heparitin Sulfate; Protein Isoforms; Sulfates; Sulfotransferases; Tandem Mass Spectrometry
PubMed: 35417268
DOI: 10.1152/ajpcell.00110.2022 -
Proceedings of the Japan Academy.... 2013Sulfation confers negative charge on glycolipids and the attached sulfate group presents a part of determinants for the molecular interactions. Mammalian... (Review)
Review
Sulfation confers negative charge on glycolipids and the attached sulfate group presents a part of determinants for the molecular interactions. Mammalian sulfoglycolipids are comprised of two major members, sulfatide (SO3-3Gal-ceramide) and seminolipid (SO3-3Gal-alkylacylglycerol). Sulfatide is abundant in the myelin sheath and seminolipid is unique to the spermatogenic cells. The carbohydrate moiety of sulfatide and seminolipid is biosynthesized via sequential reactions catalyzed by common enzymes: ceramide galactosyltransferase (CGT) and cerebroside sulfotransferase (CST). To elucidate the biological function of sulfoglycolipids, we have purified CST, cloned the CST gene, and generated CST-knockout mice. CST-null mice completely lack sulfoglycolipids all over the body. CST-null mice manifest some neurological disorders due to myelin dysfunction, an aberrant enhancement of oligodendrocyte terminal differentiation, and an arrest of spermatogenesis. CST-deficiency ameliorates L-selectin-dependent monocyte infiltration in the renal interstitial inflammation, indicating that sulfatide is an endogenous ligand of L-selectin. Studies on the molecular mechanisms underlying the biological events for which sulfoglycolipids are essential are ongoing
Topics: Animals; Cloning, Molecular; Gene Expression Regulation, Enzymologic; Gene Targeting; Glycolipids; Humans; Sulfotransferases
PubMed: 23574804
DOI: 10.2183/pjab.89.129 -
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 -
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 -
Molecules (Basel, Switzerland) Jan 2015Integration of inorganic sulfate into biological molecules plays an important role in biological systems and is directly involved in the instigation of diseases. Protein... (Review)
Review
Integration of inorganic sulfate into biological molecules plays an important role in biological systems and is directly involved in the instigation of diseases. Protein tyrosine sulfation (PTS) is a common post-translational modification that was first reported in the literature fifty years ago. However, the significance of PTS under physiological conditions and its link to diseases have just begun to be appreciated in recent years. PTS is catalyzed by tyrosylprotein sulfotransferase (TPST) through transfer of an activated sulfate from 3'-phosphoadenosine-5'-phosphosulfate to tyrosine in a variety of proteins and peptides. Currently, only a small fraction of sulfated proteins is known and the understanding of the biological sulfation mechanisms is still in progress. In this review, we give an introductory and selective brief review of PTS and then summarize the basic biochemical information including the activity and the preparation of TPST, methods for the determination of PTS, and kinetics and reaction mechanism of TPST. This information is fundamental for the further exploration of the function of PTS that induces protein-protein interactions and the subsequent biochemical and physiological reactions.
Topics: Amino Acid Sequence; Animals; Enzyme Assays; Humans; Kinetics; Molecular Sequence Data; Protein Processing, Post-Translational; Sulfotransferases; Tyrosine
PubMed: 25635379
DOI: 10.3390/molecules20022138