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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 -
The International Journal of... 2008In this review, we highlight the physical and enzymatic properties of the novel human sulfotransferase, SULT4A1. The gene is most highly expressed in selective regions... (Review)
Review
In this review, we highlight the physical and enzymatic properties of the novel human sulfotransferase, SULT4A1. The gene is most highly expressed in selective regions of the brain, although work to date has failed to identify any specific endogenous substrate for the enzyme. SULT4A1 shares low homology with other human sulfotransferases. Nevertheless, it is highly conserved between species. Despite the low homology, it is structurally very similar to other cytosolic sulfotransferases with a conserved substrate binding domain, dimerization site and partial cofactor binding sites. However, the catalytic cavity is much smaller, and it has been suggested that the cofactor may not be accommodated within it. A recent link between variability in the 5'UTR of the SULT4A1 gene and schizophrenia has heightened interest in the endogenous function of the enzyme and its possible role in human disease.
Topics: Amino Acid Motifs; Amino Acid Sequence; Binding Sites; Cloning, Molecular; Cytosol; DNA, Complementary; Dimerization; Humans; Models, Molecular; Molecular Sequence Data; Sequence Homology, Amino Acid; Substrate Specificity; Sulfotransferases
PubMed: 18248844
DOI: 10.1016/j.biocel.2007.11.010 -
The Journal of Dermatological Treatment Jun 2022Topical minoxidil (5% foam, 5% solution, and 2% solution) is FDA-approved for androgenetic alopecia (AGA) in men and women. Minoxidil acts through multiple pathways... (Review)
Review
Topical minoxidil (5% foam, 5% solution, and 2% solution) is FDA-approved for androgenetic alopecia (AGA) in men and women. Minoxidil acts through multiple pathways (vasodilator, anti-inflammatory agent, inducer of the Wnt/β-catenin signaling pathway, an antiandrogen), and may also affect the length of the anagen and telogen phases. Approximately 1.4% of topical minoxidil is absorbed through the skin. Minoxidil is a prodrug that is metabolized by follicular sulfotransferase to minoxidil sulfate (active form). Those with higher sulfotransferase activity may respond better than patients with lower sulfotransferase activity. In a five-year study, 2% minoxidil exhibited peak hair growth in males at year one with a decline in subsequent years. Topical minoxidil causes hair regrowth in both frontotemporal and vertex areas. The 5% solution and foam were not significantly different in efficacy from the 2% solution. After 6 months of administration, minoxidil 5 mg/day was significantly more effective than topical 5% and 2% in male AGA. Low-dose 0.5-5 mg/day may also be safe and effective for female pattern hair loss and chronic telogen effluvium. Sublingual minoxidil may be safe and effective in male and female pattern hair loss.
Topics: Administration, Topical; Alopecia; Alopecia Areata; Female; Hair; Humans; Male; Minoxidil; Sulfotransferases; Treatment Outcome
PubMed: 34159872
DOI: 10.1080/09546634.2021.1945527 -
Annual Review of Pharmacology and... 2000Cytosolic sulfotransferase catalyzes sulfoconjugation of relatively small lipophilic endobiotics and xenobiotics. At least 44 cytosolic sulfotransferases have been... (Review)
Review
Cytosolic sulfotransferase catalyzes sulfoconjugation of relatively small lipophilic endobiotics and xenobiotics. At least 44 cytosolic sulfotransferases have been identified from mammals, and based on their amino acid sequences, these forms are shown to constitute five different families. In humans, 10 sulfotransferase genes have been identified and shown to localize on at least five different chromosomes. The enzymatic properties characterized in the recombinant forms indicate the association of their substrate specificity with metabolisms of such nonpeptide hormones as estrogen, corticoid, and thyroxine, although most forms are also active on the sulfation of various xenobiotics. Genetic polymorphisms are observed on such human sulfotransferases as ST1A2, ST1A3, and ST2A3.
Topics: Animals; Gene Expression Regulation, Enzymologic; Humans; Isoenzymes; Polymorphism, Genetic; Sulfotransferases
PubMed: 10836131
DOI: 10.1146/annurev.pharmtox.40.1.159 -
Drug Discovery Today Dec 2004Sulfotransferases catalyze the transfer of a sulfuryl group from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to proteins, carbohydrates and small molecules. The... (Review)
Review
Sulfotransferases catalyze the transfer of a sulfuryl group from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to proteins, carbohydrates and small molecules. The sulfotransferases comprise cytosolic and Golgi-resident enzymes; Golgi-resident enzymes represent fertile territory for identifying pharmaceutical targets. Structure-based sequence alignments indicate that the structural fold, and the PAPS-binding site, is conserved between the two classes. Initial efforts to identify sulfotransferase inhibitors by screening kinase inhibitor libraries yielded competitive inhibitors of PAPS with muM IC(50) values. Within particular classes of Golgi-resident sulfotransferases that show tight in vitro specificity, the substrate-binding site might be a suitable drug target, although sulfotransferases are generally assumed to be difficult to inhibit as a result of the expected size and chemical character of the substrate-binding site.
Topics: Adenosine Diphosphate; Animals; Binding Sites; Humans; Structure-Activity Relationship; Sulfotransferases
PubMed: 15574316
DOI: 10.1016/S1359-6446(04)03273-8 -
Steroids Jan 2024Sulfation and desulfation of steroids are opposing processes that regulate the activation, metabolism, excretion, and storage of steroids, which account for steroid... (Review)
Review
Sulfation and desulfation of steroids are opposing processes that regulate the activation, metabolism, excretion, and storage of steroids, which account for steroid homeostasis. Steroid sulfation and desulfation are catalyzed by cytosolic sulfotransferase and steroid sulfatase, respectively. By modifying and regulating steroids, cytosolic sulfotransferase (SULT) and steroid sulfatase (STS) are also involved in the pathophysiology of steroid-related diseases, such as hormonal dysregulation, metabolic disease, and cancer. The estrogen sulfotransferase (EST, or SULT1E1) is a typical member of the steroid SULTs. This review is aimed to summarize the roles of SULT1E1 and STS in steroid homeostasis and steroid-related diseases.
Topics: Humans; Steryl-Sulfatase; Sulfotransferases; Neoplasms; Steroids; Homeostasis; Metabolic Diseases
PubMed: 37951289
DOI: 10.1016/j.steroids.2023.109335 -
Protein and Peptide Letters 2023Estrogen plays a key role in the development and progression of many malignant tumours, and the regulation of estrogen levels involves several metabolic pathways. Among...
Estrogen plays a key role in the development and progression of many malignant tumours, and the regulation of estrogen levels involves several metabolic pathways. Among these pathways, estrogen sulfotransferase (SULT1E1) is the enzyme with the most affinity for estrogen and is primarily responsible for catalysing the metabolic reaction of estrogen sulphation. Relevant studies have shown significant differences in the expression of SULT1E1 in different malignant tumours, suggesting that SULT1E1 plays a dual role in malignant tumours, both inhibiting the growth of malignant tumours and promoting their development. In addition, the expression level of SULT1E1 may be regulated by a variety of factors, which in turn affect the growth and therapeutic effects of malignant tumours. The aim of this paper is to review the mechanism of action of SULT1E1 in malignant tumours and the mechanisms that are regulated, in order to provide potential targets for the treatment of malignant tumour patients in the future and theoretical support for the realisation of more personalised and effective therapeutic regimens.
Topics: Humans; Estrogens; Sulfotransferases; Neoplasms
PubMed: 37724676
DOI: 10.2174/0929866530666230915103418 -
Methods in Molecular Biology (Clifton,... 2021The cytosolic sulfotransferase (SULT) enzymes are found in human liver, kidney, intestine, and other tissues. These enzymes catalyze the transfer of the -SO group from...
The cytosolic sulfotransferase (SULT) enzymes are found in human liver, kidney, intestine, and other tissues. These enzymes catalyze the transfer of the -SO group from 3'-phospho-adenosyl-5'-phosphosulfate (PAPS) to a nucleophilic hydroxyl or amine group in a drug substrate. SULTs are stable as dimers, with a highly conserved dimerization domain near the C-terminus of the protein. Crystal structures have revealed flexible loop regions in the native proteins, one of which, located near the dimerization domain, is thought to form a gate that changes position once PAPS is bound to the PAPS-binding site and modulates substrate access and enzyme properties. There is also evidence that oxidation and reduction of certain cysteine residues reversibly regulate the binding of the substrate and PAPS or PAP to the enzyme thus modulating sulfonation. Because SULT enzymes have two substrates, the drug and PAPS, it is common to report apparent kinetic constants with either the drug or the PAPS varied while the other is kept at a constant concentration. The kinetics of product formation can follow classic Michaelis-Menten kinetics, typically over a narrow range of substrate concentrations. Over a wide range of substrate concentrations, it is common to observe partial or complete substrate inhibition with SULT enzymes. This chapter describes the function, tissue distribution, structural features, and properties of the human SULT enzymes and presents examples of enzyme kinetics with different substrates.
Topics: Binding Sites; Crystallography, X-Ray; Humans; Kinetics; Models, Molecular; Protein Binding; Protein Conformation; Protein Domains; Protein Multimerization; Sulfotransferases; Tissue Distribution; Xenobiotics
PubMed: 34272699
DOI: 10.1007/978-1-0716-1554-6_11 -
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 -
Analytical and Bioanalytical Chemistry Jun 2012Sulfotransferases are enzymes that catalyze the transfer of sulfo groups from a donor, for example 3'-phosphoadenosine 5'-phosphosulfate, to an acceptor, for example the... (Review)
Review
Sulfotransferases are enzymes that catalyze the transfer of sulfo groups from a donor, for example 3'-phosphoadenosine 5'-phosphosulfate, to an acceptor, for example the amino or hydroxyl groups of a small molecule, xenobiotic, carbohydrate, or peptide. These enzymes are important targets in the design of novel therapeutics for treatment of a variety of diseases. This review examines assays used for this important class of enzyme, paying particular attention to sulfotransferases acting on carbohydrates and peptides and the major challenges associated with their analysis.
Topics: Fluorometry; Mass Spectrometry; Radiometry; Sulfotransferases
PubMed: 22526635
DOI: 10.1007/s00216-012-5944-4