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Methods in Molecular Biology (Clifton,... 2014The sulfotransferase (SULT) enzymes catalyze the formation of sulfate esters or sulfamates from substrates that contain hydroxy or amine groups, utilizing... (Review)
Review
The sulfotransferase (SULT) enzymes catalyze the formation of sulfate esters or sulfamates from substrates that contain hydroxy or amine groups, utilizing 3'-phosphoadenosyl-5'-phosphosulfate (PAPS) as the donor of the sulfonic group. The rate of product formation depends on the concentrations of PAPS and substrate as well as the sulfotransferase enzyme; thus, if PAPS is held constant while varying substrate concentration (or vice versa), the kinetic constants derived are apparent constants. When studied over a narrow range of substrate concentrations, classic Michaelis-Menten kinetics can be observed with many SULT enzymes and most substrates. Some SULT enzymes exhibit positive or negative cooperativity during conversion of substrate to product, and the kinetics fit the Hill plot. A characteristic feature of most sulfotransferase-catalyzed reactions is that, when studied over a wide range of substrate concentrations, the rate of product formation initially increases as substrate concentration increases, then decreases at high substrate concentrations, i.e., they exhibit substrate inhibition or partial substrate inhibition. This chapter gives an introduction to sulfotransferases, including a historical note, the nomenclature, a description of the function of SULTs with different types of substrates, presentation of examples of enzyme kinetics with SULTs, and a discussion of what is known about mechanisms of substrate inhibition in the sulfotransferases.
Topics: Enzyme Inhibitors; Humans; Kinetics; Phosphoadenosine Phosphosulfate; Sulfotransferases
PubMed: 24523114
DOI: 10.1007/978-1-62703-758-7_10 -
Expert Opinion on Drug Metabolism &... Jul 2015Cytosolic sulfotransferases (SULTs), one of the vital enzymes of detoxication, catalyze the sulfation of native and exogenous hydrophobic molecules. Xenobiotic... (Review)
Review
INTRODUCTION
Cytosolic sulfotransferases (SULTs), one of the vital enzymes of detoxication, catalyze the sulfation of native and exogenous hydrophobic molecules. Xenobiotic accumulation can induce a variety of diseases, including cancers. Sulfation facilitates the solubilization and removal of xenobiotics. However, sulfation may activate the pharmacological activities of xenobiotics.
AREAS COVERED
The purpose of this review was to correlate the sequence, structure and function of SULTs. We focused on understanding the sulfation mechanisms of SULT through its sequence variation. We selectively reviewed SULT drug substrates, explained the enzyme-catalyzed sulfation reaction and its kinetic mechanisms, and the effect of amino acid sequence variation, such as single-nucleotide polymorphism, on the enzyme function.
EXPERT OPINION
A wealth of information is available in the literature for understanding the detailed mechanisms underlying xenobiotic sulfation. We reviewed information regarding the sequence, structure and reaction mechanism of SULTs and explained how SULT activities altered. In addition to revealing the SULT kinetics, the mRNA expression of specific SULTs in tissues that revealed their distribution in tissues also affects overall SULT activities. Understanding of the structure-function relationship and the reaction mechanism of SULTs is valuable for understanding, preventing and treating diseases.
Topics: Amino Acid Sequence; Animals; Cytosol; Humans; Pharmacogenetics; Polymorphism, Single Nucleotide; RNA, Messenger; Sulfotransferases; Xenobiotics
PubMed: 26073579
DOI: 10.1517/17425255.2015.1045486 -
Developmental Dynamics : An Official... Dec 2023Members of the sulfotransferase superfamily (SULT) influence the activity of a wide range of hormones, neurotransmitters, metabolites and xenobiotics. However, their...
BACKGROUND
Members of the sulfotransferase superfamily (SULT) influence the activity of a wide range of hormones, neurotransmitters, metabolites and xenobiotics. However, their roles in developmental processes are not well characterized even though they are expressed during embryogenesis. We previously found in a microarray screen that Six1 up-regulates LOC100037047, which encodes XB5850668.L, an uncharacterized sulfotransferase.
RESULTS
Since Six1 is required for patterning the embryonic ectoderm into its neural plate, neural crest, preplacodal and epidermal domains, we used loss- and gain-of function assays to characterize the role of XB5850668.L during this process. Knockdown of endogenous XB5850668.L resulted in the reduction of epidermal, neural crest, cranial placode and otic vesicle gene expression domains, concomitant with neural plate expansion. Increased levels had minimal effects, but infrequently expanded neural plate and neural crest gene domains, and infrequently reduced cranial placode and otic vesicle gene domains. Mutation of two key amino acids in the sulfotransferase catalytic domain required for PAPS binding and enzymatic activity tended to reduce the effects of overexpressing the wild-type protein.
CONCLUSIONS
Our analyses indicates that XB5850668.L is a member of the SULT2 family that plays important roles in patterning the embryonic ectoderm. Some aspects of its influence likely depend on sulfotransferase activity.
Topics: Ectoderm; Neural Crest; Skull; Embryonic Development; Sulfotransferases; Gene Expression Regulation, Developmental
PubMed: 37597164
DOI: 10.1002/dvdy.648 -
The Protein Journal Feb 2022Cytosolic estrogen sulfotransferase (SULT1E1) mainly catalyzes the sulfoconjugation and deactivation of estrogens that are known to exert potent anti-atherogenic...
Cytosolic estrogen sulfotransferase (SULT1E1) mainly catalyzes the sulfoconjugation and deactivation of estrogens that are known to exert potent anti-atherogenic effects. However, it remains unknown about the connection between SULT1E1 and atherosclerosis. Recently, we reported that SULT1E1 is highly expressed in the aorta with plaques of high fat-fed ApoE knockout (KO) mice (mouse model of atherosclerosis), and interacts with oxidized low-density lipoprotein (Ox-LDL) known as a major component of atherosclerotic lesions. In this study, immunohistochemical staining for SULT1E1 in the aorta of high fat-fed ApoE KO mice showed that SULT1E1 is detected in vascular endothelial cells overlying atherosclerotic plaques. Results from Western blotting showed that Ox-LDL induces the protein expression of both SULT1E1 and peroxisome proliferator-activated receptor (PPAR) γ in human umbilical vein endothelial cells (HUVECs), and then that a PPARγ antagonist GW9662, but not a PPARα antagonist GW6471, inhibited the protein expression of SULT1E1 induced by Ox-LDL. Moreover, GW9662 significantly increased the proliferation of HUVECs induced by Ox-LDL. Our results suggest that SULT1E1 and PPARγ, both of which are increased by Ox-LDL, may interact with each other, and then may reduce cooperatively Ox-LDL-induced proliferation of vascular endothelial cells overlying atherosclerotic plaques, leading to against atherosclerosis.
Topics: Animals; Atherosclerosis; Human Umbilical Vein Endothelial Cells; Humans; Mice; PPAR gamma; Plaque, Atherosclerotic; Sulfotransferases
PubMed: 35059953
DOI: 10.1007/s10930-022-10042-z -
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 -
Journal of Chemical Information and... Jun 2023Cytosolic sulfotransferases (SULTs) are a family of enzymes responsible for the sulfation of small endogenous and exogenous compounds. SULTs contribute to the...
Cytosolic sulfotransferases (SULTs) are a family of enzymes responsible for the sulfation of small endogenous and exogenous compounds. SULTs contribute to the conjugation phase of metabolism and share substrates with the uridine 5'-diphospho-glucuronosyltransferase (UGT) family of enzymes. UGTs are considered to be the most important enzymes in the conjugation phase, and SULTs are an auxiliary enzyme system to them. Understanding how the regioselectivity of SULTs differs from that of UGTs is essential from the perspective of developing novel drug candidates. We present a general ligand-based SULT model trained and tested using high-quality experimental regioselectivity data. The current study suggests that, unlike other metabolic enzymes in the modification and conjugation phases, the SULT regioselectivity is not strongly influenced by the activation energy of the rate-limiting step of the catalysis. Instead, the prominent role is played by the substrate binding site of SULT. Thus, the model is trained only on steric and orientation descriptors, which mimic the binding pocket of SULT. The resulting classification model, which predicts whether a site is metabolized, achieved a Cohen's kappa of 0.71.
Topics: Catalysis; Binding Sites; Sulfotransferases
PubMed: 37229540
DOI: 10.1021/acs.jcim.3c00275 -
Biochimica Et Biophysica Acta Dec 2002Heparan sulfate (HS) is a long unbranched polysaccharide found covalently attached to various proteins at the cell surface and in the extracellular matrix. It plays a... (Review)
Review
Heparan sulfate (HS) is a long unbranched polysaccharide found covalently attached to various proteins at the cell surface and in the extracellular matrix. It plays a central role in embryonic development and cellular function by modulating the activities of an extensive range of growth factors and morphogens. HS 2-O-sulfotransferase (Hs2st) occupies a critical position in the succession of enzymes responsible for the biosynthesis of HS, catalysing the transfer of sulfate to the C2-position of selected hexuronic acid residues within the nascent HS chain. Previous studies have concluded that 2-O-sulfation of HS is essential for it to cooperate in many growth factor/receptor interactions. Surprisingly therefore, embryos lacking functional Hs2st survive until birth, but die perinatally, suffering complete failure to form kidneys. However, this rather late lethality belies a more intricate involvement of 2-O-sulfated HS during development. The purpose of this review is to summarise the requirements for 2-O-sulfated HS during mouse development, at the morphological and molecular level. The implications that altered HS structure may have on growth factor/receptor signalling in vivo will be discussed.
Topics: Animals; Growth Substances; Heparitin Sulfate; Mice; Phenotype; Receptors, Growth Factor; Signal Transduction; Sulfotransferases
PubMed: 12417414
DOI: 10.1016/s0304-4165(02)00399-9 -
Progress in Molecular Biology and... 2010Ndsts (N-deacetylase/N-sulfotransferases) are enzymes responsible for N-sulfation during heparan sulfate (HS) and heparin biosynthesis. In this review, basic features of... (Review)
Review
Ndsts (N-deacetylase/N-sulfotransferases) are enzymes responsible for N-sulfation during heparan sulfate (HS) and heparin biosynthesis. In this review, basic features of the Ndst1 enzyme are covered and a brief description of HS biosynthesis and its regulation is presented. Effects of Ndst1 deficiency on embryonic development are described. These include immature lungs, craniofacial dysplasia and eye developmental defects, branching defect during lacrimal gland development, delayed mineralization of the skeleton, and reduced pericyte recruitment during vascular development. A brief account of the effects of Ndst1 deficiency in selective cell types in adult mice is also given.
Topics: Animals; Blood Vessels; Mice; Mice, Knockout; Organogenesis; Sulfotransferases
PubMed: 20807640
DOI: 10.1016/S1877-1173(10)93003-2 -
Drug Metabolism Reviews Nov 2013The SULT1C enzymes are a relatively under-studied branch of the cytosolic sulfotransferase (SULT) multigene family. Concrete information about SULT1C tissue-specific... (Review)
Review
The SULT1C enzymes are a relatively under-studied branch of the cytosolic sulfotransferase (SULT) multigene family. Concrete information about SULT1C tissue-specific expression, substrate preference, role in physiology and regulation is just emerging in the literature. The role of SULT1Cs in normal physiology is uncertain, but SULT1C-catalyzed sulfonation of thyroid hormones may be a mechanism to titrate the pre-receptor levels of biologically active thyroid hormone in target tissues. Both rat and human cytosolic SULT1Cs are most noted for their ability to bioactivate potent procarcinogens such as N-hydroxy-2-acetylaminofluorene. This implicates a possible role for the SULT1Cs as modulators of environmental carcinogen exposure and determinants of neoplastic transformation. In humans, the SULT1Cs are likely to function physiologically in cell proliferation and organogenesis pathways during development, as SULT1Cs appear to be preferentially expressed during fetal life. In recent years, the SULT1C nomenclature as presented in the literature has undergone major changes in response to updated genomic information. The purpose of this review is to summarize the current literature on the SULT1Cs and to clarify perspectives on SULT1C species differences, tissue-specific expression, nomenclature and role in pathophysiology. The ultimate goal is to understand the undiscovered impact of SULT1C expression on hormone homeostasis and xenobiotic toxicity during human development and as a prelude to disease development later in life.
Topics: Animals; Humans; Isoenzymes; Species Specificity; Substrate Specificity; Sulfotransferases; Xenobiotics
PubMed: 24028175
DOI: 10.3109/03602532.2013.835634 -
Glycoconjugate Journal 2002Heparan sulphate 2-O-sulphotransferase (Hs2st) acts at an intermediate stage in the pathway of biosynthesis of heparan sulphate (HS), catalysing the transfer of sulphate... (Review)
Review
Heparan sulphate 2-O-sulphotransferase (Hs2st) acts at an intermediate stage in the pathway of biosynthesis of heparan sulphate (HS), catalysing the transfer of sulphate from 3'-phosphoadenosine-5'-phosphosulfate (PAPS) to the C2-position of selected hexuronic acid residues within the maturing HS chain. It is well established that 2-O-sulphation within HS, particularly of iduronate residues, is essential for HS to participate in a variety of high-affinity ligand-binding interactions. HS plays a central role in embryonic development and cellular function, modulating the activities of an extensive range of growth factors. Interestingly, in contrast to the early failure of embryos entirely lacking HS, Hs2st(-/-) mice survive until birth, but die perinatally due to a complete failure of kidney formation. The phenotype of Hs2st(-/-) mutant kidneys suggests that signalling between two tissues, ureteric bud and metanephric mesenchyme, is disrupted. We discuss candidate signalling molecules that may mediate this interaction. The HS generated by these mice lacks 2-O-sulphate groups but is extensively modified above wild type levels by O-sulphation at C-6 of glucosamine-N-sulfate (GlcNS) residues. We will discuss the potentially altered role of this atypical HS in growth factor signalling.
Topics: Animals; Embryonic and Fetal Development; Fibroblast Growth Factor 1; Fibroblast Growth Factor 2; Heparitin Sulfate; Kidney; Ligands; Mice; Mice, Knockout; Models, Biological; Mutagenesis, Insertional; Phenotype; Signal Transduction; Sulfotransferases
PubMed: 12975615
DOI: 10.1023/A:1025325222530