Sulfation through the looking glass—recent advances in sulfotransferase research for the curious

Coughtrie, Michael W.H.

doi:10.1038/sj.tpj.6500117

Cited by 187 publications

(153 citation statements)

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“…Notably, many drugs and/or their hydroxylated metabolites are phase II conjugated via sulfonation. Among several other important functions, sulfonation is also known to have a role in modulating the action of hormones and neurotransmitters and appears to be especially important during early human development (21,25,26,(47)(48)(49)(50)(51). There are various human sulfotransferases (both cytosolic and membrane-bound), but human cytosolic sulfotransferase SULT1A1, which acts on acetaminophen, has a broad substrate range and is one of the most important sulfotransferases for xenobiotic sulfonation as well as acting on several endogenous substrates (26,51).…”

Section: Resultsmentioning

confidence: 99%

Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism

Clayton

Baker

Lindon

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

697

573

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We provide a demonstration in humans of the principle of pharmacometabonomics by showing a clear connection between an individual's metabolic phenotype, in the form of a predose urinary metabolite profile, and the metabolic fate of a standard dose of the widely used analgesic acetaminophen. Predose and postdose urinary metabolite profiles were determined by 1 H NMR spectroscopy. The predose spectra were statistically analyzed in relation to drug metabolite excretion to detect predose biomarkers of drug fate and a human-gut microbiome cometabolite predictor was identified. Thus, we found that individuals having high predose urinary levels of p-cresol sulfate had low postdose urinary ratios of acetaminophen sulfate to acetaminophen glucuronide. We conclude that, in individuals with high bacterially mediated p-cresol generation, competitive O-sulfonation of p-cresol reduces the effective systemic capacity to sulfonate acetaminophen. Given that acetaminophen is such a widely used and seemingly well-understood drug, this finding provides a clear demonstration of the immense potential and power of the pharmacometabonomic approach. However, we expect many other sulfonation reactions to be similarly affected by competition with p-cresol and our finding also has important implications for certain diseases as well as for the variable responses induced by many different drugs and xenobiotics. We propose that assessing the effects of microbiome activity should be an integral part of pharmaceutical development and of personalized health care. Furthermore, we envisage that gut bacterial populations might be deliberately manipulated to improve drug efficacy and to reduce adverse drug reactions.T he effects of drug treatments can vary greatly between different individuals, and pharmacogenomics has been widely advocated as a potential means of personalizing human drug treatments to increase drug efficacy and to decrease adverse reactions (1-6). However, environmental factors (such as nutritional status, gut bacterial activities, age, disease, and other drug use) are also important determinants of individual metabolic phenotypes, which modulate drug metabolism, efficacy, and toxicity. Such environmental complications, which may also alter gene expression, will tend to limit the usefulness of predictions of drug-induced responses that are based only on genomic differences (7,8). For instance, for many classes of compound, enzyme induction state, which is environmentally determined, influences drug metabolism and toxicity and this is not captured in genomic data. Recognizing this important limitation of pharmacogenomics, a different approach to personalized drug treatment has recently been proposed wherein predose metabolite profiling would instead be used to predict a subject's responses to potential drug interventions (9). This ''pharmacometabonomic'' approach has a number of major advantages, which include the ready availability and relative ease of analysis of biofluids, such as urine and blood plasma, as well as the fact that ...

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Section: Resultsmentioning

confidence: 99%

Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism

Clayton

Baker

Lindon

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

697

573

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“…Sulfotransferases (SULTs) are enzymes that catalyze the sulfation (sulfonation) of hydroxylcontaining compounds [1,2]. The universal sulfuryl group donor (co-substrate) for SULTcatalyzed sulfation is adenosine 3′-phosphate 5′-phosphosulfate (PAPS).…”

Section: Introductionmentioning

confidence: 99%

Redox regulation of human estrogen sulfotransferase (hSULT1E1)

Maiti¹,

Zhang²,

Chen³

2007

Biochemical Pharmacology

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Sulfotransferases (SULTs) are enzymes that catalyze the sulfation of hydroxyl-containing compounds. Sulfation regulates hormone activities and detoxifies xenobiotics. Human estrogen sulfotransferase (hSULT1E1) catalyzes the sulfation of estrogens and regulates estrogen bioactivities. Oxidative regulation provides a biological mechanism for regulating enzyme activities in vivo. The oxidative regulation of human SULTs has not been reported. In this study, we used amino acid modification, manipulation of intracellular redox state, and site-directed mutagenesis to study the redox regulation of human SULTs and specifically the mechanism of hSULT1E1 inhibitory regulation by oxidized glutathione (GSSG). Of the four major human SULTs, hSULT1A1, hSULT1A3, and hSULT2A1 do not undergo redox regulation; hSULT1E1, on the other hand, can be redox regulated. GSSG inactivated hSULT1E1 activity in an efficient, time-and concentrationdependant manner. The co-enzyme adenosine 3′-phosphate 5′-phosphosulfate protected hSULT1E1 from GSSG-associated inactivation. A reduced glutathione (GSH) inducer (N-acetyl cysteine) significantly increased while a GSH depletor (buthionine sulfoxamine) significantly decreased hSULT1E1 activity, but both failed to affect the amount of hSULT1E1 protein in human hepatocyte carcinoma Hep G2 cells. Crystal structure suggested that no Cys residues exist near the active sites of hSULT1A1, hSULT1A3, and hSULT2A1, but Cys residues do exist within the active site of hSULT1E1. Site-directed mutagenesis demonstrated that Cys83 is critical for the redox regulation of hSULT1E1. This first report on the redox regulation of human SULTs suggests that the redox regulation of hSULT1E1 may interrupt the regulation and function of estrogens under various physiological and pathological conditions.

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“…Sulfotransferases (SULTs) 3 are phase II drug-metabolizing enzymes that catalyze the sulfation (sulfonation) of various hydroxyl-containing compounds: biosignaling molecules such as hydroxysteroid hormones, thyroid hormones, glucocorticoid hormones, bile acids, neurotransmitters, and hydroxylcontaining xenobiotics (1)(2)(3)(4)(5)(6)(7)(8). The sulfation proceeds as shown in reaction 1, where the sulfuryl group donor is adenosine 3Ј-phosphate 5Ј-phosphosulfate (PAPS), and the reaction products are adenosine 3Ј,5Ј-diphosphate (PAP) and a sulfated product.…”

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confidence: 99%

para-Nitrophenyl Sulfate Activation of Human Sulfotransferase 1A1 Is Consistent with Intercepting the E·PAP Complex and Reformation of E·PAPS

Tyapochkin

Cook

Chen

2009

Journal of Biological Chemistry

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Cytosolic sulfotransferase (SULT)-catalyzed sulfation regulates biological activities of various biosignaling molecules and metabolizes hydroxyl-containing drugs and xenobiotics. The universal sulfuryl group donor for SULT-catalyzed sulfation is adenosine 3-phosphate 5-phosphosulfate (PAPS), whereas the reaction products are a sulfated product and adenosine 3,5-diphosphate (PAP). Although SULT-catalyzed kinetic mechanisms have been studied since the 1980s, they remain unclear. Human SULT1A1 is an important phase II drug-metabolizing enzyme. Previously, isotope exchange at equilibrium indicated steady-state ordered mechanism with PAPS and PAP binding to the free SULT1A1 (Tyapochkin, E., Cook, P. F., and Chen, G. Sulfotransferases (SULTs)3 are phase II drug-metabolizing enzymes that catalyze the sulfation (sulfonation) of various hydroxyl-containing compounds: biosignaling molecules such as hydroxysteroid hormones, thyroid hormones, glucocorticoid hormones, bile acids, neurotransmitters, and hydroxylcontaining xenobiotics (1-8). The sulfation proceeds as shown in reaction 1, where the sulfuryl group donor is adenosine 3Ј-phosphate 5Ј-phosphosulfate (PAPS), and the reaction products are adenosine 3Ј,5Ј-diphosphate (PAP) and a sulfated product. R-OH ϩ PAPS L | ;One of the main biological functions of SULTs is the regulation of various hormones (9). Sulfation of xenobiotics is mainly associated with detoxification, biotransformation of a relatively hydrophobic xenobiotic into a more water-soluble sulfuric ester that is readily excreted. However, in some cases sulfation can also cause bioactivation of procarcinogens and promutagens, leading to possible toxic effects (10, 11).Studies of the SULTs kinetic mechanisms began to appear in the early 1980s (12). Although many SULT isoforms have been isolated and characterized, their biological functions and catalytic mechanisms are still not well understood. Human phenol sulfotransferase (SULT1A1) is one of the major detoxifying enzymes for phenolic xenobiotics; it also catalyzes the sulfation of endogenous hydroxyl biosignaling molecules. It has very broad substrate specificity and high activity toward most phenolic compounds. SULT1A1 is also widely distributed in the human body. On the basis of isotope exchange at equilibrium, we showed that the kinetic mechanism for human SULT1A1 is steady-state-ordered with PAPS binding to the protein first, and PAP released last (13).Substrate inhibition by the hydroxyl substrate (sulfate acceptor) is a common feature of most cytosolic SULTs (14,15). Inhibition of SULT1A1 has been observed by the substrate, naphthol. There are a number of different mechanisms that have been proposed for substrate inhibition, but the mechanism remains unclear. A ternary complex formed between substrate and the enzyme⅐PAP complex is the most likely possibility in an ordered mechanism, but binding to free enzyme is also possible (12,16). It is also possible, but unlikely, that substrate could bind to central complexes. In addition, binding of two substrate...

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Sulfation through the looking glass—recent advances in sulfotransferase research for the curious

Cited by 187 publications

References 93 publications

Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism

Pharmacometabonomic identification of a significant host-microbiome metabolic interaction affecting human drug metabolism

Redox regulation of human estrogen sulfotransferase (hSULT1E1)

para-Nitrophenyl Sulfate Activation of Human Sulfotransferase 1A1 Is Consistent with Intercepting the E·PAP Complex and Reformation of E·PAPS

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