24-Hydroxycholesterol Sulfation by Human Cytosolic Sulfotransferases: Formation of Monosulfates and Disulfates, Molecular Modeling, Sulfatase Sensitivity, and Inhibition of Liver X Receptor Activation

Cook, Ian; Duniec-Dmuchowski, Zofia; Kocarek, Thomas A.; Runge‐Morris, Melissa; Falany, Charles N.

doi:10.1124/dmd.108.025759

Cited by 78 publications

(86 citation statements)

References 44 publications

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“…The in vivo activities of these compounds are regulated by sulfation, which often profoundly alters their target affinities (5)(6)(7)(8). SULTs perform at least two essential metabolic functions: a homeostatic function, in which, for example, they regulate the receptor binding activities of peptide and steroid hormones (6,7), and a defensive function (9,10), in which they sulfonate the myriad compounds that pass through the liver and would otherwise adventitiously bind receptors and regulate cellular signaling systems.…”

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confidence: 99%

High Accuracy in Silico Sulfotransferase Models

Cook

Wang

Falany

et al. 2013

Journal of Biological Chemistry

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Background: Human sulfotransferases (SULTs) regulate the bioactivities of hundreds of compounds in vivo. Results:The in silico models of SULTs developed here proved remarkably accurate in identifying SULT substrates in a 1,455-compound library containing all FDA-approved drugs. Conclusion: Highly accurate in silico SULT models are now available. Significance: The elision of mechanism and modeling can produce remarkably accurate in silico tools for the study of biology.

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confidence: 99%

High Accuracy in Silico Sulfotransferase Models

Cook

Wang

Falany

et al. 2013

Journal of Biological Chemistry

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“…Cook et al ( 26 ) discovered that human STS can cleave the sulfate in position 3 of 24OHC3S, but not the sulfate in oxysterols are synthesized from cholesterol, they can undergo sulfonation by a sulfotransferase ( 25 ). But additionally, they could be enzymatically produced from CS, as was described by Norlin et al ( 35 ) in 2003.…”

Section: Methods Developmentmentioning

confidence: 65%

“…Additionally, the effects of the continuous presence of high concentrations of certain hydroxycholesterol sulfates, which have been proved to have regulatory capacities in some cases ( 26,28 ), should be studied in detail. position 24.…”

Section: Methods Developmentmentioning

confidence: 99%

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High levels of oxysterol sulfates in serum of patients with steroid sulfatase deficiency

Sánchez‐Guijo

Oji

Hartmann

et al. 2015

Journal of Lipid Research

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“…SULT1A1 was expressed in Escherichia coli with a maltose-binding protein (MBP) tag as described previously (Cook et al, 2009). The MBP tag was cleaved by factor Xa digestion to allow purification of the active native SULT1A1 enzyme.…”

Section: Methodsmentioning

confidence: 99%

Potent Inhibition of Human Sulfotransferase 1A1 by 17α-Ethinylestradiol: Role of 3′-Phosphoadenosine 5′-Phosphosulfate Binding and Structural Rearrangements in Regulating Inhibition and Activity

Rohn¹,

Cook²,

Leyh³

et al. 2012

Drug Metab Dispos

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ABSTRACT:Sulfotransferase (SULT) 1A1 is the major drug/xenobiotic-conjugating SULT isoform in human liver because of its broad substrate reactivity and high expression level. SULT1A1 sulfates estrogens with low micromolar K m values consistent with its affinity for sulfation of many small phenolic compounds. Binding studies showed the unexpected ability of 17␣-ethinylestradiol (EE2) to bind and inhibit SULT1A1 activity toward p-nitrophenol and ␤-naphthol at low nanomolar concentrations, whereas EE2 was not sulfated until significantly higher concentrations were reached. EE2 had a K i of 10 nM for inhibiting p-nitrophenol and ␤-naphthol sulfation and inhibited 17␤-estradiol (E2) sulfation in intact human MCF-7 breast cancer cells with a K i of 19 nM. In contrast, the K m for EE2 sulfation by SULT1A1 was 700 nM. The K d for EE2 binding of pure SULT1A1 was 0.5 ؎ 0.15 M; however, the K d for EE2 binding to the SULT1A1-PAP complex was >100-fold lower (4.3 ؎ 1.7 nM). The K d for E2 binding to SULT1A1 changed from 2.3 ؎ 0.9 to 1.2 ؎ 0.56 M in the presence of PAP. Docking studies with E2 indicate that E2 binds in a competent orientation in the resolved structure of SULT1A1 in the both presence and absence of 3-phosphoadenosine 5-phosphosulfate (PAPS). However, EE2 binds in a catalytically competent orientation in the absence of PAPS but in a noncompetent orientation via formation of a charge interaction with Tyr108 if PAPS is bound first. In conclusion, EE2 is a potent inhibitor, but not a substrate, of SULT1A1 at low nanomolar concentrations, indicating the possibility of drug-drug interactions during contraceptive therapy.

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24-Hydroxycholesterol Sulfation by Human Cytosolic Sulfotransferases: Formation of Monosulfates and Disulfates, Molecular Modeling, Sulfatase Sensitivity, and Inhibition of Liver X Receptor Activation

Cited by 78 publications

References 44 publications

High Accuracy in Silico Sulfotransferase Models

High Accuracy in Silico Sulfotransferase Models

High levels of oxysterol sulfates in serum of patients with steroid sulfatase deficiency

Potent Inhibition of Human Sulfotransferase 1A1 by 17α-Ethinylestradiol: Role of 3′-Phosphoadenosine 5′-Phosphosulfate Binding and Structural Rearrangements in Regulating Inhibition and Activity

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