Controlling Sulfuryl-Transfer Biology

Cook, Ian; Wang, Ting; Wang, Wei; Kopp, Felix; Wu, Peng; Leyh, Thomas S.

doi:10.1016/j.chembiol.2016.04.009

Cited by 11 publications

(15 citation statements)

References 58 publications

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“…Cap closure encapsulates the nucleotide, which can release only from a cap-open form (28,29). For all isoforms studied thus far (18,(31)(32)(33), nucleotide release is rate-determining (34,35), and the release rate depends on K iso , which determines the fraction of enzymebound PAP poised for escape.…”

Section: The Mechanism Of Inhibitionmentioning

confidence: 99%

Allosteres to regulate neurotransmitter sulfonation

Darrah

Wang

Cook

et al. 2019

Journal of Biological Chemistry

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Edited by Wolfgang PetiCatecholamine neurotransmitter levels in the synapses of the brain shape human disposition-cognitive flexibility, aggression, depression, and reward seeking-and manipulating these levels is a major objective of the pharmaceutical industry. Certain neurotransmitters are extensively sulfonated and inactivated by human sulfotransferase 1A3 (SULT1A3). To our knowledge, sulfonation as a therapeutic means of regulating transmitter activity has not been explored. Here, we describe the discovery of a SULT1A3 allosteric site that can be used to inhibit the enzyme. The structure of the new site is determined using spin-label-triangulation NMR. The site forms a cleft at the edge of a conserved ϳ30-residue active-site cap that must open and close during the catalytic cycle. Allosteres anchor into the site via -stacking interactions with two residues that sandwich the planar core of the allostere and inhibit the enzyme through capstabilizing interactions with substituents attached to the core. Changes in cap free energy were calculated ab initio as a function of core substituents and used to design and synthesize a series of inhibitors intended to progressively stabilize the cap and slow turnover. The inhibitors bound tightly (34 nM to 7.4 M) and exhibited progressive inhibition. The cap-stabilizing effects of the inhibitors were experimentally determined and agreed remarkably well with the theoretical predictions. These studies establish a reliable heuristic for the design of SULT1A3 allosteric inhibitors and demonstrate that the free-energy changes of a small, dynamic loop that is critical for SULT substrate selection and turnover can be calculated accurately.

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Section: The Mechanism Of Inhibitionmentioning

confidence: 99%

Allosteres to regulate neurotransmitter sulfonation

Darrah

Wang

Cook

et al. 2019

Journal of Biological Chemistry

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“…Transfectants were grown at 37 °C ± 2 deg. C to 60 to 70% confluency in 12-well plates, washed (3×) with PBS (25 °C), and lysed using RIPA buffer (0.50 ml) ( 75 ). Lysate was centrifuged (15,000 g for 10 min, 25 °C) and the supernatant was collected, assayed, flash-frozen, with liquid nitrogen, and stored at −80 °C.…”

Section: Methodsmentioning

confidence: 99%

“…The final concentrations of DMSO were ≤0.10%. Cells were then washed twice with PBS before adding pNpp (5.0 mM) in PBS ( 75 ). Following incubation with pNpp for 3 h at 25 °C ± 2 deg.…”

Section: Methodsmentioning

confidence: 99%

The molecular basis of OH-PCB estrogen receptor activation

Wang

Cook

Leyh

2021

Journal of Biological Chemistry

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Polychlorinated bisphenols (PCBs) continue to contaminate food chains globally where they concentrate in tissues and disrupt the endocrine systems of species throughout the ecosphere. Hydroxylated PCBs (OH-PCBs) are major PCB metabolites and high-affinity inhibitors of human estrogen sulfotransferase (SULT1E1), which sulfonates estrogens and thus prevents them from binding to and activating their receptors. OH-PCB inhibition of SULT1E1 is believed to contribute significantly to PCB-based endocrine disruption. Here, for the first time, the molecular basis of OH-PCB inhibition of SULT1E1 is revealed in a structure of SULT1E1 in complex with OH-PCB1 (4ʹ-OH-2,6-dichlorobiphenol) and its substrates, estradiol (E2), and PAP (3’-phosphoadenosine-5-phosphosulfate). OH-PCB1 prevents catalysis by intercalating between E2 and catalytic residues and establishes a new E2-binding site whose E2 affinity and positioning are greater than and competitive with those of the reactive-binding pocket. Such complexes have not been observed previously and offer a novel template for the design of high-affinity inhibitors. Mutating residues in direct contact with OH-PCB weaken its affinity without compromising the enzyme’s catalytic parameters. These OH-PCB resistant mutants were used in stable transfectant studies to demonstrate that OH-PCBs regulate estrogen receptors in cultured human cell lines by binding the OH-PCB binding pocket of SULT1E1.

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“…A better understanding of sulfotransferase enzymes may have direct translational potential for drug development (Cook et al 2016): Raloxifene is an approved selective estrogen receptor modulator that is quickly sulfated, and thus inactivated, in human cells. Modulating this compound in a way that prevented sulfation, but left its interaction with the estrogen receptor untouched, resulted in an enormous increase in estrogen receptor activation efficacy (Cook et al 2016). It is likely that this approach could also work with other compounds.…”

Section: Substrate Specificity and Regulation Of Sulfotransferasesmentioning

confidence: 99%

SULFATION PATHWAYS: Insights into steroid sulfation and desulfation pathways

Foster

Mueller

2018

Journal of Molecular Endocrinology

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Sulfation and desulfation pathways represent highly dynamic ways of shuttling, repressing and re-activating steroid hormones, thus controlling their immense biological potency at the very heart of endocrinology. This theme currently experiences growing research interest from various sides, including, but not limited to, novel insights about phospho-adenosine-5'-phosphosulfate synthase and sulfotransferase function and regulation, novel analytics for steroid conjugate detection and quantification. Within this review, we will also define how sulfation pathways are ripe for drug development strategies, which have translational potential to treat a number of conditions, including chronic inflammatory diseases and steroid-dependent cancers.

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Controlling Sulfuryl-Transfer Biology

Cited by 11 publications

References 58 publications

Allosteres to regulate neurotransmitter sulfonation

Allosteres to regulate neurotransmitter sulfonation

The molecular basis of OH-PCB estrogen receptor activation

SULFATION PATHWAYS: Insights into steroid sulfation and desulfation pathways

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