Crystal structure‐based studies of cytosolic sulfotransferase

Yoshinari, Kouichi; Petrotchenko, Evgeniy V.; Pedersen, Lars C.; Negishi, Masahiko

doi:10.1002/jbt.1

Cited by 60 publications

(56 citation statements)

References 59 publications

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“…Both kinetic and crystallographic studies have shown that PAP and PAPS bind at the same binding site in each SULT (Yoshinari et al, 2001;Chapman et al, 2004;Wang and James, 2006), and we determined binding at this site by titration with PAP. These studies were conducted in 0.25 M potassium phosphate, pH 7.4, with an excitation wavelength of 290 nm and an emission wavelength of 347 nm (entrance and the exit slits were set at 5 and 7 nm, respectively).…”

Section: Methodsmentioning

confidence: 99%

Modification of the Catalytic Function of Human Hydroxysteroid Sulfotransferase hSULT2A1 by Formation of Disulfide Bonds

Qin¹,

Teesch²,

Duffel³

2013

Drug Metab Dispos

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The human cytosolic sulfotransferase hSULT2A1 catalyzes the sulfation of a broad range of xenobiotics, as well as endogenous hydroxysteroids and bile acids. Reversible modulation of the catalytic activity of this enzyme could play important roles in its physiologic functions. Whereas other mammalian sulfotransferases are known to be reversibly altered by changes in their redox environment, this has not been previously shown for hSULT2A1. We have examined the hypothesis that the formation of disulfide bonds in hSULT2A1 can reversibly regulate the catalytic function of the enzyme. Three thiol oxidants were used as model compounds to investigate their effects on homogeneous preparations of hSULT2A1: glutathione disulfide, 5,59-dithiobis(2-nitrobenzoic acid), and 1,1'-azobis(N,N-dimethylformamide) (diamide). Examination of the effects of disulfide bond formation with these agents indicated that the activity of the enzyme is reversibly altered. Studies on the kinetics of the hSULT2A1-catalyzed sulfation of dehydroepiandrosterone (DHEA) showed the effects of disulfide bond formation on the substrate inhibition characteristics of the enzyme. The effects of these agents on the binding of substrates and products, liquid chromatography-mass spectrometry identification of the disulfides formed, and structural modeling of the modified enzyme were examined. Our results indicate that conformational changes at cysteines near the nucleotide binding site affect the binding of both the nucleotide and DHEA to the enzyme, with the specific effects dependent on the structure of the resulting disulfide. Thus, the formation of disulfide bonds in hSULT2A1 is a potentially important reversible mechanism for alterations in the rates of sulfation of both endogenous and xenobiotic substrates.

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Section: Methodsmentioning

confidence: 99%

Modification of the Catalytic Function of Human Hydroxysteroid Sulfotransferase hSULT2A1 by Formation of Disulfide Bonds

Qin¹,

Teesch²,

Duffel³

2013

Drug Metab Dispos

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“…The three cytosolic SULT structures are highly conserved, and a number of key features of the SULT active site and reaction mechanism (reviewed in 36 ) can be deduced from these and other studies (see Figure 2). The amino acids involved in binding the sulfuryl donor PAPS are, as would be expected, highly conserved throughout the SULT family.…”

Section: Structure-function Studies On Sulfotransferasesmentioning

confidence: 95%

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

2002

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Members of the cytosolic sulfotransferase (SULT) superfamily catalyse the sulfation of a multitude of xenobiotics, hormones and neurotransmitters. Humans have at least 10 functional SULT genes, and a number of recent advances reviewed here have furthered our understanding of SULT function. Analysis of expression patterns has shown that sulfotransferases are highly expressed in the fetus, and SULTs may in fact be a major detoxification enzyme system in the developing human. The X-ray crystal structures of three SULTs have been solved and combined with mutagenesis experiments and molecular modelling, they have provided the first clues as to the factors that govern the unique substrate specificities of some of these enzymes. In the future these and other studies will facilitate prediction of the fate of chemicals metabolised by sulfation. Variation in sulfation capacity may be important in determining an individual's response to xenobiotics, and there has been an explosion in information on sulfotransferase polymorphisms and their functional consequences, including the influence of SULT1A1 genotype on susceptibility to colorectal and breast cancer. Finally, the first gene knockout experiments with SULTs have recently been described, with the generation of estrogen sulfotransferase deficient mice in which reproductive capacity is compromised. Our improved understanding of these enzymes will have significant benefits in such diverse areas as drug design and development, cancer susceptibility, reproduction and development.

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“…Dashed lines outline the extended amino-and carboxy-terminal ends of SULT2B1a and SULT2B1b. Boxed residues delineate conserved amino acids involved in 5Ј-phosphoadenosine-3Ј-phosphosulfate cofactor interaction (129,130). Multiple alignment analysis was carried out using the MacVector 7.0 system, which is based on the Clustal W algorithm (131).…”

Section: Cholesterol Sulfotransferasesmentioning

confidence: 99%

Cholesterol sulfate in human physiology: what's it all about?

Strott

Higashi

2003

Journal of Lipid Research

205

184

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Cholesterol sulfate is quantitatively the most important known sterol sulfate in human plasma, where it is present in a concentration that overlaps that of the other abundant circulating steroid sulfate, dehydroepiandrosterone (DHEA) sulfate. Although these sulfolipids have similar production and metabolic clearance rates, they arise from distinct sources and are metabolized by different pathways. While the function of DHEA sulfate remains an enigma, cholesterol sulfate has emerged as an important regulatory molecule. Cholesterol sulfate is a component of cell membranes where it has a stabilizing role, e.g., protecting erythrocytes from osmotic lysis and regulating sperm capacitation. It is present in platelet membranes where it supports platelet adhesion. Cholesterol sulfate can regulate the activity of serine proteases, e.g., those involved in blood clotting, fibrinolysis, and epidermal cell adhesion. As a result of its ability to regulate the activity of selective protein kinase C isoforms and modulate the specificity of phosphatidylinositol 3-kinase, cholesterol sulfate is involved in signal transduction. Cholesterol sulfate functions in keratinocyte differentiation, inducing genes that encode for key components involved in development of the barrier. The accumulating evidence demonstrating a regulatory function for cholesterol sulfate appears solid; the challenge now is to work out the molecular mechanisms whereby this interesting molecule carries out its various roles. -Strott, C. A., and Y. Higashi. Cholesterol sulfate in human physiology: what's it all about? J.

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Crystal structure‐based studies of cytosolic sulfotransferase

Cited by 60 publications

References 59 publications

Modification of the Catalytic Function of Human Hydroxysteroid Sulfotransferase hSULT2A1 by Formation of Disulfide Bonds

Modification of the Catalytic Function of Human Hydroxysteroid Sulfotransferase hSULT2A1 by Formation of Disulfide Bonds

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

Cholesterol sulfate in human physiology: what's it all about?

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