Molecular Cloning, Expression, and Functional Characterization of Novel Mouse Sulfotransferases

doi:10.1006/bbrc.1998.8872

Biochemical and Biophysical Research Communications

Volume 247, Issue 3, 29 June 1998, Pages 681-686

https://doi.org/10.1006/bbrc.1998.8872 Get rights and content

Abstract

Nucleotide sequences of two mouse cDNAs encoding new sulfotransferase enzymes were determined. Analysis of the deduced amino acid sequences revealed that one represents a novel member of the phenol sulfotransferase family and the other is highly homologous to human SULT2B1 hydroxysteroid sulfotransferases. The recombinant enzymes, transiently expressed in COS-7 cells, were characterized with respect to their substrate specificity using a variety of substrates for different types of sulfotransferases. The tissue-specific expression of these two new mouse sulfotransferases was examined by Northern blot analysis.

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Although the mouse liver does not have a high basal expression of SULT2B1b, the hepatic expression of SULT2B1b is highly inducible, such as in response to 1, 4-bis [2-(3, 5-dichloropyridyloxy)] benzene (TCPOBOP), an agonist for CAR.26 The human SULT2B1b is highly conserved with the mouse SULT2B1b.27 The human SULT2B1 also has two isoforms, SULT2B1a and SULT2B1b, which are encoded by a single gene as a result of alternative transcription initiation and alternative splicing.
The nuclear receptor hepatocyte nuclear factor 4alpha (HNF4α) plays a critical role in the regulation of metabolic homeostasis, including glucose homeostasis. Sulfotransferases (SULTs) catalyze the transfer of a sulfate group from 3-phosphoadenosine 5-phosphosulfate (PAPS) to an acceptor molecule. Sulfonation plays an essential role in regulating the chemical and functional homeostasis of endogenous and exogenous molecules. Among SULTs, the cholesterol sulfotransferase 2B1b (SULT2B1b) preferentially catalyzes the sulfoconjugation of cholesterol and oxysterols to form cholesterol sulfate and oxysterol sulfates. Hepatic gluconeogenesis represents a critical component of energy metabolism. Although there have been reviews on the regulation of glucose homeostasis by HNF4α, the interplay between HNF4α and SULT2B1b in hepatic glucose homeostasis remains scattered. In this review, we intend to provide an overview on how HNF4α functionally cross-talks with SULT2B1b to regulate hepatic glucose homeostasis and whether the HNF4α-SULT2B1b axis represents a novel therapeutic target for the management of metabolic liver disease and metabolic syndrome.
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This article contains data related to the research article entitled “Id2 determines intestinal identity through repression of the foregut transcription factor, Irx5” [1]. Id2 deficient (Id2^−/−) mice developed gastric tumors and heterotopic squamous epithelium in the small intestine. These tumors and heterotopic tissues were derived from ectopic gastric cells and squamous cells formed in the small intestine respectively during development. In this study, microarray data of the developing small intestine of Id2^−/− mice was analyzed.
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It is also found in the placenta, particularly the cotyledon [39], but not in the endometrium [56]. The SULT2B1 gene was first identified more or less simultaneously in humans [57] and mice [58]. The human gene produces two independently functional proteins of 350 (SULT2B1a) and 365 (SULT2B1b) amino acids through the use of alternate transcription start sites resulting in the different N-terminal sequences.
The sulfuryl transfer reaction is of fundamental biological importance. One of the most important manifestations of this process are the reactions catalyzed by members of the cytosolic sulfotransferase (SULT) superfamily. These enzymes transfer the sulfuryl moiety from the universal donor PAPS (3′-phosphoadenosine 5′-phosphosulfate) to a wide variety of substrates with hydroxyl- or amino-groups. Normally a detoxification reaction this facilitates the elimination of a multitude of xenobiotics, although for some molecules sulfation is a bioactivation step. In addition, sulfation plays a key role in endocrine and other signalling pathways since many steroids, sterols, thyroid hormones and catecholamines exist primarily as sulfate conjugates in humans. This article summarizes much of our current knowledge of the organization and function of the human cytosolic sulfotransferases and highlights some of the important interspecies differences that have implications for, among other things, drug development and chemical safety analysis.
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Preparation of four distinct mSULT1D1 crystals. Procedures for the expression, purification, and crystallization of recombinant mSULT1D1 have previously been reported [8–10]. mSULT1D1–PAPS complex.
We report the crystal structure of mouse sulfotransferase, mSULT1D1, complexed with donor substrate 3′-phosphoadenosine 5′-phosphosulfate and accepter substrate p-nitrophenol. The structure is the first report of the native Michaelis complex of sulfotransferase. In the structure, three proposed catalytic residues (Lys48, Lys106, and His108) were in proper positions for engaging in the sulfuryl transfer reaction. The data strongly support that the sulfuryl transfer reaction proceeds through an S_N2-like in-line displacement mechanism.
Structural basis for the broad range substrate specificity of a novel mouse cytosolic sulfotransferase-mSULT1D1
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The mouse cytosolic sulfotransferase, mSULT1D1, catalyzes the sulfonation of a wide range of phenolic molecules including p-nitrophenol (pNP), α-naphthol (αNT), serotonin, as well as dopamine and its metabolites. To gain insight into the structural basis for its broad range substrate specificity, we solved two distinct ternary crystal structures of mSULT1D1, complexed with 3′-phosphoadenosine-5′-phosphate (PAP) plus pNP or PAP plus αNT. The structures revealed that the mSULT1D1 contains an L-shaped accepter-binding site which comprises 20 amino acid residues and four conserved water molecules. The shape of the accepter-binding site can be adjusted by conformational changes of two residues, Ile148 and Glu247, upon binding with respective substrates.

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^☆: Abbreviations: PST, phenol sulfotransferase; PAPS, 3′-phosphoadenosine 5′-phosphosulfate; SDS, sodium dodecyl sulfate; EST, expressed sequence tag

^☆☆: Mulder, G. J.

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Regular ArticleMolecular Cloning, Expression, and Functional Characterization of Novel Mouse Sulfotransferases☆,☆☆

Abstract

Chem.-Biol. Interact.

Biochim. Biophys. Acta

Anal. Biochem.

Anal. Biochem.

Biochim. Biophys. Acta

Chem.-Biol. Interact.

Biochem. Biophys. Res. Commun.

Genomics

J. Biol. Chem.

Science

Regular Article
Molecular Cloning, Expression, and Functional Characterization of Novel Mouse Sulfotransferases☆,☆☆