Crystal structure of human sulfotransferase SULT1A3 in complex with dopamine and 3′-phosphoadenosine 5′-phosphate

Lu, Jinghua; Li, Haitao; Liu, Ming‐Cheh; Zhang, Jiping; Li, Mei; An, Xiaohong; Chang, Wenrui

doi:10.1016/j.bbrc.2005.07.091

Cited by 60 publications

(73 citation statements)

References 25 publications

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“…In the upper left of Fig. 4, the residues corresponding to Tyr-238 of SULT2A1 have been highlighted and are as follows: Phe-247 of human SULT1A1, Leu-247 of human SULT1A3, Met-247 of mouse SULT1E1, and Leu-249 of human SULT2B1_v1 (Kakuta et al, 1997;Gamage et al, 2003;Lee et al, 2003;Lu et al, 2005). This comparison leads us to hypothesize that the Tyr-238 corresponding residue in other sulfotransferases may play a similar role in substrate inhibition because these residues all demonstrate possible steric hindrance for the release of substrate from the substrate-binding cavity, and therefore they may modulate substrate inhibition for their own preferred substrates.…”

Section: Dissociation Constants Of Pap Dhea and Adt In Binary And Tmentioning

confidence: 99%

Identification and Characterization of Two Amino Acids Critical for the Substrate Inhibition of Human Dehydroepiandrosterone Sulfotransferase (SULT2A1)

Hsieh

Liu

et al. 2007

Mol Pharmacol

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Substrate inhibition is a characteristic feature of many cytosolic sulfotransferases. The differences between the complex structures of SULT2A1/DHEA and SULT2A1/PAP or SULT2A1/ADT (Protein Data Bank codes are 1J99, 1EFH, and 1OV4, respectively) have enabled us to elucidate the specific amino acids responsible for substrate inhibition. Based on the structural analyses, substitution of the smaller residue alanine for Tyr-238 (Y238A) significantly increases the K i value for dehydroepiandrosterone (DHEA) and totally eliminates substrate inhibition for androsterone (ADT). In addition, Met-137 was proposed to regulate the binding orientations of DHEA and ADT in SULT2A1. Complete elimination or regeneration of substrate inhibition for SULT2A1 with DHEA or ADT as substrate, respectively, was demonstrated with the mutations of Met-137 on Y238A mutant. Analysis of the Met-137 mutants and Met-137/ Tyr-238 double mutants uncovered the relationship between substrate binding orientations and inhibition in SULT2A1. Our data indicate that, in the substrate inhibition mode, Tyr-238 regulates the release of bound substrate, and Met-137 controls substrate binding orientation of DHEA and ADT in SULT2A1. The proposed substrate inhibition mechanism is further confirmed by the crystal structures of SULT2A1 mutants at Met-137. We propose that both substrate binding orientations exhibited substrate inhibition. In addition, a corresponding residue in other cytosolic sulfotransferases was shown to have a function similar to that of Tyr-238 in SULT2A1.

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Section: Dissociation Constants Of Pap Dhea and Adt In Binary And Tmentioning

confidence: 99%

Identification and Characterization of Two Amino Acids Critical for the Substrate Inhibition of Human Dehydroepiandrosterone Sulfotransferase (SULT2A1)

Hsieh

Liu

et al. 2007

Mol Pharmacol

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“…METH treatment is known to cause the change of dopamine in CNS. Dopamine is one of the most important endogenous neurotransmitters as well as an important endogenous substrate of SULTs (Yasuda et al, 2009;Salman et al, 2009;Lu et al, 2005). It has been demonstrated that the expression of CYPs can be regulated by dopamine receptor-linked signaling pathway by changing the hormone (GH, thyroid hormones, glucocorticoids and so on) levels in vivo (Wojcikowski, 2004;Wojcikowski et al, 2007;2008;Konstandi et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

Methamphetamine Regulation of Sulfotransferases in Rat Liver and Brain

Zhou¹

2010

American Journal of Pharmacology and Toxicology

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Problem statement: Sulfotransferases (SULTs) are important phase II drug metabolizing enzymes. They also regulate the biological activities of various hormones. To the best of our knowledge, psychostimulants regulation of SULTs is basically not studied except one article reported that Methamphetamine (METH) treatment induced rat amygdale rSULT1A1 mRNA 4.3 fold by using microarray method to identify a series of candidate genes after single-dose METH treatment. The psychostimulant METH is used to treat disorders such as attention deficit, narcolepsy and obesity. It is also a highly addictive drug that causes serious social problems. The abuse of this drug leads to the damage of monoaminergic systems in the mammalian brain. It is important to understand how SULT expressions are regulated by psychostimulants. Approach: This study was performed to evaluate the effect of METH on SULT gene expressions in rat liver and brain. METH (0, 1, 5, 20 mg kg −1 day −1 ) was used to treat male and female rats for 7 days by oral administration. Rat livers and brains were collected 24 h after the final drug treatment. Western blot and real-time RT-PCR were used to investigate the effect of METH on SULT protein and mRNA expression, respectively, in rat liver and brain. Results: Proteins and mRNAs of rSULT1A1, rSULT2A1 and rSULT1E1 were induced in liver and brain of both male and female rats following METH treatment. rSULT1E1 was induced at much higher level compared to that of rSULT1A1 and rSULT2A1. Brain inductions were found to be much higher than those found in liver. Conclusion: These data suggest an important role of the central dopaminergic system in the regulation of liver and brain rSULT expressions.

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“…Molecular dynamics modeling. SWISS-MODEL (26) was used to create a ligandfree model of SULT1A1 from the SULT1A1·PAP (Protein Data Bank ID code 3G3M) structure (27), which was missing 23 atoms. The model was protonated at pH 7.4, and energy was minimized in GROMACS (28).…”

Section: Methodsmentioning

confidence: 99%

The structure of the catechin-binding site of human sulfotransferase 1A1

Cook

Wang

Girvin

et al. 2016

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

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We are just beginning to understand the allosteric regulation of the human cytosolic sulfotransferase (SULTs) family-13 disease-relevant enzymes that regulate the activities of hundreds, if not thousands, of signaling small molecules. SULT1A1, the predominant isoform in adult liver, harbors two noninteracting allosteric sites, each of which binds a different molecular family: the catechins (naturally occurring flavonols) and nonsteroidal antiinflammatory drugs (NSAIDs). Here, we present the structure of an SULT allosteric binding site-the catechin-binding site of SULT1A1 bound to epigallocatechin gallate (EGCG). The allosteric pocket resides in a dynamic region of the protein that enables EGCG to control opening and closure of the enzyme's active-site cap. Furthermore, the structure offers a molecular explanation for the isozyme specificity of EGCG, which is corroborated experimentally. The bindingsite structure was obtained without X-ray crystallography or multidimensional NMR. Instead, a SULT1A1 apoprotein structure was used to guide positioning of a small number of spin-labeled single-Cys mutants that coat the entire enzyme surface with a paramagnetic field of sufficient strength to determine its contribution to the bound ligand's transverse (T 2 ) relaxation from its 1D solution spectrum. EGCG protons were mapped to the protein surface by triangulation using the T 2 values to calculate their distances to a trio of spin-labeled Cys mutants. The final structure was obtained using distance-constrained molecular dynamics docking. This approach, which is readily extensible to other systems, is applicable over a wide range of ligand affinities, requires little protein, avoids the need for isotopically labeled protein, and has no protein molecular weight limitations.sulfotransferase | structure | NMR | allostery | catechin C ytosolic SULTs regulate disease-relevant process in virtually every tissue in the human body (1-5). This small family of broadspecificity enzymes regulates the activities of hundreds, perhaps thousands, of signaling small molecules (e.g., endogenous metabolites, drugs, and other xenobiotics) via regiospecific transfer of the sulfuryl moiety (-SO 3 ) from 3′-phosphoadenosine 5′-phosphosulfate (PAPS) to the hydroxyls and amines of acceptors (1, 6). Sulfonation often radically alters the interactions of a compound with its target and substantially enhances the target's solubility, transport, and clearance (1, 6, 7). Through these and other mechanisms, SULTs contribute in critical ways to maintaining signaling homeostasis and neutralizing toxins (6,8).Given their wide-ranging roles in regulating cellular processes, it is perhaps expected that SULTs would have evolved means of communicating with their environments-mechanisms that enable them to read and respond to the small-molecule composition of their "milieu." Early screening studies intimated that SULTs might be subject to small-molecule allosteric control (9, 10), and recent work confirms this (11). SULT1A1, the most abundant isoform in adult h...

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Crystal structure of human sulfotransferase SULT1A3 in complex with dopamine and 3′-phosphoadenosine 5′-phosphate

Cited by 60 publications

References 25 publications

Identification and Characterization of Two Amino Acids Critical for the Substrate Inhibition of Human Dehydroepiandrosterone Sulfotransferase (SULT2A1)

Identification and Characterization of Two Amino Acids Critical for the Substrate Inhibition of Human Dehydroepiandrosterone Sulfotransferase (SULT2A1)

Methamphetamine Regulation of Sulfotransferases in Rat Liver and Brain

The structure of the catechin-binding site of human sulfotransferase 1A1

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