Sulfotransferase 4A1

Minchin, Rodney F.; Lewis, Aaron; Mitchell, Deanne J.; Kadlubar, Fred F.; McManus, Michael E.

doi:10.1016/j.biocel.2007.11.010

Cited by 25 publications

(23 citation statements)

References 19 publications

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“…Another interesting and perplexing discovery was the upregulation of SULT4A1 mRNA in NASH (not fatty/cirrhosis). SULT4A1 is almost exclusively expressed in brain, and is very highly conserved among species although it has no known endogenous ligand (Gamage et al, 2006;Minchin et al, 2008). One study has shown an elevation in hepatic SULT4A1 expression after ventromedial hypothalamic lesions, which are known to cause significant disruptions in metabolic homeostasis manifesting as obesity and hyperinsulinemia similar to that seen in metabolic syndrome, an accompanying feature of NAFLD (King, 2006;Kiba et al, 2009;McCullough, 2011).…”

Section: Discussionmentioning

confidence: 99%

Altered UDP-Glucuronosyltransferase and Sulfotransferase Expression and Function during Progressive Stages of Human Nonalcoholic Fatty Liver Disease

et al. 2012

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The UDP-glucuronosyltransferases (UGTs) and sulfotransferases (SULTs) represent major phase II drug-metabolizing enzymes that are also responsible for maintaining cellular homeostasis by metabolism of several endogenous molecules. Perturbations in the expression or function of these enzymes can lead to metabolic disorders and improper management of xenobiotics and endobiotics. Nonalcoholic fatty liver disease (NAFLD) represents a spectrum of liver damage ranging from steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis. Because the liver plays a central role in the metabolism of xenobiotics, the purpose of the current study was to determine the effect of human NAFLD progression on the expression and function of UGTs and SULTs in normal, steatosis, NASH (fatty), and NASH (not fatty/cirrhosis) samples. We identified upregulation of UGT1A9, 2B10, and 3A1 and SULT1C4 mRNA in both stages of NASH, whereas UGT2A3, 2B15, and 2B28 and SULT1A1, 2B1, and 4A1 as well as 39-phosphoadenosine-59-phosphosulfate synthase 1 were increased in NASH (not fatty/ cirrhosis) only. UGT1A9 and 1A6 and SULT1A1 and 2A1 protein levels were decreased in NASH; however, SULT1C4 was increased. Measurement of the glucuronidation and sulfonation of acetaminophen (APAP) revealed no alterations in glucuronidation; however, SULT activity was increased in steatosis compared with normal samples, but then decreased in NASH compared with steatosis. In conclusion, the expression of specific UGT and SULT isoforms appears to be differentially regulated, whereas sulfonation of APAP is disrupted during progression of NAFLD.

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Section: Discussionmentioning

confidence: 99%

Altered UDP-Glucuronosyltransferase and Sulfotransferase Expression and Function during Progressive Stages of Human Nonalcoholic Fatty Liver Disease

et al. 2012

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“…SULT4A1 mRNA can exist as two different transcripts depending on the splicing of an aberrant exon between exons 6 and 7 (Minchin et al, 2008). In Neuro2a cells, the variant transcript was the major transcript detected, whereas in the mouse primary neurons, only the wild-type transcript was detected (Fig.…”

Section: Overexpression Of Creb and Atf-2 Increases Sult4a1mentioning

confidence: 99%

“…which would produce a truncated protein (Minchin et al, 2008). The truncated protein may lack the antibody binding site(s), or the resultant protein may be rapidly degraded.…”

Section: Downloaded Frommentioning

confidence: 99%

“…Nevertheless, it is highly conserved between species and is found primarily in specific regions of the brain (Liyou et al, 2003). In humans, the SULT4A1 gene is located on chromosome 22 in a region often deleted in schizophrenia (Minchin et al, 2008). Surprisingly, mutations in the coding sequence are extremely rare, and SULT4A1 has the lowest overall mutation rate of all of the known human sulfotransferases (Hildebrandt et al, 2007;Lewis and Minchin, 2009).…”

Section: Introductionmentioning

confidence: 99%

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Regulation of Mouse Brain-Selective Sulfotransferase Sult4a1 by cAMP Response Element-Binding Protein and Activating Transcription Factor-2

Butcher

Mitchell²,

Burow³

et al. 2010

Mol Pharmacol

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Sulfotransferase 4A1 (SULT4A1) is a novel cytosolic sulfotransferase that is primarily expressed in the brain. To date, no significant enzyme activity or biological function for the protein has been identified, although it is highly conserved between species. Mutations in the SULT4A1 gene have been linked to schizophrenia susceptibility, and recently, its stability was shown to be regulated by Pin1, a peptidyl-prolyl cis-trans isomerase implicated in several neurodegenerative diseases. In this study, we investigated the transcriptional regulation of mouse Sult4a1. Using a series of promoter deletion constructs, we identified three cAMP-responsive elements (CREs) that were required for maximal promoter activity. The CREs are located within 100 base pairs of the major transcription start site and are also present in the same region of the human SULT4A1 promoter. Electrophoretic mobility shift assays (EMSAs) identified two specific complexes that formed on each of the CREs. One complex contained cAMP response element-binding protein (CREB), and the other contained activating transcription factor-2 (ATF-2) and c-Jun. Overexpression of CREB or ATF-2 increased not only reporter promoter activity but also endogenous Sult4a1 mRNA levels in ]enkephalin (DAMGO) treatment increased both reporter promoter activity and Sult4a1 levels in -opioid receptor expressing Neuro2a/-opioid receptor cells, and EMSAs showed this to be due to increased binding of CREB and ATF-2 to the Sult4a1 promoter. We also show that DAMGO treatment increases Sult4a1 mRNA and protein levels in primary mouse neurons. These results suggest that Sult4a1 is a target gene for the -opioid receptor signaling pathway and other pathways involving activation of CREB and ATF-2.

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“…A number of independent clones were identified, and their binding to SULT4A1 was confirmed. One set of clones was SULT4A1 itself, which is expected given that the cytosolic sulfotransferases, including SULT4A1, contain a dimerization site in their C termini (Minchin et al, 2008). A second set of clones contained the complete open-reading frame for Pin1, a ubiquitously expressed protein that belongs to the parvulin family of peptidyl-prolyl cis-trans isomerases.…”

Section: Resultsmentioning

confidence: 99%

Cytosolic Aryl Sulfotransferase 4A1 Interacts with the Peptidyl Prolyl Cis-Trans Isomerase Pin1

Mitchell

Minchin²

2009

Mol Pharmacol

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Sulfonation by cytosolic sulfotransferases plays an important role in the metabolism of both endogenous and exogenous compounds. Sulfotransferase 4A1 (SULT4A1) is a novel sulfotransferase found primarily in neurons in the brain. It is highly conserved between species, but no substantial enzyme activity has been identified for the protein. Consequently, little is known about the role of this enzyme in the brain. We performed a yeast two-hybrid screen of a human brain library to isolate potential SULT4A1-interacting proteins that might identify the role or regulation of the sulfotransferase in humans. The screen isolated the peptidyl-prolyl cis-trans isomerase Pin1. Its interaction with SULT4A1 was confirmed by coimmunoprecipitation studies in HeLa cells and by in vitro pull-down of expressed proteins. Moreover, Pin1 binding was dependent on phosphorylation of the SULT4A1 protein. Pin1 destabilized SULT4A1, decreasing its half-life from more than 8 h to approximately 4.5 h. This effect was dependent on the isomerase activity of Pin1 and was inhibited by okadaic acid, suggesting a role for the phosphatase PP2A. Pin1-mediated SULT4A1 degradation did not involve the proteosomes or macroautophagy, but it was inhibited by the calpain antagonists N-acetyl-Leu-Leu-Nle-CHO and Z-Val-Phe-CHO. Finally, Pin1 binding was mapped to two threonine-proline motifs (Thr 8 and Thr 11 ) that are not present in any of the other human cytosolic sulfotransferases. Our findings suggest that SULT4A1 is subject to post-translational modification that alters its stability in the cell. These modifications may also be important for enzyme activity, which explains why specific substrates for SULT4A1 have not yet been identified.

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Sulfotransferase 4A1

Cited by 25 publications

References 19 publications

Altered UDP-Glucuronosyltransferase and Sulfotransferase Expression and Function during Progressive Stages of Human Nonalcoholic Fatty Liver Disease

Altered UDP-Glucuronosyltransferase and Sulfotransferase Expression and Function during Progressive Stages of Human Nonalcoholic Fatty Liver Disease

Regulation of Mouse Brain-Selective Sulfotransferase Sult4a1 by cAMP Response Element-Binding Protein and Activating Transcription Factor-2

Cytosolic Aryl Sulfotransferase 4A1 Interacts with the Peptidyl Prolyl Cis-Trans Isomerase Pin1

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