Abstract

of Work: Metabolism by sulfotransferases is an inactivation of biological signals such as steroid hormones and also a defense system against environmental toxicants and carcinogens. To encounter virtually unlimited numbers of structurally diverse chemiclas, these enzymes exhibit broad substrate specificity. Thus, it is important to investigate the structural principle determining the substrate specificity in order to predict the metabolisms and the resulted consequences to human susceptibililty to chemical exposure. For the investigation, we have used x-ray crystallography and site-directed mutagenesis. We have solved the crystal structure of estrogen sulfotransferase (EST) complexed with PAP and estradiol and that with PAP and vanadate. These structures provided the insight into understanding the reaction mechanism catalyzed by sulfotransferase. Site-directed mutagenesis based on the structres defined the stricture- like gate in the substrate pocket of EST that confers estrogen specificity to the enzyme. - Sulfotranserase, x-ray crystallography, enzyme action, site-directed mutagenesis, protein expression and purification

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Environmental Health Sciences (NIEHS)
Type
Intramural Research (Z01)
Project #
1Z01ES071005-01
Application #
6227948
Study Section
Special Emphasis Panel (LRDT)
Project Start
Project End
Budget Start
Budget End
Support Year
1
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
National Institute of Environmental Health Sciences
Department
Type
DUNS #
City
State
Country
United States
Zip Code

  Publications

Hashiguchi, Takuyu; Shindo, Sawako; Chen, Shih-Heng et al. (2018) Sulfotransferase 4A1 Increases Its Expression in Mouse Neurons as They Mature. Drug Metab Dispos 46:860-864
Negishi, Masahiko (2017) Phenobarbital Meets Phosphorylation of Nuclear Receptors. Drug Metab Dispos 45:532-539
Hori, Takeshi; Moore, Rick; Negishi, Masahiko (2016) p38 MAP Kinase Links CAR Activation and Inactivation in the Nucleus via Phosphorylation at Threonine 38. Drug Metab Dispos 44:871-6
Li, Linhao; Li, Haishan; Garzel, Brandy et al. (2015) SLC13A5 is a novel transcriptional target of the pregnane X receptor and sensitizes drug-induced steatosis in human liver. Mol Pharmacol 87:674-82
Gotoh, Saki; Negishi, Masahiko (2015) Statin-activated nuclear receptor PXR promotes SGK2 dephosphorylation by scaffolding PP2C to induce hepatic gluconeogenesis. Sci Rep 5:14076
Sueyoshi, Tatsuya; Li, Linhao; Wang, Hongbing et al. (2014) Flame retardant BDE-47 effectively activates nuclear receptor CAR in human primary hepatocytes. Toxicol Sci 137:292-302
Saito, Kosuke; Moore, Rick; Negishi, Masahiko (2013) Nuclear receptor CAR specifically activates the two-pore K+ channel Kcnk1 gene in male mouse livers, which attenuates phenobarbital-induced hepatic hyperplasia. Toxicol Sci 132:151-61
Shindo, Sawako; Sakuma, Tsutomu; Negishi, Masahiko et al. (2012) Phosphorylation of serine 212 confers novel activity to human estrogen receptor ?. Steroids 77:448-53
Yamazaki, Yuichi; Moore, Rick; Negishi, Masahiko (2011) Nuclear receptor CAR (NR1I3) is essential for DDC-induced liver injury and oval cell proliferation in mouse liver. Lab Invest 91:1624-33
Yamamoto, Yukio; Moore, Rick; Flavell, Richard A et al. (2010) Nuclear receptor CAR represses TNFalpha-induced cell death by interacting with the anti-apoptotic GADD45B. PLoS One 5:e10121

Showing the most recent 10 out of 47 publications