Sulfation is a major biochemical pathway in humans for the biotransformation and excretion of drugs and endogenous compounds, such as steroids and catecholamines. The overall goal of this project is to investigate the biochemistry and molecular biology of the human cytosolic sulfotransferases (STs) and to understand the role of sulfation in the metabolism of drugs, xenobiotics and endogenous substrates in normal and cancerous human tissues. Several human STs have already been identified. Continuing with the aims of the previous application, two additional unique forms of human cytosolic ST are being characterized.
The Specific Aims of this project are expanded to include the investigation of the protein chemistry and molecular biology of all human cytosolic STs. This proposal focuses on the characterization of the six human cytosolic STs which have been identified and will also focus on the role of the STs in regulating estrogen-responsiveness of normal and cancerous breast cells.
The Specific Aims of this proposal are to: 1) characterize the structure and properties of the two recently identified forms of human ST; 2) investigate the structure, properties and functions of the human PSTs, DHEA-ST and EST; 3) investigate the expression of the human STs in normal and cancerous breast tissue, in primary breast epithelial cells, and in breast cancer cell lines; 4) investigate the responsiveness of MCF-7 breast cancer cells either expressing EST or over-expressing P-PST to 17-estradiol and to estrogens used for estrogen supplementation; 5) investigate the role of EST and P-PST in the response of breast cancer cells to endogenous, therapeutic and environmental estrogens.

Agency
National Institute of Health (NIH)
Institute
National Institute of General Medical Sciences (NIGMS)
Type
Research Project (R01)
Project #
5R01GM038953-13
Application #
2734585
Study Section
Pharmacology A Study Section (PHRA)
Project Start
1987-07-01
Project End
2000-06-30
Budget Start
1998-07-01
Budget End
1999-06-30
Support Year
13
Fiscal Year
1998
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Pharmacology
Type
Schools of Dentistry
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
Tibbs, Zachary E; Guidry, Amber L; Falany, Josie L et al. (2018) A high frequency missense SULT1B1 allelic variant (L145V) selectively expressed in African descendants exhibits altered kinetic properties. Xenobiotica 48:79-88
Guidry, Amber L; Tibbs, Zachary E; Runge-Morris, Melissa et al. (2017) Expression, purification and characterization of human cytosolic sulfotransferase (SULT) 1C4. Horm Mol Biol Clin Investig 29:27-36
Tibbs, Zachary E; Falany, Charles N (2016) An engineered heterodimeric model to investigate SULT1B1 dependence on intersubunit communication. Biochem Pharmacol 115:123-33
Tibbs, Zachary E; Rohn-Glowacki, Katie Jo; Crittenden, Frank et al. (2015) Structural plasticity in the human cytosolic sulfotransferase dimer and its role in substrate selectivity and catalysis. Drug Metab Pharmacokinet 30:3-20
Tibbs, Zachary E; Falany, Charles N (2015) Dimeric human sulfotransferase 1B1 displays cofactor-dependent subunit communication. Pharmacol Res Perspect 3:e00147
Wang, Ting; Cook, Ian; Falany, Charles N et al. (2014) Paradigms of sulfotransferase catalysis: the mechanism of SULT2A1. J Biol Chem 289:26474-80
Duniec-Dmuchowski, Zofia; Rondini, Elizabeth A; Tibbs, Zachary E et al. (2014) Expression of the orphan cytosolic sulfotransferase SULT1C3 in human intestine: characterization of the transcript variant and implications for function. Drug Metab Dispos 42:352-60
Rohn-Glowacki, Katie Jo; Falany, Charles N (2014) The potent inhibition of human cytosolic sulfotransferase 1A1 by 17?-ethinylestradiol is due to interactions with isoleucine 89 on loop 1. Horm Mol Biol Clin Investig 20:81-90
Cook, Ian; Wang, Ting; Almo, Steven C et al. (2013) The gate that governs sulfotransferase selectivity. Biochemistry 52:415-24
Leyh, Thomas S; Cook, Ian; Wang, Ting (2013) Structure, dynamics and selectivity in the sulfotransferase family. Drug Metab Rev 45:423-30

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