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3'-Phosphoadenosine 5'-phosphosulfate allosterically regulates sulfotransferase turnover.
Ting Wang1, Ian Cook, Thomas S Leyh
1Department of Microbiology and Immunology, Albert Einstein College of Medicine , 1300 Morris Park Avenue, Bronx, New York 10461-1926, United States.
Biochemistry
|October 15, 2014
Summary
Human cytosolic sulfotransferases (SULTs) regulate drug and metabolite activity. A newly discovered allosteric regulation in SULT1A1 modulates its efficiency across tissues, impacting xenobiotic metabolism.
Area of Science:
- Biochemistry
- Enzymology
- Drug Metabolism
Background:
- Human cytosolic sulfotransferases (SULTs) are crucial enzymes involved in the metabolism of numerous endogenous and exogenous compounds.
- SULT1A1, the most abundant SULT in the liver, exhibits a broad substrate specificity, making it a key player in xenobiotic detoxification.
Purpose of the Study:
- To discover and characterize a novel allosteric regulatory mechanism of SULT1A1.
- To elucidate the molecular basis of this allosteric regulation and its impact on enzyme catalytic efficiency.
Main Methods:
- Detailed structural and biochemical analyses of SULT1A1.
- Investigation of nucleotide binding and its effect on enzyme conformation and activity.
Main Results:
- A new form of SULT1A1 allosteric regulation was identified, altering catalytic efficiency over a 130-fold range.
- This regulation is mediated by energetic coupling between active-site caps in SULT1A1 dimers, influenced by nucleotide binding.
- Nucleotide binding induces conformational changes in active-site caps, affecting substrate access and enzyme turnover.
Conclusions:
- SULT1A1 activity is dynamically regulated by allosteric mechanisms involving nucleotide binding and conformational changes.
- Tissue-specific variations in 3"-phosphoadenosine 5"-phosphosulfate (PAPS) levels suggest that SULT1A1 catalytic efficiency varies significantly across organs.
- Enzyme efficiency is highest in tissues with substantial xenobiotic exposure, indicating an adaptive metabolic response.
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