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3'-Phosphoadenosine 5'-phosphosulfate allosterically regulates sulfotransferase turnover.

Wang T, Cook I, Leyh TS - Biochemistry (2014)

Bottom Line: The first nucleotide to bind causes closure of the cap to which it is bound and at the same time stabilizes the cap in the adjacent subunit in the open position.Cap closure sterically controls active-site access of the nucleotide and acceptor; consequently, the structural changes in the cap that occur as a function of nucleotide occupancy lead to changes in the substrate affinities and turnover of the enzyme.PAPS levels in tissues from a variety of organs suggest that the catalytic efficiency of the enzyme varies across tissues over the full 130-fold range and that efficiency is greatest in those tissues that experience the greatest xenobiotic "load".

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine , 1300 Morris Park Avenue, Bronx, New York 10461-1926, United States.

ABSTRACT
Human cytosolic sulfotransferases (SULTs) regulate the activities of thousands of small molecules-metabolites, drugs, and other xenobiotics-via the transfer of the sulfuryl moiety (-SO3) from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to the hydroxyls and primary amines of acceptors. SULT1A1 is the most abundant SULT in liver and has the broadest substrate spectrum of any SULT. Here we present the discovery of a new form of SULT1A1 allosteric regulation that modulates the catalytic efficiency of the enzyme over a 130-fold dynamic range. The molecular basis of the regulation is explored in detail and is shown to be rooted in an energetic coupling between the active-site caps of adjacent subunits in the SULT1A1 dimer. The first nucleotide to bind causes closure of the cap to which it is bound and at the same time stabilizes the cap in the adjacent subunit in the open position. Binding of the second nucleotide causes both caps to open. Cap closure sterically controls active-site access of the nucleotide and acceptor; consequently, the structural changes in the cap that occur as a function of nucleotide occupancy lead to changes in the substrate affinities and turnover of the enzyme. PAPS levels in tissues from a variety of organs suggest that the catalytic efficiency of the enzyme varies across tissues over the full 130-fold range and that efficiency is greatest in those tissues that experience the greatest xenobiotic "load".

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Predicted fraction of E·(PAPS)2 in humantissues.Fractions were calculated using reported PAPS concentrations.24−27
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fig6: Predicted fraction of E·(PAPS)2 in humantissues.Fractions were calculated using reported PAPS concentrations.24−27

Mentions: For the PAPS concentrationto be used to regulate SULT1A1 reactivity in the cell, its in vivo concentration must be sufficiently high to populatethe second nucleotide binding site. PAPS levels have been quantitatedin numerous human tissues that express SULT1A1,24−27 and its concentrations can becalculated using tissue-specific, weight/volume conversion factors.28 While these calculations are gross in that theyassume a uniform distribution of nucleotide throughout the tissue,they nevertheless provide a likely lower limit of the cellular PAPSconcentration. These concentrations were used to calculate the fractionof dimers that have PAPS bound at both subunits in the various tissues(Figure 6). The calculations predict that PAPSconcentrations in all tissues are sufficiently high to saturate thefirst subunit, but only in certain tissues is it high enough to substantiallypopulate the second.


3'-Phosphoadenosine 5'-phosphosulfate allosterically regulates sulfotransferase turnover.

Wang T, Cook I, Leyh TS - Biochemistry (2014)

Predicted fraction of E·(PAPS)2 in humantissues.Fractions were calculated using reported PAPS concentrations.24−27
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4230322&req=5

fig6: Predicted fraction of E·(PAPS)2 in humantissues.Fractions were calculated using reported PAPS concentrations.24−27
Mentions: For the PAPS concentrationto be used to regulate SULT1A1 reactivity in the cell, its in vivo concentration must be sufficiently high to populatethe second nucleotide binding site. PAPS levels have been quantitatedin numerous human tissues that express SULT1A1,24−27 and its concentrations can becalculated using tissue-specific, weight/volume conversion factors.28 While these calculations are gross in that theyassume a uniform distribution of nucleotide throughout the tissue,they nevertheless provide a likely lower limit of the cellular PAPSconcentration. These concentrations were used to calculate the fractionof dimers that have PAPS bound at both subunits in the various tissues(Figure 6). The calculations predict that PAPSconcentrations in all tissues are sufficiently high to saturate thefirst subunit, but only in certain tissues is it high enough to substantiallypopulate the second.

Bottom Line: The first nucleotide to bind causes closure of the cap to which it is bound and at the same time stabilizes the cap in the adjacent subunit in the open position.Cap closure sterically controls active-site access of the nucleotide and acceptor; consequently, the structural changes in the cap that occur as a function of nucleotide occupancy lead to changes in the substrate affinities and turnover of the enzyme.PAPS levels in tissues from a variety of organs suggest that the catalytic efficiency of the enzyme varies across tissues over the full 130-fold range and that efficiency is greatest in those tissues that experience the greatest xenobiotic "load".

View Article: PubMed Central - PubMed

Affiliation: Department of Microbiology and Immunology, Albert Einstein College of Medicine , 1300 Morris Park Avenue, Bronx, New York 10461-1926, United States.

ABSTRACT
Human cytosolic sulfotransferases (SULTs) regulate the activities of thousands of small molecules-metabolites, drugs, and other xenobiotics-via the transfer of the sulfuryl moiety (-SO3) from 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to the hydroxyls and primary amines of acceptors. SULT1A1 is the most abundant SULT in liver and has the broadest substrate spectrum of any SULT. Here we present the discovery of a new form of SULT1A1 allosteric regulation that modulates the catalytic efficiency of the enzyme over a 130-fold dynamic range. The molecular basis of the regulation is explored in detail and is shown to be rooted in an energetic coupling between the active-site caps of adjacent subunits in the SULT1A1 dimer. The first nucleotide to bind causes closure of the cap to which it is bound and at the same time stabilizes the cap in the adjacent subunit in the open position. Binding of the second nucleotide causes both caps to open. Cap closure sterically controls active-site access of the nucleotide and acceptor; consequently, the structural changes in the cap that occur as a function of nucleotide occupancy lead to changes in the substrate affinities and turnover of the enzyme. PAPS levels in tissues from a variety of organs suggest that the catalytic efficiency of the enzyme varies across tissues over the full 130-fold range and that efficiency is greatest in those tissues that experience the greatest xenobiotic "load".

Show MeSH
Related in: MedlinePlus