3′-Phosphoadenosine 5′-phosphosulfate allosterically regulates sulfotransferase turnover

Research output: Contribution to journalArticle

17 Citations (Scopus)

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 (-SO<inf>3</inf>) 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".

Original languageEnglish (US)
Pages (from-to)6893-6900
Number of pages8
JournalBiochemistry
Volume53
Issue number44
DOIs
StatePublished - Nov 11 2014

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Phosphoadenosine Phosphosulfate
Sulfotransferases
Nucleotides
Xenobiotics
Tissue
Catalytic Domain
Enzymes
Allosteric Regulation
Substrates
Metabolites
Hydroxyl Radical
Dimers
Liver
Amines
Molecules
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Biochemistry
  • Medicine(all)

Cite this

3′-Phosphoadenosine 5′-phosphosulfate allosterically regulates sulfotransferase turnover. / Wang, Ting; Cook, Ian T.; Leyh, Thomas S.

In: Biochemistry, Vol. 53, No. 44, 11.11.2014, p. 6893-6900.

Research output: Contribution to journalArticle

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