The crystal structure of mouse SULT2A8 reveals the mechanism of 7α-hydroxyl, bile acid sulfation

Biochem Biophys Res Commun. 2021 Jul 12:562:15-20. doi: 10.1016/j.bbrc.2021.04.113. Epub 2021 May 21.

Abstract

Bile acids play essential roles in facilitating the intestinal absorption of lipophilic nutrients as well as regulation of glucose, lipid, and energy homeostasis via activation of some receptors. Bile acids are cytotoxic, and consequently their concentrations are tightly controlled. A critical pathway for bile acid elimination and detoxification is sulfation. The pattern of bile acid sulfation differs by species. Sulfation preferentially occurs at the 3α-OH of bile acids in humans, but at the 7α-OH in mice. A recent study identified mouse cytosolic sulfotransferase 2A8 (mSULT2A8) as the major hepatic 7α-hydroxyl bile acid-sulfating enzyme. To elucidate the 7α-OH specific sulfation mechanism of mSULT2A8, instead of 3α-OH specific sulfation in humans, we determined a crystal structure of mSULT2A8 in complex with cholic acid, a major bile acid, and 3'-phosphoadenosine-5'-phosphate, the sulfate donor product. Our study shows that bile acid-binding mode of mSULT2A8 and how the enzyme holds the 7α-OH group of bile acids at the catalytic center, revealing that the mechanism underlying 7α-OH specific sulfation. The structure shows the substrate binds to mSULT2A8 in an orientation perpendicular to that of human 3α-hydroxyl bile acid-sulfotransferase (hSULT2A1). The structure of the complex provides new insight into species different bile acid metabolism.

Keywords: Bile acid and salts/metabolism; Bile acid metabolism; Cytosolic sulfotransferase; Enzymology; Liver; Species differences; Sulfation; X-ray crystallography.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amino Acid Sequence
  • Animals
  • Bile Acids and Salts / metabolism*
  • Binding Sites
  • Biocatalysis
  • Crystallography, X-Ray
  • Humans
  • Kinetics
  • Mice
  • Models, Molecular
  • Mutant Proteins / chemistry
  • Mutant Proteins / metabolism
  • Substrate Specificity
  • Sulfates / metabolism*
  • Sulfotransferases / chemistry*
  • Sulfotransferases / metabolism

Substances

  • Bile Acids and Salts
  • Mutant Proteins
  • Sulfates
  • Sulfotransferases
  • Sult2a8 protein, mouse