Structure of a gut microbial diltiazem-metabolizing enzyme suggests possible substrate binding mode

Biochem Biophys Res Commun. 2020 Jun 30;527(3):799-804. doi: 10.1016/j.bbrc.2020.04.116. Epub 2020 May 16.


When administrated orally, the vasodilating drug diltiazem can be metabolized into diacetyl diltiazem in the presence of Bacteroides thetaiotaomicron, a human gut microbe. The removal of acetyl group from the parent drug is carried out by the GDSL/SGNH-family hydrolase BT4096. Here the crystal structure of the enzyme was solved by mercury soaking and single-wavelength anomalous diffraction. The protein folds into two parts. The N-terminal part comprises the catalytic domain which is similar to other GDSL/SGNH hydrolases. The flanking C-terminal part is made up of a β-barrel subdomain and an α-helical subdomain. Structural comparison shows that the catalytic domain is most akin to acetyl-xylooligosaccharide esterase and allows a plausible binding mode of diltiazem to be proposed. The β-barrel subdomain is similar in topology to the immunoglobulin-like domains, including some carbohydrate-binding modules, of various bacterial glycoside hydrolases. Consequently, BT4096 might originally function as an oligosaccharide deacetylase with additional subdomains that could enhance substrate binding, and it acts on diltiazem just by accident.

Keywords: Diltiazem; GDSL/SGNH-Family hydrolase; Gut microbiota; X-ray crystallography.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acetylation
  • Bacterial Proteins / chemistry
  • Bacterial Proteins / metabolism*
  • Bacteroides thetaiotaomicron / chemistry
  • Bacteroides thetaiotaomicron / enzymology*
  • Bacteroides thetaiotaomicron / metabolism
  • Catalytic Domain
  • Diltiazem / metabolism*
  • Gastrointestinal Microbiome*
  • Humans
  • Hydrolases / chemistry
  • Hydrolases / metabolism*
  • Models, Molecular
  • Protein Conformation
  • Substrate Specificity
  • Vasodilator Agents / metabolism*


  • Bacterial Proteins
  • Vasodilator Agents
  • Hydrolases
  • Diltiazem