Download MendeleyStructure of a gut microbial diltiazem-metabolizing enzyme suggests possible substrate binding mode.
Zhou, S., Ko, T.P., Huang, J.W., Liu, W., Zheng, Y., Wu, S., Wang, Q., Xie, Z., Liu, Z., Chen, C.C., Guo, R.T.(2020) Biochem Biophys Res Commun 527: 799-804
- PubMed: 32423809
- DOI: https://doi.org/10.1016/j.bbrc.2020.04.116
- Primary Citation of Related Structures:
7BR2 - PubMed Abstract:
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.
Organizational Affiliation:
School of Life Science, University of Science and Technology of China, Anhui, 230026, China; Industrial Enzymes National Engineering Laboratory, Tianjin Institute of Industrial Biotechnology, Chinese Academy of Sciences, Tianjin, 300308, China.
