Sequence similarity network analysis of drug- and dye-modifying azoreductase enzymes found in the human gut microbiome.

Autor: Long AR; Department of Chemistry and Biochemistry, Providence College, 1 Cunningham Square, Providence, RI, 02918, United States., Mortara EL; Department of Chemistry and Biochemistry, Providence College, 1 Cunningham Square, Providence, RI, 02918, United States., Mendoza BN; Department of Chemistry and Biochemistry, Providence College, 1 Cunningham Square, Providence, RI, 02918, United States., Fink EC; Department of Chemistry and Biochemistry, Providence College, 1 Cunningham Square, Providence, RI, 02918, United States., Sacco FX; Department of Chemistry and Biochemistry, Providence College, 1 Cunningham Square, Providence, RI, 02918, United States., Ciesla MJ; Department of Chemistry and Biochemistry, Providence College, 1 Cunningham Square, Providence, RI, 02918, United States., Stack TMM; Department of Chemistry and Biochemistry, Providence College, 1 Cunningham Square, Providence, RI, 02918, United States. Electronic address: tstack@providence.edu.
Jazyk: angličtina
Zdroj: Archives of biochemistry and biophysics [Arch Biochem Biophys] 2024 Jul; Vol. 757, pp. 110025. Date of Electronic Publication: 2024 May 11.
DOI: 10.1016/j.abb.2024.110025
Abstrakt: Drug metabolism by human gut microbes is often exemplified by azo bond reduction in the anticolitic prodrug sulfasalazine. Azoreductase activity is often found in incubations with cell cultures or ex vivo gut microbiome samples and contributes to the xenobiotic metabolism of drugs and food additives. Applying metagenomic studies to personalized medicine requires knowledge of the genes responsible for sulfasalazine and other drug metabolism, and candidate genes and proteins for drug modifications are understudied. A representative gut-abundant azoreductase from Anaerotignum lactatifermentan DSM 14214 efficiently reduces sulfasalazine and another drug, phenazopyridine, but could not reduce all azo-bonded drugs in this class. We used enzyme kinetics to characterize this enzyme for its NADH-dependent reduction of these drugs and food additives and performed computational docking to provide the groundwork for understanding substrate specificity in this family. We performed an analysis of the Flavodoxin-like fold InterPro family (IPR003680) by computing a sequence similarity network to classify distinct subgroups of the family and then performed chemically-guided functional profiling to identify proteins that are abundant in the NIH Human Microbiome Project dataset. This strategy aims to reduce the number of unique azoreductases needed to characterize one protein family in the diverse set of potential drug- and dye-modifying activities found in the human gut microbiome.
Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
(Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze: MEDLINE
Externí odkaz: