Substrate space analysis of the bacterial proton-coupled oligopeptide transporter YdgR by cheminformatics
Research output: Contribution to journal › Journal article › Research › peer-review
Standard
Substrate space analysis of the bacterial proton-coupled oligopeptide transporter YdgR by cheminformatics. / Sajid, Salvia; Nielsen, Marcus M K; Khalil, Ruqaiya; Hansen, Paul R; Franzyk, Henrik; Jørgensen, Mikkel Girke; Christensen, Lars P; Mirza, Osman; Prabhala, Bala Krishna.
In: FEMS Microbiology Letters, Vol. 370, fnad052, 2023.Research output: Contribution to journal › Journal article › Research › peer-review
Harvard
APA
Vancouver
Author
Bibtex
}
RIS
TY - JOUR
T1 - Substrate space analysis of the bacterial proton-coupled oligopeptide transporter YdgR by cheminformatics
AU - Sajid, Salvia
AU - Nielsen, Marcus M K
AU - Khalil, Ruqaiya
AU - Hansen, Paul R
AU - Franzyk, Henrik
AU - Jørgensen, Mikkel Girke
AU - Christensen, Lars P
AU - Mirza, Osman
AU - Prabhala, Bala Krishna
N1 - © The Author(s) 2023. Published by Oxford University Press on behalf of FEMS.
PY - 2023
Y1 - 2023
N2 - Proton-dependent oligopeptide transporters (POTs) are recognized for their substrate promiscuity due to their ability to transport a wide range of substrates. POTs are conserved in all forms of life ranging from bacteria to humans. A dipeptide-fluorophore conjugate, H-(β-Ala)-Lys(AMCA)-OH, is a well-known substrate of the transporter YdgR that is commonly used as a fluorescent reporter. In order to understand the substrate space of YdgR, we used this dipeptide as a bait reference, when screening an ensemble of compounds (previously tested in PEPT/PTR/NPF space) via a cheminformatic analysis based on the Tanimoto similarity index. Eight compounds (sinalbin, abscisic acid, carnosine, jasmonic acid, N-acetyl-aspartate, N-acetyl-lysine, aspartame, and N-acetyl-aspartylglutamate), covering a wide range on the Tanimoto scale, were tested for YdgR-mediated transport. Carnosine was the only compound observed to be a YdgR substrate based on cell-based transport assays and molecular docking. The other compounds tested were neither inhibitors nor substrates. Thus, we found that neither the Tanimoto similarity index nor ADME (absorption, distribution, metabolism, and excretion) properties appear useful for the identification of substrates (e.g., dipeptides) in YdgR-mediated drug transport.
AB - Proton-dependent oligopeptide transporters (POTs) are recognized for their substrate promiscuity due to their ability to transport a wide range of substrates. POTs are conserved in all forms of life ranging from bacteria to humans. A dipeptide-fluorophore conjugate, H-(β-Ala)-Lys(AMCA)-OH, is a well-known substrate of the transporter YdgR that is commonly used as a fluorescent reporter. In order to understand the substrate space of YdgR, we used this dipeptide as a bait reference, when screening an ensemble of compounds (previously tested in PEPT/PTR/NPF space) via a cheminformatic analysis based on the Tanimoto similarity index. Eight compounds (sinalbin, abscisic acid, carnosine, jasmonic acid, N-acetyl-aspartate, N-acetyl-lysine, aspartame, and N-acetyl-aspartylglutamate), covering a wide range on the Tanimoto scale, were tested for YdgR-mediated transport. Carnosine was the only compound observed to be a YdgR substrate based on cell-based transport assays and molecular docking. The other compounds tested were neither inhibitors nor substrates. Thus, we found that neither the Tanimoto similarity index nor ADME (absorption, distribution, metabolism, and excretion) properties appear useful for the identification of substrates (e.g., dipeptides) in YdgR-mediated drug transport.
U2 - 10.1093/femsle/fnad052
DO - 10.1093/femsle/fnad052
M3 - Journal article
C2 - 37300868
VL - 370
JO - F E M S Microbiology Letters
JF - F E M S Microbiology Letters
SN - 0378-1097
M1 - fnad052
ER -
ID: 356066957