Version 1
: Received: 4 June 2024 / Approved: 5 June 2024 / Online: 5 June 2024 (12:57:10 CEST)
How to cite:
Iosifidou, N.; Anagnostopoulou, E.; Botou, M.; Kalfa, E.; Tatsaki, E.; Frillingos, S. Elucidation of the Gemcitabine Transporters of Escherichia coli K-12 and Gamma-Proteobacteria Linked to Gemcitabine-Related Chemoresistance. Preprints2024, 2024060274. https://doi.org/10.20944/preprints202406.0274.v1
Iosifidou, N.; Anagnostopoulou, E.; Botou, M.; Kalfa, E.; Tatsaki, E.; Frillingos, S. Elucidation of the Gemcitabine Transporters of Escherichia coli K-12 and Gamma-Proteobacteria Linked to Gemcitabine-Related Chemoresistance. Preprints 2024, 2024060274. https://doi.org/10.20944/preprints202406.0274.v1
Iosifidou, N.; Anagnostopoulou, E.; Botou, M.; Kalfa, E.; Tatsaki, E.; Frillingos, S. Elucidation of the Gemcitabine Transporters of Escherichia coli K-12 and Gamma-Proteobacteria Linked to Gemcitabine-Related Chemoresistance. Preprints2024, 2024060274. https://doi.org/10.20944/preprints202406.0274.v1
APA Style
Iosifidou, N., Anagnostopoulou, E., Botou, M., Kalfa, E., Tatsaki, E., & Frillingos, S. (2024). Elucidation of the Gemcitabine Transporters of Escherichia coli K-12 and Gamma-Proteobacteria Linked to Gemcitabine-Related Chemoresistance. Preprints. https://doi.org/10.20944/preprints202406.0274.v1
Chicago/Turabian Style
Iosifidou, N., Ekaterini Tatsaki and Stathis Frillingos. 2024 "Elucidation of the Gemcitabine Transporters of Escherichia coli K-12 and Gamma-Proteobacteria Linked to Gemcitabine-Related Chemoresistance" Preprints. https://doi.org/10.20944/preprints202406.0274.v1
Abstract
Gemcitabine (2',2'-difluoro-2'-deoxycytidine), a widely used anticancer drug, is considered as a gold standard in treating aggressive pancreatic cancers. Gamma-proteobacteria that colonize the pancreatic tumors contribute to chemoresistance against gemcitabine by metabolizing the drug to a less active, deaminated, form. The gemcitabine transporters of these bacteria are unknown to date. Furthermore, there is no complete knowledge on the gemcitabine transporters in Escherichia coli or any other related proteobacteria. In this study, we investigate the complement of gemcitabine transporters in E. coli K-12 and two common chemoresistance-related bacteria (Klebsiella pneumoniae, Citrobacter freundii). We find that E. coli K-12 has two high-affinity gemcitabine transporters with distinct specificity properties, namely NupC and NupG, whereas the gemcitabine transporters of C. freundii and K. pneumoniae include the NupC and NupG orthologs, indistinguishable functionally from their counterparts, and, in K. pneumoniae, one additional NupC variant, designated KpNupC2. All these bacterial transporters have higher affinity for gemcitabine than their human counterparts. The highest affinity (KM 2.5-3.0 μΜ) is exhibited by NupGs of the Bacteria-specific Nucleoside-H+ Symporter (NHS) family followed by NupCs (KM 10-13 μΜ) of the Concentrative Nucleoside Transporter (CNT) family, 15-100 times higher than the affinities reported for the human gemcitabine transporter hENT1/SLC29A1 which is primarily associated with gemcitabine uptake in the pancreatic adenocarcinoma cells. Our results offer a basis for further insight into the role of specific bacteria in drug availability within tumors and understanding the structure-function differences of bacterial and human drug transporters.
Biology and Life Sciences, Biochemistry and Molecular Biology
Copyright:
This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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