ArticleBiochemistry2014
Reaction dynamics of ATP hydrolysis catalyzed by P-glycoprotein.
Article in Biochemistry, 2014. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 8 papers.
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Who cites it
8 citing papers in PubMed, 23 citations in OpenAlex.
- Pharmacogenomics influence on MDR1-associated cancer resistance and innovative drug delivery approaches: advancing precision oncology.Medical oncology (Northwood, London, England) · 2025Review
- Regulation of Placental Efflux Transporters during Pregnancy Complications.Drug metabolism and disposition: the biological fate of chemicals · 2022Review
- Stable Isotope Phosphate Labelling of Diverse Metabolites is Enabled by a Family ofAngewandte Chemie (International ed. in English) · 2022Article
- Stable Isotope Phosphate Labelling of Diverse Metabolites is Enabled by a Family ofAngewandte Chemie (Weinheim an der Bergstrasse, Germany) · 2022Article
- Comparison of mechanistic transport cycle models of ABC exporters.Biochimica et biophysica acta. Biomembranes · 2018Review
- Insights Into the Molecular Mechanism of Triptan Transport by P-glycoprotein.Journal of pharmaceutical sciences · 2017Article
- Drug-protein hydrogen bonds govern the inhibition of the ATP hydrolysis of the multidrug transporter P-glycoprotein.Biochemical pharmacology · 2016Article
- Kinetic validation of the models for P-glycoprotein ATP hydrolysis and vanadate-induced trapping. Proposal for additional steps.PloS one · 2014Article
Corrections and comments
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Authors and funding
4 authors at 1 institution in 1 country.
Funding
Abstract
P-glycoprotein (P-gp) is a member of the ABC transporter family that confers drug resistance to many tumors by catalyzing their efflux, and it is a major component of drug-drug interactions. P-gp couples drug efflux with ATP hydrolysis by coordinating conformational changes in the drug binding sites with the hydrolysis of ATP and release of ADP. To understand the relative rates of the chemical step for hydrolysis and the conformational changes that follow it, we exploited isotope exchange methods to determine the extent to which the ATP hydrolysis step is reversible. With γ(18)O4-labeled ATP, no positional isotope exchange is detectable at the bridging β-phosphorus-O-γ-phosphorus bond. Furthermore, the phosphate derived from hydrolysis includes a constant ratio of three (18)O/two (18)O/one (18)O that reflects the isotopic composition of the starting ATP in multiple experiments. Thus, H2O-exchange with HPO4(2-) (Pi) was negligible, suggesting that a [P-gp·ADP·Pi] is not long-lived. This further demonstrates that the hydrolysis is essentially irreversible in the active site. These mechanistic details of ATP hydrolysis are consistent with a very fast conformational change immediately following, or concomitant with, hydrolysis of the γ-phosphate linkage that ensures a high commitment to catalysis in both drug-free and drug-bound states.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.