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Molecular pharmacological characterization of two multidrug transporters in Lactococcus lactis
H W van Veen1, M Putman, A Margolles
1Department of Microbiology, Groningen Biomolecular Sciences and Biotechnology Institute, University of Groningen, Kerklaan 30, NL-9751 NN, Haren, The Netherlands. h.w.van.veen@biol.rug.nl
Abstract:
The active extrusion of cytotoxic compounds from the cell by multidrug transporters is one of the major causes of failure of chemotherapeutic treatment of tumor cells and of infections by pathogenic microorganisms. A multidrug transporter in Lactococcus lactis, LmrA, is a member of the ATP-binding cassette superfamily and a bacterial homolog of the human multidrug resistance P-glycoprotein. Another multidrug transporter in Lactococcus lactis, LmrP, belongs to the major facilitator superfamily, and is one example of a rapidly expanding group of secondary multidrug transporters in microorganisms. Thus, LmrA and LmrP are transport proteins with very different protein structures, which use different mechanisms of energy coupling to transport drugs out of the cell. Surprisingly, both proteins have overlapping specificities for drugs, are inhibited by the same set of modulators, and transport drugs via a similar transport mechanism. The structure-function relationships that dictate drug recognition and transport by LmrP and LmrA represent an intriguing area of research.
Insights
Multidrug transporters like LmrA and LmrP actively expel cytotoxic drugs, contributing to treatment failure. Despite different structures and energy mechanisms, they share drug specificities and transport similarities.
Area of Science:
- Microbiology and Molecular Biology
- Biochemistry
- Drug Resistance
Background:
- Multidrug transporters actively extrude cytotoxic compounds, a key factor in chemotherapy and antimicrobial resistance.
- Lactococcus lactis possesses two major multidrug transporters: LmrA (ATP-binding cassette superfamily) and LmrP (major facilitator superfamily).
- These transporters are bacterial homologs of human P-glycoprotein and represent distinct classes of secondary transporters, respectively.
Purpose of the Study:
- To investigate the structure-function relationships of LmrA and LmrP in Lactococcus lactis.
- To understand how these distinct transporters recognize and transport drugs.
- To explore the surprising similarities in drug specificity and transport mechanisms despite structural differences.
Main Methods:
- Comparative analysis of LmrA and LmrP protein structures and functions.
- Studies on drug recognition and binding specificities.
- Investigation of drug transport mechanisms and energy coupling.
Main Results:
- LmrA and LmrP, despite differing structures and energy coupling mechanisms, exhibit overlapping drug specificities.
- Both transporters are inhibited by the same modulators.
- A similar drug transport mechanism was observed for both LmrA and LmrP.
Conclusions:
- The study highlights intriguing structure-function relationships in multidrug transporters.
- Despite distinct evolutionary origins and mechanisms, LmrA and LmrP display convergent functional properties in drug transport.
- Understanding these relationships is crucial for developing strategies to overcome multidrug resistance.