Multidrug efflux pumps: Substrate selection in ATP‐binding cassette multidrug efflux pumps – first come, first served?

Ernst, Robert; Kueppers, Petra; Stindt, Jan; Kuchler, Karl; Schmitt, Lutz

doi:10.1111/j.1742-4658.2009.07485.x

Cited by 113 publications

(98 citation statements)

References 51 publications

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“…Furthermore, glyphosate entry into the cell can be markedly inhibited by vanadate pretreatment. These characteristics are similar to those of ATP-binding cassette transporters in plants (Hetherington et al, 1998;Rea, 2007;Verrier et al, 2008;Prosecka et al, 2009;Conte and Lloyd, 2011) and mammalian cells (van de Ven et al, 2009;Ernst et al, 2010).…”

supporting

confidence: 54%

In Vivo 31P-Nuclear Magnetic Resonance Studies of Glyphosate Uptake, Vacuolar Sequestration, and Tonoplast Pump Activity in Glyphosate-Resistant Horseweed

Ge¹,

d’Avignon²,

Ackerman

et al. 2014

Plant Physiology

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Horseweed (Conyza canadensis) is considered a significant glyphosate-resistant (GR) weed in agriculture, spreading to 21 states in the United States and now found globally on five continents. This laboratory previously reported rapid vacuolar sequestration of glyphosate as the mechanism of resistance in GR horseweed. The observation of vacuole sequestration is consistent with the existence of a tonoplast-bound transporter. 31 P-Nuclear magnetic resonance experiments performed in vivo with GR horseweed leaf tissue show that glyphosate entry into the plant cell (cytosolic compartment) is (1) first order in extracellular glyphosate concentration, independent of pH and dependent upon ATP; (2) competitively inhibited by alternative substrates (aminomethyl phosphonate [AMPA] and N-methyl glyphosate [NMG]), which themselves enter the plant cell; and (3) blocked by vanadate, a known inhibitor/blocker of ATP-dependent transporters. Vacuole sequestration of glyphosate is (1) first order in cytosolic glyphosate concentration and dependent upon ATP; (2) competitively inhibited by alternative substrates (AMPA and NMG), which themselves enter the plant vacuole; and (3) saturable.31 P-Nuclear magnetic resonance findings with GR horseweed are consistent with the active transport of glyphosate and alternative substrates (AMPA and NMG) across the plasma membrane and tonoplast in a manner characteristic of ATP-binding cassette transporters, similar to those that have been identified in mammalian cells.

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supporting

confidence: 54%

In Vivo 31P-Nuclear Magnetic Resonance Studies of Glyphosate Uptake, Vacuolar Sequestration, and Tonoplast Pump Activity in Glyphosate-Resistant Horseweed

Ge¹,

d’Avignon²,

Ackerman

et al. 2014

Plant Physiology

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“…Random and site-directed mutagenesis together with biochemical studies on yeast PDR5 and Candida albicans CANDIDA DRUG RESISTANCE1 transporters have revealed the existence of multiple substrate-binding sites in different TMDs and that some substrates can associate with more than one site (Jungwirth and Kuchler, 2006;Tanabe et al, 2011). For example, the S 1260 F substitution in PDR5 affects the transport only of a subset of substrates (Ernst et al, 2010). Thus, the observed uncoupling of a subset of PEN3-mediated responses in pen3-5 and pen3-6 plants could be explained by impaired substrate selectivity and/or binding of a subset of PEN3 substrates (Fig.…”

Section: Single-amino Acid Substitutions In Tmds Uncouple a Subset Ofmentioning

confidence: 99%

Mutant Allele-Specific Uncoupling of PENETRATION3 Functions Reveals Engagement of the ATP-Binding Cassette Transporter in Distinct Tryptophan Metabolic Pathways

Dittgen

Piślewska‐Bednarek

et al. 2015

Plant Physiol.

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Arabidopsis (Arabidopsis thaliana) PENETRATION (PEN) genes quantitatively contribute to the execution of different forms of plant immunity upon challenge with diverse leaf pathogens. PEN3 encodes a plasma membrane-resident pleiotropic drug resistance-type ATP-binding cassette transporter and is thought to act in a pathogen-inducible and PEN2 myrosinasedependent metabolic pathway in extracellular defense. This metabolic pathway directs the intracellular biosynthesis and activation of tryptophan-derived indole glucosinolates for subsequent PEN3-mediated efflux across the plasma membrane at pathogen contact sites. However, PEN3 also functions in abiotic stress responses to cadmium and indole-3-butyric acid (IBA)-mediated auxin homeostasis in roots, raising the possibility that PEN3 exports multiple functionally unrelated substrates. Here, we describe the isolation of a pen3 allele, designated pen3-5, that encodes a dysfunctional protein that accumulates in planta like wild-type PEN3. The specific mutation in pen3-5 uncouples PEN3 functions in IBA-stimulated root growth modulation, callose deposition induced with a conserved peptide epitope of bacterial flagellin (flg22), and pathogen-inducible salicylic acid accumulation from PEN3 activity in extracellular defense, indicating the engagement of multiple PEN3 substrates in different PEN3-dependent biological processes. We identified 4-O-b-D-glucosyl-indol-3-yl formamide (4OGlcI3F) as a pathogen-inducible, tryptophan-derived compound that overaccumulates in pen3 leaf tissue and has biosynthesis that is dependent on an intact PEN2 metabolic pathway. We propose that a precursor of 4OGlcI3F is the PEN3 substrate in extracellular pathogen defense. These precursors, the shared indole core present in IBA and 4OGlcI3F, and allele-specific uncoupling of a subset of PEN3 functions suggest that PEN3 transports distinct indole-type metabolites in distinct biological processes.

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“…Apart from being the engine for these pump proteins, they may also play a role in substrate selection (29). One hallmark of yeast ABC transporters is that, unlike their mammalian counterparts, they elicit high basal ATPase activity that is not stimulated by the addition of substrates, indicating that transporters like Cdr1p and Pdr5p are uncoupled ABC transporters that constantly hydrolyzes ATP to ensure active substrate transport (24,30,31). It is believed that, by retaining high basal ATPase activity, such pumps probably remain in a transport-competent state (29).…”

Section: The Conserved Nbds Power Drug Effluxmentioning

confidence: 99%

The ABCs of Candida albicans Multidrug Transporter Cdr1

et al. 2015

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bIn the light of multidrug resistance (MDR) among pathogenic microbes and cancer cells, membrane transporters have gained profound clinical significance. Chemotherapeutic failure, by far, has been attributed mainly to the robust and diverse array of these proteins, which are omnipresent in every stratum of the living world. Candida albicans, one of the major fungal pathogens affecting immunocompromised patients, also develops MDR during the course of chemotherapy. The pivotal membrane transporters that C. albicans has exploited as one of the strategies to develop MDR belongs to either the ATP binding cassette (ABC) or the major facilitator superfamily (MFS) class of proteins. The ABC transporter Candida drug resistance 1 protein (Cdr1p) is a major player among these transporters that enables the pathogen to outplay the battery of antifungals encountered by it. The promiscuous Cdr1 protein fulfills the quintessential need of a model to study molecular mechanisms of multidrug transporter regulation and structure-function analyses of asymmetric ABC transporters. In this review, we cover the highlights of two decades of research on Cdr1p that has provided a platform to study its structure-function relationships and regulatory circuitry for a better understanding of MDR not only in yeast but also in other organisms.

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Multidrug efflux pumps: Substrate selection in ATP‐binding cassette multidrug efflux pumps – first come, first served?

Cited by 113 publications

References 51 publications

In Vivo 31P-Nuclear Magnetic Resonance Studies of Glyphosate Uptake, Vacuolar Sequestration, and Tonoplast Pump Activity in Glyphosate-Resistant Horseweed

In Vivo 31P-Nuclear Magnetic Resonance Studies of Glyphosate Uptake, Vacuolar Sequestration, and Tonoplast Pump Activity in Glyphosate-Resistant Horseweed

Mutant Allele-Specific Uncoupling of PENETRATION3 Functions Reveals Engagement of the ATP-Binding Cassette Transporter in Distinct Tryptophan Metabolic Pathways

The ABCs of Candida albicans Multidrug Transporter Cdr1

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