Multidrug and Toxin Extrusion Proteins

Wright, Stephen H.

doi:10.1002/9781118705308.ch12

Cited by 6 publications

(8 citation statements)

References 112 publications

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“…The qualifier, the external face of the transporter, is important. The present observations, indeed those from virtually all studies on MATE transport to date (Wright, 2014), focused on the kinetic characteristics of the transporter operating in an uptake mode. However, in its normal physiologic role as the second step in OC secretion, MATE1 mediates efflux of its organic substrates.…”

Section: Discussionmentioning

confidence: 91%

Lack of Influence of Substrate on Ligand Interaction with the Human Multidrug and Toxin Extruder, MATE1

et al. 2016

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Multidrug and toxin extruder (MATE) 1 plays a central role in mediating renal secretion of organic cations, a structurally diverse collection of compounds that includes ∼40% of prescribed drugs. Because inhibition of transport activity of other multidrug transporters, including the organic cation transporter (OCT) 2, is influenced by the structure of the transported substrate, the present study screened over 400 drugs as inhibitors of the MATE1-mediated transport of four structurally distinct organic cation substrates: the commonly used drugs: 1) metformin and 2) cimetidine; and two prototypic cationic substrates, 3) 1-methyl-4-phenylpyridinium (MPP), and 4) the novel fluorescent probe, N,N,N-trimethyl-2-[methyl(7-Transport was measured in Chinese hamster ovary cells that stably expressed the human ortholog of MATE1. Comparison of the resulting inhibition profiles revealed no systematic influence of substrate structure on inhibitory efficacy. Similarly, IC 50 values for 26 structurally diverse compounds revealed no significant influence of substrate structure on the kinetic interaction of inhibitor with MATE1. The IC 50 data were used to generate three-dimensional quantitative pharmacophores that identified hydrophobic regions, H-bond acceptor sites, and an ionizable (cationic) feature as key determinants for ligand binding to MATE1. In summary, in contrast to the behavior observed with some other multidrug transporters, including OCT2, the results suggest that substrate identity exerts comparatively little influence on ligand interaction with MATE1.

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Section: Discussionmentioning

confidence: 91%

Lack of Influence of Substrate on Ligand Interaction with the Human Multidrug and Toxin Extruder, MATE1

et al. 2016

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“…We assumed that the BAF-sensitive accumulation of OCs in rabbit RPTs reflected the functional expression of rabbit Mate1 (and/or rabbit Mate2-K) within the ELP, as well as in the luminal membrane, of these cells. Three lines of evidence support this assumption, which is predicated on the wide acceptance that MATEs are the functional basis for the OC/H ϩ activity of the apical membrane of mammalian RPTs (including rabbit RPTs) (23,38,41). First, cells of rabbit cortical tissue do express orthologs of both Mate1 and Mate2-K (42).…”

Section: Discussionmentioning

confidence: 99%

“…The second step in renal OC secretion involves the exit of drugs from RPT cells into the tubular filtrate across the apical (luminal) membrane and is dominated by the activity of one or more members of the SLC47A family of OC/H ϩ exchangers (23,38,41), i.e., multidrug and toxin extruders (MATEs); in humans, this includes human (h)MATE1 (21,23). This step is the active and rate-limiting element of proximal tubular OC secretion (28,30) and is driven by the electroneutral exchange of luminal H ϩ for cytosolic OC (11,36), consistent with MATE1-mediated OC/H ϩ activity (36).…”

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confidence: 99%

“…To date, the primary focus of studies of MATE function has been establishing the interaction of MATE transporters (typically MATE1) with distinct structural classes of drugs (33,38). However, whereas in their proposed physiological role MATEs mediate the efflux of OCs, the characterization of MATEmediated OC transport has, with few exceptions, relied on measurements of uptake, i.e., influx, with the tacit assumption that MATEs interact symmetrically with their substrates.…”

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confidence: 99%

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The multidrug transporter MATE1 sequesters OCs within an intracellular compartment that has no influence on OC secretion in renal proximal tubules

Martinez-Guerrero

Evans

Dantzler

et al. 2016

American Journal of Physiology-Renal Physiology

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Secretion of organic cations (OCs) across renal proximal tubules (RPTs) involves basolateral OC transporter (OCT)2-mediated uptake from the blood followed by apical multidrug and toxin extruder (MATE)1/2-mediated efflux into the tubule filtrate. Whereas OCT2 supports electrogenic OC uniport, MATE is an OC/H(+) exchanger. As assessed by epifluorescence microscopy, cultured Chinese hamster ovary (CHO) cells that stably expressed human MATE1 accumulated the fluorescent OC N,N,N-trimethyl-2-[methyl(7-nitrobenzo[c][l,2,5]oxadiazol-4-yl)amino]ethanaminium (NBD-MTMA) in the cytoplasm and in a smaller, punctate compartment; accumulation in human OCT2-expressing cells was largely restricted to the cytoplasm. A second intracellular compartment was also evident in the multicompartmental kinetics of efflux of the prototypic OC [(3)H]1-methyl-4-phenylpyridinium (MPP) from MATE1-expressing CHO cells. Punctate accumulation of NBD-MTMA was markedly reduced by coexposure of MATE1-expressing cells with 5 μM bafilomycin (BAF), an inhibitor of V-type H(+)-ATPase, and accumulation of [(3)H]MPP and [(3)H]NBD-MTMA was reduced by >30% by coexposure with 5 μM BAF. BAF had no effect on the initial rate of MATE1-mediated uptake of NBD-MTMA, suggesting that the influence of BAF was a secondary effect involving inhibition of V-type H(+)-ATPase. The accumulation of [(3)H]MPP by isolated single nonperfused rabbit RPTs was also reduced >30% by coexposure to 5 μM BAF, suggesting that the native expression in RPTs of MATE protein within endosomes can increase steady-state OC accumulation. However, the rate of [(3)H]MPP secretion by isolated single perfused rabbit RPTs was not affected by 5 μM BAF, suggesting that vesicles loaded with OCs(+) are not likely to recycle into the apical plasma membrane at a rate sufficient to provide a parallel pathway for OC secretion.

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“…Since then, MATE transporters have been identified in almost all organisms, including humans and plants. In humans, MATE transporters play a key role in secreting organic drugs, toxins, and metabolites into the renal tubular lumen (1).…”

Section: Introductionmentioning

confidence: 99%

Functional characterization and discovery of modulators of SbMATE, the agronomically important aluminium tolerance transporter fromSorghum bicolor

Doshi

McGrath

Piñeros

et al. 2017

Preprint

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About 50% of the world's arable land is strongly acidic (soil pH < 5). The low pH of these soils solubilizes root-toxic ionic aluminium (Al 3+ ) species from clay minerals, driving the evolution of various counteractive adaptations in cultivated crops. The food crop Sorghum bicolor, for example, upregulates the membrane-embedded transporter protein SbMATE in its roots. SbMATE mediates efflux of the anionic form of the organic acid, citrate, into the soil rhizosphere, chelating Al 3+ ions and thereby imparting Al-resistance based on excluding Al +3 from the growing root tip. Here, we use electrophysiological, radiolabeled, and fluorescence-based transport assays in two heterologous expression systems to establish a broad substrate recognition profile of SbMATE, showing the transport of 14C -citrate anion, as well as the organic monovalent cation, ethidium, but not the divalent ethidium-derivative, propidium. The transport cycle is proton and/or sodium-driven, and shares certain molecular mechanisms with bacterial MATE-family transporters. We further complement our transport assays by directly measuring substrate binding to detergent-purified SbMATE protein.Finally, we use the functionally-folded, purified membrane protein as an antigen to discover high-affinity, native conformation-binding and transport function-altering nanobodies using an animal-free, mRNA/cDNA display technology. Our results demonstrate the utility of using Pichia pastoris as an efficient eukaryotic host to express large quantities of functional plant transporter proteins for in vitro characterization. The nanobody discovery approach is applicable to other low immunogenic plant proteins.

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Multidrug and Toxin Extrusion Proteins

Cited by 6 publications

References 112 publications

Lack of Influence of Substrate on Ligand Interaction with the Human Multidrug and Toxin Extruder, MATE1

Lack of Influence of Substrate on Ligand Interaction with the Human Multidrug and Toxin Extruder, MATE1

The multidrug transporter MATE1 sequesters OCs within an intracellular compartment that has no influence on OC secretion in renal proximal tubules

Functional characterization and discovery of modulators of SbMATE, the agronomically important aluminium tolerance transporter fromSorghum bicolor

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