Transport of cystine across<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" altimg="si1.gif" overflow="scroll"><mml:mrow><mml:mi mathvariant="bold">x</mml:mi><mml:msup><mml:mrow><mml:mi mathvariant="bold">C</mml:mi></mml:mrow><mml:mrow><mml:mo>−</mml:mo></mml:mrow></mml:msup></mml:mrow></mml:math>antiporter

Ghasemitarei, Maryam; Yusupov, Maksudbek; Razzokov, Jamoliddin; Shokri, Babak; Bogaerts, Annemie

doi:10.1016/j.abb.2019.01.039

Cited by 11 publications

(8 citation statements)

References 72 publications

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“…Other predicted points of interaction between l-Glu and xCT include a stabilizing hydrogen bond between the distal carboxylate and T139, which is near the interacting R135 and R396 residues, as well as multiple hydrogen bonds with T56, I57, A60, and G61 residues along the backbone of helix TM1 that may stabilize the α-amino group. Lastly, the positioning of l-Glu is also consistent with the proposed location of l-Cys 2 in the substrate site of xCT in a comparable modeling study [38].…”

Section: Resultssupporting

confidence: 83%

“…Docked poses for glutamate and competitive inhibitors were screened for similarities between favored poses, with the positioning of the α-carboxylate oxygens of the substrate l-arginine (l-Arg) captured in the 3OB6 crystal structure used as a reference point. Ghasemitarei et al [38] also reported an orientation of l-Cys 2 in a Sx c − comparative model that is consistent with the pose of glutamate reported below (Fig. 2a).…”

Section: Molecular Modelingsupporting

confidence: 85%

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System X−c Antiporter Inhibitors: Azo-Linked Amino-Naphthyl-Sulfonate Analogues of Sulfasalazine

et al. 2019

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The cystine/glutamate antiporter system x c − (Sx c − ) mediates the exchange of intracellular l-glutamate (l-Glu) with extracellular l-cystine (l-Cys 2 ). Both the import of l-Cys 2 and the export of l-Glu take on added significance in CNS cells, especially astrocytes. When the relative activity of Sx c − overwhelms the regulatory capacity of the EAATs, the efflux of l-Glu through the antiporter can be significant enough to trigger excitotoxic pathology, as is thought to occur in glioblastoma. This has prompted considerable interest in the pharmacological specificity of Sx c − and the development of inhibitors. The present study explores a series of analogues that are structurally related to sulfasalazine, a widely employed inhibitor of Sx c − . We identify a number of novel aryl-substituted amino-naphthylsulfonate analogues that inhibit Sx c − more potently than sulfasalazine. Interestingly, the inhibitors switch from a competitive to noncompetitive mechanism with increased length and lipophilic substitutions, a structure-activity relationship that was previously observed with aryl-substituted isoxazole. These results suggest that the two classes of inhibitors may interact with some of the same domains on the antiporter protein and that the substrate and inhibitor binding sites may be in close proximity to one another. Molecular modeling is used to explore this possibility.

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Section: Resultssupporting

confidence: 83%

Section: Molecular Modelingsupporting

confidence: 85%

System X−c Antiporter Inhibitors: Azo-Linked Amino-Naphthyl-Sulfonate Analogues of Sulfasalazine

et al. 2019

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“…From the modeled structures of different YATs as well as from docking calculations and biochemical and mutational data have emerged the residues that are engaged in interactions with their amino acid substrate. As for the AR Table 6 Overview of the investigations on eukaryotic APC transporters using AdiC and/or GadC as templates For more information on the crystal structures see Table 2 a The ApcT structure (Shaffer et al 2009) (Ghasemitarei et al 2019) antiporter, the residues, involved in recognition of the substrate amino acid backbone, belong to two motifs in the unwound portions of TM1 (GTG) and TM6 ((F/Y)(S/A/T) (F/Y)xGxE) (Ghaddar et al 2014a;Gournas et al 2016) and are highly conserved in YATs (Fig. 7).…”

Section: Ar Antiporters Structures As Templates To Study Eukaryotic Amentioning

confidence: 99%

“…Residues identified to be important for cystine affinity/transport in CgCYN1 have been shown to be conserved or replaced by a functionally similar amino acid in xCT suggesting that xCT and CgCYN1 share a similar transport mechanism. A recent study combining targeted, steered and classical MD simulations of xCT modeled structure stressed the residues important for transport and the protein portions involved in conformational transitions during transport (Ghasemitarei et al 2019).…”

Section: Ar Antiporters Structures As Templates To Study Eukaryotic Amentioning

confidence: 99%

Function and Regulation of Acid Resistance Antiporters

Krammer

Prévost

2019

J Membrane Biol

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Bacterial pathogens are a major cause of foodborne diseases and food poisoning. To cope with the acid conditions encountered in different environments such as in fermented food or in the gastric compartment, neutralophilic bacteria have developed several adaptive mechanisms. One of those mechanisms, the amino acid dependent system, consumes intracellular protons in biochemical reactions. It involves an antiporter that facilitates the exchange of external substrate amino acid for internal product and a cytoplasmic decarboxylase that catalyzes a proton-consuming decarboxylation of the substrate. So far, four acid resistance antiporters have been discovered, namely the glutamate-γ-aminobutyric acid antiporter GadC, the arginine-agmatine antiporter AdiC, the lysine-cadaverine antiporter CadB, and the ornithine-putrescine antiporter PotE. The 3D structures of AdiC and GadC, reveal an inverted-repeat fold of two times 5 transmembrane helices, typical of the amino acid-polyamine-organocation (APC) superfamily of transporters. This review summarizes our current knowledge on the transport mechanism, the pH regulation and the selectivity of these four acid resistance antiporters. It also highlights that AdiC is a paradigm for eukaryotic amino acid transporters of the APC superfamily as structural models of several of these transporters built using AdiC structures were exploited to unveil their mechanisms of amino acid recognition and translocation.

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“…Figure 1 schematically illustrates the light and heavy subunits of xCantiporter. During the counter-transport (i.e., the import of CYC and export of Glu), the xCT subunit of xCantiporter can have three conformations, i.e., outward facing (OF), occluded (OCC) and inward facing (IF), the structures of which were modeled recently, and more information about their functions is given in [33]. One of the important amino acids of the xCT subunit is Cys 327 , which is not highly conserved, i.e., it is a main target for modification (e.g., mutation or oxidation).…”

Section: Introductionmentioning

confidence: 99%

Effect of oxidative stress on cystine transportation by xC‾ antiporter

Ghasemitarei

Yusupov

Razzokov

et al. 2019

Archives of Biochemistry and Biophysics

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We performed computer simulations to investigate the effect of oxidation on the extracellular cystine (CYC) uptake by the xCantiporter. The latter is important for killing of cancer cells. Specifically, applying molecular dynamics (MD) simulations we studied the transport of CYC across xCT, i.e., the light subunit of the xCantiporter, in charge of bidirectional transport of CYC and glutamate. We considered the outward facing (OF) configuration of xCT, and to study the effect of oxidation, we modified the Cys 327 residue, located in the vicinity of the extracellular milieu, to cysteic acid (CYO 327 ).Our computational results showed that oxidation of Cys 327 results in a free energy barrier for CYC translocation, thereby blocking the access of CYC to the substrate binding site of the OF system. The formation of the energy barrier was found to be due to the conformational changes in the channel. Analysis of the MD trajectories revealed that the reorganization of the side chains of the Tyr 244 and CYO 327 residues play a critical role in the OF channel blocking. Indeed, the calculated distance between Tyr 244 and either Cys 327 or CYO 327 showed a narrowing of the channel after oxidation. The obtained free energy barrier for CYC translocation was found to be 33.9 kJmol −1 , indicating that oxidation of Cys 327 , by e.g., cold atmospheric plasma, is more effective in inhibiting the xCantiporter than in the mutation of this amino acid to Ala (yielding a barrier of 32.4 kJmol −1 ). The inhibition of the xCantiporter may lead to Cys starvation in some cancer cells, eventually resulting in cancer cell death.

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Transport of cystine acrossxC−antiporter

Cited by 11 publications

References 72 publications

System X−c Antiporter Inhibitors: Azo-Linked Amino-Naphthyl-Sulfonate Analogues of Sulfasalazine

System X−c Antiporter Inhibitors: Azo-Linked Amino-Naphthyl-Sulfonate Analogues of Sulfasalazine

Function and Regulation of Acid Resistance Antiporters

Effect of oxidative stress on cystine transportation by xC‾ antiporter

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