MetaCyc Transporter: cystine/glutamate antiporter system xc-

Synonyms: system xc-, xc- cystine/glutamate -exchange transporter

Species: Homo sapiens

Subunit composition of cystine/glutamate antiporter system xc- = [SLC3A2][SLC7A11]
         4F2 cell-surface antigen heavy chain = SLC3A2 (summary available)
         cystine/glutamate transporter = SLC7A11

The cystine/glutamate antiporter system xc- is a membrane amino acid transporter in animal cells that catalyzes the exchange of L-cystine for L-glutamate. It has been described as an obligate, electroneutral, anionic amino acid antiporter (reviewed in [Lo08]). L-cystine, the oxidized form of L-cysteine, is the predominant form in the circulation. L-cystine enters cells and is then rapidly reduced to L-cysteine, which enters protein biosynthesis. L-cysteine is also the rate-limiting substrate for the glutathione biosynthesis pathway which is important to the maintenence of intracellular redox balance and protection from oxidative stress. The L-cysteine/ L-cystine couple is the major low molecular weight extracellular redox couple. Reviewed in [Lo08, Savaskan09, Go08].

This membrane transport system is important to the maintenence of both intracellular glutathione levels and the extracellular L-cystine and L-cysteine redox balance (in [Sato02] and in [Banjac08]) . Inhibition of this transport system is being investigated as a potential target for cancer therapy. A variety of compounds have been shown to inhibit the transporter. Studies have also shown that the transporter can mediate uptake of L-glutamate. L-glutamate has been shown to be an inhibitor of L-cystine uptake and L-cystine is a competitive inhibitor of L-glutamate uptake Reviewed in [Lo08] and [Savaskan09].

This transporter is expressed on cells such as fibroblasts, activated macrophages and dendritic cells which take up extracellular L-cystine in a 1:1 exchange for intracellular L-glutamate. L-glutamate is generally present in higher concentrations intracellularly than extracellularly, providing a concentration gradient. L-cystine is rapidly reduced to L-cysteine inside the cell and L-cysteine is secreted back into the extracellular space. The reduction of L-cystine inside the cell (a reducing environment) can occur by nonenzymatic, or enzymatic reactions (in [Wu04b]). The transporter may be chloride-dependent. Reviewed in [Lo08] and [McBean02]. In LRM55 glioma cells chloride-dependent. L-glutamate uptake was demonstrated [Patel04a].

The transporter system is a heterodimer composed of the xCT protein encoded by human gene SLC7A11 (TC# 2.A.3.8.5, [Saier09]) and the 4F2hc (CD98) protein encoded by human gene SLC7A6 (TC# 8.A.9.2.1, [Saier09]). The two subunits are joined by a disulfide bridge. The xCT protein confers L-cystine specificity and the 4F2hc subunit is a type II membrane glycoprotein that also acts as a subunit for other amino acid transporters (reviewed in [Lo08]).

The response of the SLC7A6 gene to cellular oxidative stress, or the presence of electrophilic compounds is regulated at the transcriptional level. The transporter is expressed predominantly in brain, pancreatic islets, stromal cells and immune cells (reviewed in [Lo08]).

Gene-Reaction Schematic

Gene-Reaction Schematic

Created 23-Oct-2009 by Fulcher CA, SRI International

Enzymatic reaction of: cystine/glutamate antiport

Inferred from experiment

Transport reaction diagram for cystine/glutamate antiport

The kinetics of the cystine/glutamate transport system were studied in cultured human diploid fibroblasts. Both L-cystine and L-glutamate could be taken up in a Na+-independent process. L-cystine could inhibit L-glutamate uptake and L-glutamate could inhibit L-cystine uptake in an immediate, reversible and competitive manner. L-glutamate taken up could be recovered from the cells, but L-cystine was rapidly converted to L-cysteine. D-glutamate could inhibit the uptake of L-cystine and L-glutamate. The uptake of L-cystine followed Michaelis-Menten kinetics. [Bannai80]. Inhibitors of L-cystine and L-glutamate uptake included L-2-aminoadipate, alpha-aminopimelate and L-homocysteate [Bannai81].

Kinetic Parameters:
Substrate Km (μM) Citations
L-cystine 43.0 [Bannai80]

Subunit of cystine/glutamate antiporter system xc-: 4F2 cell-surface antigen heavy chain

Synonyms: CD_antigen=CD98, lymphocyte activation antigen 4F2 large subunit, 4F2 heavy chain antigen, 4F2hc, CD98

Gene: SLC3A2 Accession Number: HS09679 (MetaCyc)

Locations: membrane

Sequence Length: 32767/3 AAs

Molecular Weight: 67.994 kD (from nucleotide sequence)

GO Terms:
Biological Process:
GO:0005975 - carbohydrate metabolic process []
GO:0006865 - amino acid transport []
GO:0016049 - cell growth []
Molecular Function:
GO:0004556 - alpha-amylase activity []
GO:0015171 - amino acid transmembrane transporter activity []
Cellular Component:
GO:0016021 - integral component of membrane []

Unification Links: Entrez:AAA35489, Entrez:AAA35536, Entrez:AAA51540, Entrez:AAA52497, Entrez:AAH01061, Entrez:AAH03000, Entrez:BAA84649, Mint:MINT-4999018, PhosphoSite:P08195, Pride:P08195, Protein Model Portal:P08195, SMR:P08195, UniProt:P08195

Relationship Links: CAZy:IN-FAMILY:GH13, InterPro:IN-FAMILY:IPR006047, InterPro:IN-FAMILY:IPR013780, InterPro:IN-FAMILY:IPR013781, InterPro:IN-FAMILY:IPR015902, InterPro:IN-FAMILY:IPR017853, Panther:IN-FAMILY:PTHR10357, PDB:Structure:2DH2, PDB:Structure:2DH3, Pfam:IN-FAMILY:PF00128

SLC3A2 encodes a single pass type II transmembrane protein that is covalently associated with a number of transport proteins (SLC7A5, SLC7A6, SLC7A7, SLC7A8, SLC7A10, SLC7A11). Disulfide heterodimerization with SLC7A5 and SLC7A8 is required for plasma membrane localization and uptake of large neutral amino acids--phenylalanine, tyrosine. leucine, arginine and tryptophan [Mastroberardino98, Torrents98, Pfeiffer99]. Heterodimerization with SLC7A6 or SLC7A7 forms an arginine/glutamine exchanger important for efflux of arginine from cells and nitric oxide production [Broer00, ArancibiaGaravi03].

Subunit of cystine/glutamate antiporter system xc-: cystine/glutamate transporter

Synonyms: Amino acid transport system xc-, Calcium channel blocker resistance protein CCBR1, Solute carrier family 7 member 11, xCT

Gene: SLC7A11 Accession Number: HS07701 (MetaCyc)

Locations: membrane

Molecular Weight: 55.423 kD (from nucleotide sequence)

GO Terms:
Biological Process:
GO:0006461 - protein complex assembly []
GO:0006865 - amino acid transport []
Molecular Function:
GO:0005215 - transporter activity []
GO:0015171 - amino acid transmembrane transporter activity []
GO:0015327 - cystine:glutamate antiporter activity []
Cellular Component:
GO:0016021 - integral component of membrane []

MultiFun Terms: Genes

Unification Links: Entrez:AAG35592, Entrez:AAH12087, Entrez:AAK49111, Entrez:BAA82628, Entrez:BAB40574, Entrez:CAC81905, PhosphoSite:Q9UPY5, PhylomeDB:Q9UPY5, Pride:Q9UPY5, Protein Model Portal:Q9UPY5, SMR:Q9UPY5, UniProt:Q9UPY5

Relationship Links: InterPro:IN-FAMILY:IPR002293, InterPro:IN-FAMILY:IPR004760, Panther:IN-FAMILY:PTHR11785, Pfam:IN-FAMILY:PF13520

Citations: [Sato99]


ArancibiaGaravi03: Arancibia-Garavilla Y, Toledo F, Casanello P, Sobrevia L (2003). "Nitric oxide synthesis requires activity of the cationic and neutral amino acid transport system y+L in human umbilical vein endothelium." Exp Physiol 88(6);699-710. PMID: 14603368

Banjac08: Banjac A, Perisic T, Sato H, Seiler A, Bannai S, Weiss N, Kolle P, Tschoep K, Issels RD, Daniel PT, Conrad M, Bornkamm GW (2008). "The cystine/cysteine cycle: a redox cycle regulating susceptibility versus resistance to cell death." Oncogene 27(11);1618-28. PMID: 17828297

Bannai80: Bannai S, Kitamura E (1980). "Transport interaction of L-cystine and L-glutamate in human diploid fibroblasts in culture." J Biol Chem 255(6);2372-6. PMID: 7358676

Bannai81: Bannai S, Kitamura E (1981). "Role of proton dissociation in the transport of cystine and glutamate in human diploid fibroblasts in culture." J Biol Chem 256(11);5770-2. PMID: 6113240

Broer00: Broer A, Wagner CA, Lang F, Broer S (2000). "The heterodimeric amino acid transporter 4F2hc/y+LAT2 mediates arginine efflux in exchange with glutamine." Biochem J 349 Pt 3;787-95. PMID: 10903140

Go08: Go YM, Jones DP (2008). "Redox compartmentalization in eukaryotic cells." Biochim Biophys Acta 1780(11);1273-90. PMID: 18267127

Lo08: Lo M, Wang YZ, Gout PW (2008). "The x(c)- cystine/glutamate antiporter: a potential target for therapy of cancer and other diseases." J Cell Physiol 215(3);593-602. PMID: 18181196

Mastroberardino98: Mastroberardino L, Spindler B, Pfeiffer R, Skelly PJ, Loffing J, Shoemaker CB, Verrey F (1998). "Amino-acid transport by heterodimers of 4F2hc/CD98 and members of a permease family." Nature 395(6699);288-91. PMID: 9751058

McBean02: McBean GJ (2002). "Cerebral cystine uptake: a tale of two transporters." Trends Pharmacol Sci 23(7);299-302. PMID: 12119142

Patel04a: Patel SA, Warren BA, Rhoderick JF, Bridges RJ (2004). "Differentiation of substrate and non-substrate inhibitors of transport system xc(-): an obligate exchanger of L-glutamate and L-cystine." Neuropharmacology 46(2);273-84. PMID: 14680765

Pfeiffer99: Pfeiffer R, Rossier G, Spindler B, Meier C, Kuhn L, Verrey F (1999). "Amino acid transport of y+L-type by heterodimers of 4F2hc/CD98 and members of the glycoprotein-associated amino acid transporter family." EMBO J 18(1);49-57. PMID: 9878049

Saier09: Saier MH, Yen MR, Noto K, Tamang DG, Elkan C (2009). "The Transporter Classification Database: recent advances." Nucleic Acids Res 37(Database issue);D274-8. PMID: 19022853

Sato02: Sato H, Tamba M, Okuno S, Sato K, Keino-Masu K, Masu M, Bannai S (2002). "Distribution of cystine/glutamate exchange transporter, system x(c)-, in the mouse brain." J Neurosci 22(18);8028-33. PMID: 12223556

Sato99: Sato H, Tamba M, Ishii T, Bannai S (1999). "Cloning and expression of a plasma membrane cystine/glutamate exchange transporter composed of two distinct proteins." J Biol Chem 274(17);11455-8. PMID: 10206947

Savaskan09: Savaskan NE, Hahnen E, Eyupoglu IY (2009). "The x(c)(-) cystine/glutamate antiporter (xCT) as a potential target for therapy of cancer: yet another cytotoxic anticancer approach?." J Cell Physiol 220(2);531-2; author reply 533-4. PMID: 19415694

Torrents98: Torrents D, Estevez R, Pineda M, Fernandez E, Lloberas J, Shi YB, Zorzano A, Palacin M (1998). "Identification and characterization of a membrane protein (y+L amino acid transporter-1) that associates with 4F2hc to encode the amino acid transport activity y+L. A candidate gene for lysinuric protein intolerance." J Biol Chem 273(49);32437-45. PMID: 9829974

Wu04b: Wu G, Fang YZ, Yang S, Lupton JR, Turner ND (2004). "Glutathione metabolism and its implications for health." J Nutr 134(3);489-92. PMID: 14988435

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Please cite the following article in publications resulting from the use of MetaCyc: Caspi et al, Nucleic Acids Research 42:D459-D471 2014
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