# Citrin

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> Markdown URL: https://mediated.wiki/source/Citrin.md
> Source: https://en.wikipedia.org/wiki/Citrin
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Mammalian protein found in humans

For the Michelin-starred restaurant in California, see [Citrin (restaurant)](/source/Citrin_(restaurant)).

For other uses, see [Flavonoid](/source/Flavonoid).

Not to be confused with [Citrine](/source/Citrine) or [Citrine (protein)](/source/Citrine_(protein)).

solute carrier family 25, member 13 (citrin) The protein citrin (PDB 4P5W) is a dimer and is composed of two equal polypeptide chains. Identifiers Symbol SLC25A13 Alt. symbols CTLN2 NCBI gene 10165 HGNC 10983 OMIM 603859 RefSeq NM_014251 UniProt Q9UJS0 Other data Locus Chr. 7 q21.3 Search for Structures Swiss-model Domains InterPro

**Citrin**, also known as **solute carrier family 25, member 13 (citrin)** or **SLC25A13**, is a [protein](/source/Protein) which in humans is encoded by the *SLC25A13* gene.[1]

Citrin is associated with type II [citrullinemia](/source/Citrullinemia)[2][3][4] and neonatal intrahepatic cholestasis caused by citrin deficiency (NICCD).

## Function

Citrin (74 kDa) is a dimeric calcium-activated glutamate/aspartate carrier found in the mitochondrial membrane of mammals. Citrin is one of two isoforms of these mitochondrial calcium-activated glutamate/aspartate carriers found in humans and is predominately expressed in non-excitable tissues.[5]

Upon binding calcium, citrin catalyzes the transport of [glutamate](/source/Glutamate) and a proton into the mitochondrial matrix in exchange for [aspartate](/source/Aspartate) transport to the [cytosol](/source/Cytosol). Upon being transported by citrin from the mitochondrial matrix to the cytosol, aspartate is converted into [oxaloacetate](/source/Oxaloacetate), and then into [malate](/source/Malate), which is then transported back into the matrix by means of the [malate-aspartate shuttle](/source/Malate-aspartate_shuttle). Upon entering the mitochondrial matrix, malate is converted back into oxaloacetate to participate in the [citric acid cycle](/source/Citric_acid_cycle). Citrin is also important because it supplies liver cells with aspartate that is used during the [urea cycle](/source/Urea_cycle) and [gluconeogenesis](/source/Gluconeogenesis).[5]

## Structure

Calcium binding site within the N-terminal domain of citrin (PDB 4P5W).

The citrin monomer peptide has a three-domain structure, consisting of an N-terminal domain, a carrier domain, and a C-terminal domain. The N-terminal domain contains eight [EF-hand](/source/EF-hand) motifs and is responsible for the binding of a single calcium ion. The N-terminal domain is also responsible for the [dimerization](/source/Dimerization) of the protein to form the full glutamate/aspartate carrier. The carrier domain is responsible for transport activity and consists of six helical loops that link the N-terminal and C-terminal domains together. The C-terminal domain’s function is not fully understood yet, but it is thought to be an extra helix for the carrier domain to help account for its [hydrophobicity](/source/Hydrophobicity).[5]

Upon the binding of two calcium ions to the citrin dimer’s N-terminal domains, a structural change causes an [amphipathic](/source/Amphipathic) helix within the C-terminal domain to bind to a hydrophobic loop within the N-terminal domain, causing an opening. This opening gives the substrates such as glutamate and aspartate access to the inner carrier domain which transports them across the membrane. Upon the unbinding of calcium, the first and second EF motifs within the N-terminal domain block off and close the opening, preventing the passage of substrates.[5]

## Diseases

[Citrin deficiency](/source/Citrin_deficiency) is a liver metabolic disease and [urea cycle disorder](/source/Urea_cycle_disorder) caused by mutations in the *SLC25A13* gene, which codes for the citrin protein. Most of these mutations lead to an unfunctional citrin protein, meaning it cannot work to properly transport aspartate from the mitochondria to the cytosol. Aspartate plays a vital role in the urea cycle by reacting with [citrulline](/source/Citrulline) to form [argininosuccinate](/source/Argininosuccinate). Without adequate amounts of aspartate in the cytosol, this intermediate step in the urea cycle cannot happen, leading to an increase in the concentration of citrulline, ammonia, and other toxins since they can no longer be converted to urea by the liver.

## See also

- [Solute carrier family](/source/Solute_carrier_family)

- [Citrin deficiency](/source/Citrin_deficiency)

## References

1. **[^](#cite_ref-pmid10369257_1-0)** Kobayashi K, Sinasac DS, Iijima M, Boright AP, Begum L, Lee JR, Yasuda T, Ikeda S, Hirano R, Terazono H, Crackower MA, Kondo I, Tsui LC, Scherer SW, Saheki T (June 1999). "The gene mutated in adult-onset type II citrullinaemia encodes a putative mitochondrial carrier protein". *Nature Genetics*. **22** (2): 159–63. [doi](/source/Doi_(identifier)):[10.1038/9667](https://doi.org/10.1038%2F9667). [PMID](/source/PMID_(identifier)) [10369257](https://pubmed.ncbi.nlm.nih.gov/10369257). [S2CID](/source/S2CID_(identifier)) [20137905](https://api.semanticscholar.org/CorpusID:20137905).

1. **[^](#cite_ref-pmid12111366_2-0)** Saheki T, Kobayashi K (2002). ["Mitochondrial aspartate glutamate carrier (citrin) deficiency as the cause of adult-onset type II citrullinemia (CTLN2) and idiopathic neonatal hepatitis (NICCD)"](https://doi.org/10.1007%2Fs100380200046). *J. Hum. Genet*. **47** (7): 333–41. [doi](/source/Doi_(identifier)):[10.1007/s100380200046](https://doi.org/10.1007%2Fs100380200046). [PMID](/source/PMID_(identifier)) [12111366](https://pubmed.ncbi.nlm.nih.gov/12111366).

1. **[^](#cite_ref-pmid12602510_3-0)** Saheki T, Kobayashi K, Iijima M, Nishi I, Yasuda T, Yamaguchi N, Gao HZ, Jalil MA, Begum L, Li MX (2002). "Pathogenesis and pathophysiology of citrin (a mitochondrial aspartate glutamate carrier) deficiency". *Metab Brain Dis*. **17** (4): 335–46. [doi](/source/Doi_(identifier)):[10.1023/A:1021961919148](https://doi.org/10.1023%2FA%3A1021961919148). [PMID](/source/PMID_(identifier)) [12602510](https://pubmed.ncbi.nlm.nih.gov/12602510). [S2CID](/source/S2CID_(identifier)) [1712349](https://api.semanticscholar.org/CorpusID:1712349).

1. **[^](#cite_ref-pmid15050970_4-0)** Saheki T, Kobayashi K, Iijima M, Horiuchi M, Begum L, Jalil MA, Li MX, Lu YB, Ushikai M, Tabata A, Moriyama M, Hsiao KJ, Yang Y (2004). "Adult-onset type II citrullinemia and idiopathic neonatal hepatitis caused by citrin deficiency: involvement of the aspartate glutamate carrier for urea synthesis and maintenance of the urea cycle". *Mol. Genet. Metab*. 81. Suppl 1: S20–6. [doi](/source/Doi_(identifier)):[10.1016/j.ymgme.2004.01.006](https://doi.org/10.1016%2Fj.ymgme.2004.01.006). [PMID](/source/PMID_(identifier)) [15050970](https://pubmed.ncbi.nlm.nih.gov/15050970).

1. ^ [***a***](#cite_ref-pmid25410934_5-0) [***b***](#cite_ref-pmid25410934_5-1) [***c***](#cite_ref-pmid25410934_5-2) [***d***](#cite_ref-pmid25410934_5-3) Thangaratnarajah C, Ruprecht J, Kunji E (2014). ["Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers"](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250520). *Nat Commun*. **5** (5491): 5491. [Bibcode](/source/Bibcode_(identifier)):[2014NatCo...5.5491T](https://ui.adsabs.harvard.edu/abs/2014NatCo...5.5491T). [doi](/source/Doi_(identifier)):[10.1038/ncomms6491](https://doi.org/10.1038%2Fncomms6491). [PMC](/source/PMC_(identifier)) [4250520](https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4250520). [PMID](/source/PMID_(identifier)) [25410934](https://pubmed.ncbi.nlm.nih.gov/25410934).

## External links

- [citrin](https://meshb.nlm.nih.gov/record/ui?name=citrin) at the U.S. National Library of Medicine [Medical Subject Headings](/source/Medical_Subject_Headings) (MeSH)

- [GeneReviews/NCBI/NIH/UW entry on Citrin Deficiency](https://www.ncbi.nlm.nih.gov/books/NBK1181/)

- [*SLC25A13*](https://genome.ucsc.edu/cgi-bin/hgTracks?db=hg38&singleSearch=knownCanonical&position=SLC25A13) human gene location in the [UCSC Genome Browser](/source/UCSC_Genome_Browser).

- [*SLC25A13*](https://genome.ucsc.edu/cgi-bin/hgGene?db=hg38&hgg_type=knownGene&hgg_gene=SLC25A13) human gene details in the [UCSC Genome Browser](/source/UCSC_Genome_Browser).

- [Citrin Foundation](https://citrinfoundation.org/) non-profit funding research to cure citrin deficiency.

- [Citrin Foundation patient website](https://patient.citrinfoundation.org/en/) website with resources for citrin deficiency patients and families.

v t e Membrane proteins, carrier proteins: membrane transport proteins solute carrier (TC 2A) By group SLC1–10 (1): High affinity glutamate and neutral amino-acid transporter SLC1A1 SLC1A2 SLC1A3 SLC1A4 SLC1A5 SLC1A6 SLC1A7 (2): Facilitative GLUT transporter SLC2A1 SLC2A2 SLC2A3 SLC2A4 SLC2A5 SLC2A6 SLC2A7 SLC2A8 SLC2A9 SLC2A10 SLC2A11 SLC2A12 SLC2A13 SLC2A14 (3): Heavy subunits of heterodimeric amino-acid transporters SLC3A1 SLC3A2 (4): Bicarbonate transporter SLC4A1 SLC4A2 SLC4A3 SLC4A4 SLC4A5 SLC4A6 SLC4A7 SLC4A8 SLC4A9 SLC4A10 SLC4A11 (5): Sodium glucose cotransporter SLC5A1 SLC5A2 SLC5A3 SLC5A4 SLC5A5 SLC5A6 SLC5A7 SLC5A8 SLC5A9 SLC5A10 SLC5A11 SLC5A12 (6): Sodium- and chloride- dependent sodium:neurotransmitter symporters SLC6A1 SLC6A2 SLC6A3 SLC6A4 SLC6A5 SLC6A6 SLC6A7 SLC6A8 SLC6A9 SLC6A10 SLC6A11 SLC6A12 SLC6A13 SLC6A14 SLC6A15 SLC6A16 SLC6A17 SLC6A18 SLC6A19 SLC6A20 (7): Cationic amino-acid transporter/glycoprotein-associated SLC7A1 SLC7A2 SLC7A3 SLC7A4 Glycoprotein-associated/light or catalytic subunits of heterodimeric amino-acid transporters SLC7A5 SLC7A6 SLC7A7 SLC7A8 SLC7A9 SLC7A10 SLC7A11 SLC7A13 SLC7A14 (8): Na+/Ca2+ exchanger SLC8A1 SLC8A2 SLC8A3 (9): Na+/H+ exchanger SLC9A1 SLC9A2 SLC9A3 SLC9A4 SLC9A5 SLC9A6 SLC9A7 SLC9A8 SLC9A9 SLC9A10 SLC9A11 (10): Sodium bile salt cotransport SLC10A1 SLC10A2 SLC10A3 SLC10A4 SLC10A5 SLC10A6 SLC10A7 SLC11–20 (11): Proton coupled metal ion transporter SLC11A1 SLC11A2 SLC11A3 (12): Electroneutral cation-Cl cotransporter SLC12A1 SLC12A2 SLC12A3 SLC12A4 SLC12A5 SLC12A6 SLC12A7 SLC12A8 SLC12A9 (13): human Na+-sulfate/carboxylate cotransporter SLC13A1 SLC13A2 SLC13A3 SLC13A4 SLC13A5 (14): Urea transporter SLC14A1 SLC14A2 (15): Proton oligopeptide cotransporter SLC15A1 SLC15A2 SLC15A3 SLC15A4 (16): Monocarboxylate transporter SLC16A1 SLC16A2 SLC16A3 SLC16A4 SLC16A5 SLC16A6 SLC16A7 SLC16A8 SLC16A9 SLC16A10 SLC16A11 SLC16A12 SLC16A13 SLC16A14 (17): Vesicular glutamate transporter 1 SLC17A1 SLC17A2 SLC17A3 SLC17A4 SLC17A5 SLC17A6 SLC17A7 SLC17A8 SLC17A9 (18): Vesicular monoamine transporter SLC18A1 SLC18A2 SLC18A3 (19): Folate/thiamine transporter SLC19A1 SLC19A2 SLC19A3 (20): Type III Na+-phosphate cotransporter SLC20A1 SLC20A2 SLC21–30 (21): Organic anion-transporting polypeptide SLCO1A2 SLCO1B1 SLCO1B3 SLCO1B4 SLCO1C1 SLCO2A1 SLCO2B1 SLCO3A1 SLCO4A1 SLCO4C1 SLCO5A1 SLCO6A1 (22): Organic cation/anion/zwitterion transporter SLC22A1 SLC22A2 SLC22A3 SLC22A4 SLC22A5 SLC22A6 SLC22A7 SLC22A8 SLC22A9 SLC22A10 SLC22A11 SLC22A12 SLC22A13 SLC22A14 SLC22A15 SLC22A16 SLC22A17 SLC22A18 SLC22A20 SLC22A25 (23): Na+-dependent ascorbic acid transporter SLC23A1 SLC23A2 SLC23A3 SLC23A4 (24): Na+/(Ca2+-K+) exchanger SLC24A1 SLC24A2 SLC24A3 SLC24A4 SLC24A5 SLC24A6 (25): Mitochondrial carrier SLC25A1 SLC25A2 SLC25A3 SLC25A4 SLC25A5 SLC25A6 SLC25A7 SLC25A8 SLC25A9 SLC25A10 SLC25A11 SLC25A12 SLC25A13 SLC25A14 SLC25A15 SLC25A16 SLC25A17 SLC25A18 SLC25A19 SLC25A20 SLC25A21 SLC25A22 SLC25A23 SLC25A24 SLC25A25 SLC25A26 SLC25A27 SLC25A28 SLC25A29 SLC25A30 SLC25A31 SLC25A32 SLC25A33 SLC25A34 SLC25A35 SLC25A36 SLC25A37 SLC25A38 SLC25A39 SLC25A40 SLC25A41 SLC25A42 SLC25A43 SLC25A44 SLC25A45 SLC25A46 (26): Multifunctional anion exchanger SLC26A1 SLC26A2 SLC26A3 SLC26A4 SLC26A5 SLC26A6 SLC26A7 SLC26A8 SLC26A9 SLC26A10 SLC26A11 (27): Fatty acid transport proteins SLC27A1 SLC27A2 SLC27A3 SLC27A4 SLC27A5 SLC27A6 (28): Na+-coupled nucleoside transport SLC28A1 SLC28A2 SLC28A3 (29): Facilitative nucleoside transporter SLC29A1 SLC29A2 SLC29A3 SLC29A4 (30): Zinc efflux SLC30A1 SLC30A2 SLC30A3 SLC30A4 SLC30A5 SLC30A6 SLC30A7 SLC30A8 SLC30A9 SLC30A10 SLC31–40 (31): Copper transporter SLC31A1 (32): Vesicular glutamate transporter 1 SLC32A1 (33): Acetyl-CoA transporter SLC33A1 (34): type II Na+-phosphate cotransporter SLC34A1 SLC34A2 SLC34A3 (35): Nucleoside-sugar transporter SLC35A1 SLC35A2 SLC35A3 SLC35A4 SLC35A5 SLC35B1 SLC35B2 SLC35B3 SLC35B4 SLC35C1 SLC35C2 SLC35D1 SLC35D2 SLC35D3 SLC35E1 SLC35E2 SLC35E3 SLC35E4 (36): Proton coupled amino acid transporter SLC36A1 SLC36A2 SLC36A3 SLC36A4 (37): Sugar-phosphate/phosphate exchanger SLC37A1 SLC37A2 SLC37A3 SLC37A4 (38): System A & N, sodium-coupled neutral amino-acid transporter SLC38A1 SLC38A2 SLC38A3 SLC38A4 SLC38A5 SLC38A6 SLC38A10 (39): Metal ion transporter SLC39A1 SLC39A2 SLC39A3 SLC39A4 SLC39A5 SLC39A6 SLC39A7 SLC39A8 SLC39A9 SLC39A10 SLC39A11 SLC39A12 SLC39A13 SLC39A14 (40): Basolateral iron transporter SLC40A1 SLC41–48 (41): Magnesium transporter E SLC41A1 SLC41A2 SLC41A3 (42): Ammonia transporter SLC42A1 SLC42A2 SLC42A3 (43): Na+-independent, system-L like amino-acid transporter SLC43A1 SLC43A2 SLC43A3 (44): Choline-like transporter SLC44A1 SLC44A2 SLC44A3 SLC44A4 SLC44A5 (45): Putative sugar transporter SLC45A1 SLC45A2 SLC54A3 SLC45A4 (46): Folate transporter SLC46A1 SLC46A2 SLC46A3 (47): Multidrug and toxin extrusion SLC47A1 SLC47A2 (48): Heme transporter SLCO1–4 SLCO1A2 SLCO1B1 SLCO1B3 SLCO2B1 SLCO3A1 SLCO4A1 Ion pumps Symporter, Cotransporter Na+/K+,Cl− Na+/Pi3 Na+/Cl− Na+/glucose Na+/I− Cl−/K+ 4 5 Antiporter (exchanger) Na+/H+ Na+/Ca2+ Na+/(Ca2+-K+) - Cl−/HCO− 3 (Band 3) Cl−-formate Cl−-oxalate see also solute carrier disorders

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Adapted from the Wikipedia article [Citrin](https://en.wikipedia.org/wiki/Citrin) by Wikipedia contributors ([contributor history](https://en.wikipedia.org/wiki/Citrin?action=history)). Available under [Creative Commons Attribution-ShareAlike 4.0 International](https://creativecommons.org/licenses/by-sa/4.0/). Changes may have been made.