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SLC25A1
Identifiers
Aliases	SLC25A1, CTP, D2L2AD, SEA, SLC20A3, solute carrier family 25 member 1, CMS23
External IDs	OMIM: 190315; MGI: 1345283; HomoloGene: 136551; GeneCards: SLC25A1; OMA:SLC25A1 - orthologs
Gene location (Human) Chr. Chromosome 22 (human) Band 22q11.21 Start 19,175,581 bp End 19,178,739 bp
Gene location (Mouse) Chr. Chromosome 16 (mouse) Band 16 A3|16 11.11 cM Start 17,743,087 bp End 17,746,083 bp
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in mucosa of transverse colon right lobe of liver right adrenal cortex left adrenal cortex mucosa of ileum duodenum left coronary artery stromal cell of endometrium popliteal artery tibial arteries Top expressed in brown adipose tissue lactiferous gland facial motor nucleus left lobe of liver subcutaneous adipose tissue right kidney otolith organ adrenal gland utricle lip More reference expression data BioGPS More reference expression data
Gene ontology Molecular function citrate transmembrane transporter activity tricarboxylic acid transmembrane transporter activity transmembrane transporter activity citrate secondary active transmembrane transporter activity Cellular component extracellular exosome membrane mitochondrion nucleus mitochondrial inner membrane integral component of membrane Biological process gluconeogenesis transmembrane transport tricarboxylic acid transmembrane transport mitochondrial citrate transmembrane transport fatty-acyl-CoA biosynthetic process mitochondrial transport transport Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 6576 13358 Ensembl ENSG00000100075 ENSMUSG00000003528 UniProt P53007 Q8JZU2 RefSeq (mRNA) NM_001256534 NM_001287387 NM_005984 NM_153150 RefSeq (protein) NP_001243463 NP_001274316 NP_005975 NP_001243463.1 NP_001274316.1 NP_694790 Location (UCSC) Chr 22: 19.18 – 19.18 Mb Chr 16: 17.74 – 17.75 Mb PubMed search
Wikidata
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Tricarboxylate transport protein, mitochondrial, also known as tricarboxylate carrier protein and citrate transport protein (CTP), is a protein that in humans is encoded by the SLC25A1 gene. SLC25A1 belongs to the mitochondrial carrier gene family SLC25. High levels of the tricarboxylate transport protein are found in the liver, pancreas and kidney. Lower or no levels are present in the brain, heart, skeletal muscle, placenta and lung.

The tricarboxylate transport protein is located within the inner mitochondria membrane. It provides a link between the mitochondrial matrix and cytosol by transporting citrate through the impermeable inner mitochondrial membrane in exchange for malate from the cytosol. The citrate transported out of the mitochondrial matrix by the tricarboxylate transport protein is catalyzed by citrate lyase to acetyl CoA, the starting material for fatty acid biosynthesis, and oxaloacetate. As well, cytosolic NADPH + H necessary for fatty acid biosynthesis is generated in the reduction of oxaloacetate to malate and pyruvate by malate dehydrogenase and the malic enzyme. For these reasons, the tricarboxylate transport protein is considered to play a key role in fatty acid synthesis.

Structure

The structure of the tricarboxylate transport protein is consistent with the structures of other mitochondrial carriers. In particular, the tricarboxylate transport protein has a tripartite structure consisting of three repeated domains that are approximately 100 amino acids in length. Each repeat forms a transmembrane domain consisting of two hydrophobic α-helices. The amino and carboxy termini are located on the cytosolic side of the inner mitochondrial membrane. Each domain is linked by two hydrophilic loops located on the cytosolic side of the membrane. The two α-helices of each repeated domain are connected by hydrophilic loops located on the matrix side of the membrane. A salt bridge network is present on both the matrix side and cytoplasmic side of the tricarboxylate transport protein.

Transport mechanism

The tricarboxylate transport protein exists in two states: a cytoplasmic state where it accepts malate from the cytoplasm and a matrix state where it accepts citrate from the mitochondrial matrix. A single binding site is present near the center of the cavity of the tricarboxylate transport protein, which can be either exposed to the cytosol or the mitochondrial matrix depending on the state. A substrate induced conformational change occurs when citrate enters from the matrix side and binds to the central cavity of the tricarboxylate transport protein. This conformational change opens a gate on the cytosolic side and closes the gate on the matrix side. Likewise, when malate enters from the cytosolic side, the matrix gate opens and the cytosolic gate closes. Each side of the transporter is open and closed by the disruption and formation of the salt bridge networks, which allows access to the single binding site.

Disease relevance

Mutations in this gene have been associated with the inborn error of metabolism combined D-2- and L-2-hydroxyglutaric aciduria, which was the first reported case of a pathogenic mutation of the SLC25A1 gene. Patients with D-2/L-2-hydroxyglutaric aciduria display neonatal onset metabolic encephalopathy, infantile epilepsy, global developmental delay, muscular hypotonia and early death. It is believed low levels of citrate in the cytosol and high levels of citrate in the mitochondria caused by the impaired citrate transport plays a role in the disease. In addition, increased expression of the tricarboxylate transport protein has been linked to cancer and the production of inflammatory mediators. Therefore, it has been suggested that inhibition of the tricarboxylate transport protein may have a therapeutic effect in chronic inflammation diseases and cancer.

See also

• SLC25A1+protein,+human at the U.S. National Library of Medicine Medical Subject Headings (MeSH)

References

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Further reading

• Ewing RM, Chu P, Elisma F, Li H, Taylor P, Climie S, McBroom-Cerajewski L, Robinson MD, O'Connor L, Li M, Taylor R, Dharsee M, Ho Y, Heilbut A, Moore L, Zhang S, Ornatsky O, Bukhman YV, Ethier M, Sheng Y, Vasilescu J, Abu-Farha M, Lambert JP, Duewel HS, Stewart II, Kuehl B, Hogue K, Colwill K, Gladwish K, Muskat B, Kinach R, Adams SL, Moran MF, Morin GB, Topaloglou T, Figeys D (2007). "Large-scale mapping of human protein-protein interactions by mass spectrometry". Molecular Systems Biology. 3 (1): 89. doi:10.1038/msb4100134. PMC 1847948. PMID 17353931.
• Rual JF, Venkatesan K, Hao T, Hirozane-Kishikawa T, Dricot A, Li N, Berriz GF, Gibbons FD, Dreze M, Ayivi-Guedehoussou N, Klitgord N, Simon C, Boxem M, Milstein S, Rosenberg J, Goldberg DS, Zhang LV, Wong SL, Franklin G, Li S, Albala JS, Lim J, Fraughton C, Llamosas E, Cevik S, Bex C, Lamesch P, Sikorski RS, Vandenhaute J, Zoghbi HY, Smolyar A, Bosak S, Sequerra R, Doucette-Stamm L, Cusick ME, Hill DE, Roth FP, Vidal M (October 2005). "Towards a proteome-scale map of the human protein-protein interaction network". Nature. 437 (7062): 1173–8. Bibcode:2005Natur.437.1173R. doi:10.1038/nature04209. PMID 16189514. S2CID 4427026.
• Gong W, Emanuel BS, Collins J, Kim DH, Wang Z, Chen F, Zhang G, Roe B, Budarf ML (June 1996). "A transcription map of the DiGeorge and velo-cardio-facial syndrome minimal critical region on 22q11". Human Molecular Genetics. 5 (6): 789–800. CiteSeerX 10.1.1.539.9441. doi:10.1093/hmg/5.6.789. PMID 8776594.
• Goldmuntz E, Wang Z, Roe BA, Budarf ML (April 1996). "Cloning, genomic organization, and chromosomal localization of human citrate transport protein to the DiGeorge/velocardiofacial syndrome minimal critical region". Genomics. 33 (2): 271–6. doi:10.1006/geno.1996.0191. PMID 8660975.
• Bonofiglio D, Santoro A, Martello E, Vizza D, Rovito D, Cappello AR, Barone I, Giordano C, Panza S, Catalano S, Iacobazzi V, Dolce V, Andò S (June 2013). "Mechanisms of divergent effects of activated peroxisome proliferator-activated receptor-γ on mitochondrial citrate carrier expression in 3T3-L1 fibroblasts and mature adipocytes". Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids. 1831 (6): 1027–36. doi:10.1016/j.bbalip.2013.01.014. hdl:11586/65706. PMID 23370576.

This article incorporates text from the United States National Library of Medicine, which is in the public domain.

• Genes on human chromosome 22
• Solute carrier family