Citrin

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solute carrier family 25, member 13 (citrin)
Citrin Structure.png
The protein citrin (PDB 4P5W) is a dimer and is composed of two equal polypeptide chains.
Identifiers
SymbolSLC25A13
Alt. symbolsCTLN2
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 which in humans is encoded by the SLC25A13 gene. [1]

Contents

Citrin is associated with type II 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 and a proton into the mitochondrial matrix in exchange for aspartate transport to the cytosol. Upon being transported by citrin from the mitochondrial matrix to the cytosol, aspartate is converted into oxaloacetate, and then into malate, which is then transported back into the matrix by means of the malate-aspartate shuttle. Upon entering the mitochondrial matrix, malate is converted back into oxaloacetate to participate in the citric acid cycle. Citrin is also important because it supplies liver cells with aspartate that is used during the urea cycle and gluconeogenesis. [5]

Structure

Calcium binding site within the N-terminal domain of citrin (PDB 4P5W). Calcium Binding to Citrin.png
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 motifs and is responsible for the binding of a single calcium ion. The N-terminal domain is also responsible for the 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. [5]

Upon the binding of two calcium ions to the citrin dimer’s N-terminal domains, a structural change causes an 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

Type II citrullinemia is a liver disease 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 to form 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

Related Research Articles

<span class="mw-page-title-main">Citric acid cycle</span> Interconnected biochemical reactions releasing energy

The citric acid cycle—also known as the Krebs cycle, Szent-Györgyi-Krebs cycle or the TCA cycle (tricarboxylic acid cycle)—is a series of biochemical reactions to release the energy stored in nutrients through the oxidation of acetyl-CoA derived from carbohydrates, fats, and proteins. The chemical energy released is available under the form of ATP. The Krebs cycle is used by organisms that respire (as opposed to organisms that ferment) to generate energy, either by anaerobic respiration or aerobic respiration. In addition, the cycle provides precursors of certain amino acids, as well as the reducing agent NADH, that are used in numerous other reactions. Its central importance to many biochemical pathways suggests that it was one of the earliest components of metabolism. Even though it is branded as a 'cycle', it is not necessary for metabolites to follow only one specific route; at least three alternative segments of the citric acid cycle have been recognized.

The urea cycle (also known as the ornithine cycle) is a cycle of biochemical reactions that produces urea (NH2)2CO from ammonia (NH3). Animals that use this cycle, mainly amphibians and mammals, are called ureotelic.

<span class="mw-page-title-main">Ornithine transcarbamylase</span> Mammalian protein found in Homo sapiens

Ornithine transcarbamylase (OTC) is an enzyme that catalyzes the reaction between carbamoyl phosphate (CP) and ornithine (Orn) to form citrulline (Cit) and phosphate (Pi). There are two classes of OTC: anabolic and catabolic. This article focuses on anabolic OTC. Anabolic OTC facilitates the sixth step in the biosynthesis of the amino acid arginine in prokaryotes. In contrast, mammalian OTC plays an essential role in the urea cycle, the purpose of which is to capture toxic ammonia and transform it into urea, a less toxic nitrogen source, for excretion.

<span class="mw-page-title-main">Oxaloacetic acid</span> Organic compound

Oxaloacetic acid (also known as oxalacetic acid or OAA) is a crystalline organic compound with the chemical formula HO2CC(O)CH2CO2H. Oxaloacetic acid, in the form of its conjugate base oxaloacetate, is a metabolic intermediate in many processes that occur in animals. It takes part in gluconeogenesis, the urea cycle, the glyoxylate cycle, amino acid synthesis, fatty acid synthesis and the citric acid cycle.

<span class="mw-page-title-main">Malate dehydrogenase</span> Class of enzymes

Malate dehydrogenase (EC 1.1.1.37) (MDH) is an enzyme that reversibly catalyzes the oxidation of malate to oxaloacetate using the reduction of NAD+ to NADH. This reaction is part of many metabolic pathways, including the citric acid cycle. Other malate dehydrogenases, which have other EC numbers and catalyze other reactions oxidizing malate, have qualified names like malate dehydrogenase (NADP+).

<span class="mw-page-title-main">Mitochondrial matrix</span> Space within the inner membrane of the mitochondrion

In the mitochondrion, the matrix is the space within the inner membrane. The word "matrix" stems from the fact that this space is viscous, compared to the relatively aqueous cytoplasm. The mitochondrial matrix contains the mitochondrial DNA, ribosomes, soluble enzymes, small organic molecules, nucleotide cofactors, and inorganic ions.[1] The enzymes in the matrix facilitate reactions responsible for the production of ATP, such as the citric acid cycle, oxidative phosphorylation, oxidation of pyruvate, and the beta oxidation of fatty acids.

<span class="mw-page-title-main">Citrullinemia</span> Medical condition

Citrullinemia is an autosomal recessive urea cycle disorder that causes ammonia and other toxic substances to accumulate in the blood.

<span class="mw-page-title-main">Pyruvate carboxylase</span> Enzyme

Pyruvate carboxylase (PC) encoded by the gene PC is an enzyme of the ligase class that catalyzes the physiologically irreversible carboxylation of pyruvate to form oxaloacetate (OAA).

<span class="mw-page-title-main">Argininosuccinate synthase</span> Enzyme

Argininosuccinate synthase or synthetase is an enzyme that catalyzes the synthesis of argininosuccinate from citrulline and aspartate. In humans, argininosuccinate synthase is encoded by the ASS gene located on chromosome 9.

<span class="mw-page-title-main">N-Acetylglutamate synthase deficiency</span> Medical condition

N-Acetylglutamate synthase deficiency is an autosomal recessive urea cycle disorder.

<span class="mw-page-title-main">Malate–aspartate shuttle</span> Biochemical system for transporting electrons produced during glycolysis

The malate–aspartate shuttle is a biochemical system for translocating electrons produced during glycolysis across the semipermeable inner membrane of the mitochondrion for oxidative phosphorylation in eukaryotes. These electrons enter the electron transport chain of the mitochondria via reduction equivalents to generate ATP. The shuttle system is required because the mitochondrial inner membrane is impermeable to NADH, the primary reducing equivalent of the electron transport chain. To circumvent this, malate carries the reducing equivalents across the membrane.

<span class="mw-page-title-main">Mitochondrial carrier</span>

Mitochondrial carriers are proteins from solute carrier family 25 which transfer molecules across the membranes of the mitochondria. Mitochondrial carriers are also classified in the Transporter Classification Database. The Mitochondrial Carrier (MC) Superfamily has been expanded to include both the original Mitochondrial Carrier (MC) family and the Mitochondrial Inner/Outer Membrane Fusion (MMF) family.

The mitochondrial shuttles are biochemical transport systems used to transport reducing agents across the inner mitochondrial membrane. NADH as well as NAD+ cannot cross the membrane, but it can reduce another molecule like FAD and [QH2] that can cross the membrane, so that its electrons can reach the electron transport chain.

<span class="mw-page-title-main">GOT2</span> Mitochondrial enzyme involved in amino acid metabolism

Aspartate aminotransferase, mitochondrial is an enzyme that in humans is encoded by the GOT2 gene. Glutamic-oxaloacetic transaminase is a pyridoxal phosphate-dependent enzyme which exists in cytoplasmic and inner-membrane mitochondrial forms, GOT1 and GOT2, respectively. GOT plays a role in amino acid metabolism and the urea and Kreb's cycle. Also, GOT2 is a major participant in the malate-aspartate shuttle, which is a passage from the cytosol to the mitochondria. The two enzymes are homodimeric and show close homology. GOT2 has been seen to have a role in cell proliferation, especially in terms of tumor growth.

<span class="mw-page-title-main">Phosphate carrier protein, mitochondrial</span>

Phosphate carrier protein, mitochondrial is a protein that in humans is encoded by the SLC25A3 gene. The encoded protein is a transmembrane protein located in the mitochondrial inner membrane and catalyzes the transport of phosphate ions across it for the purpose of oxidative phosphorylation. There are two significant isoforms of this gene expressed in human cells, which differ slightly in structure and function. Mutations in this gene can cause mitochondrial phosphate carrier deficiency (MPCD), a fatal disorder of oxidative phosphorylation symptomized by lactic acidosis, neonatal hypotonia, hypertrophic cardiomyopathy, and death within the first year of life.

<span class="mw-page-title-main">Calcium-binding mitochondrial carrier protein Aralar1</span> Protein-coding gene in the species Homo sapiens

Calcium-binding mitochondrial carrier protein Aralar1 is a protein that in humans is encoded by the SLC25A12 gene. Aralar is an integral membrane protein located in the inner mitochondrial membrane. Its primary function as an antiporter is the transport of cytoplasmic glutamate with mitochondrial aspartate across the inner mitochondrial membrane, dependent on the binding of one calcium ion. Mutations in this gene cause early infantile epileptic encephalopathy 39 (EIEE39), symptomized by global hypomyelination of the central nervous system, refractory seizures, and neurodevelopmental impairment. This gene has connections to autism.

<span class="mw-page-title-main">Malate dehydrogenase 2</span> Enzyme that oxidizes malate to oxaloacetate in Krebs cycle

Malate dehydrogenase, mitochondrial also known as malate dehydrogenase 2 is an enzyme that in humans is encoded by the MDH2 gene.

<span class="mw-page-title-main">Tricarboxylate transport protein, mitochondrial</span> Mammalian protein found in Homo sapiens

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.

<span class="mw-page-title-main">Citrullinemia type I</span> Medical condition

Citrullinemia type I (CTLN1), also known as arginosuccinate synthetase deficiency, is a rare disease caused by a deficiency in argininosuccinate synthetase, an enzyme involved in excreting excess nitrogen from the body. There are mild and severe forms of the disease, which is one of the urea cycle disorders.

<span class="mw-page-title-main">Citrate–malate shuttle</span>

The citrate-malate shuttle is a series of chemical reactions, commonly referred to as a biochemical cycle or system, that transports acetyl-CoA in the mitochondrial matrix across the inner and outer mitochondrial membranes for fatty acid synthesis. Mitochondria are enclosed in a double membrane. As the inner mitochondrial membrane is impermeable to acetyl-CoA, the shuttle system is essential to fatty acid synthesis in the cytosol. It plays an important role in the generation of lipids in the liver.

References

  1. 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:10.1038/9667. PMID   10369257. S2CID   20137905.
  2. 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)". J. Hum. Genet. 47 (7): 333–41. doi: 10.1007/s100380200046 . PMID   12111366.
  3. 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:10.1023/A:1021961919148. PMID   12602510. S2CID   1712349.
  4. 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:10.1016/j.ymgme.2004.01.006. PMID   15050970.
  5. 1 2 3 4 Thangaratnarajah C, Ruprecht J, Kunji E (2014). "Calcium-induced conformational changes of the regulatory domain of human mitochondrial aspartate/glutamate carriers". Nat Commun. 5 (5491): 5491. doi:10.1038/ncomms6491. PMC   4250520 . PMID   25410934.