Citrin, also known as solute carrier family 25, member 13 (citrin) or SLC25A13, is a

protein Proteins are large biomolecules and macromolecules that comprise one or more long chains of amino acid residue (biochemistry), residues. Proteins perform a vast array of functions within organisms, including Enzyme catalysis, catalysing metab ...

which in humans is encoded by the ''SLC25A13'' gene. Citrin is associated with type II

citrullinemia Citrullinemia is an autosomal recessive urea cycle disorder that causes ammonia and other toxic substances to accumulate in the blood.Freedberg, et al. (2003). ''Fitzpatrick's Dermatology in General Medicine''. (6th ed.). McGraw-Hill. . Two for ...

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. Upon binding calcium, citrin catalyzes the transport of

glutamate Glutamic acid (symbol Glu or E; known as glutamate in its anionic form) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a Essential amino acid, non-essential nutrient for humans, meaning that ...

and a proton into the mitochondrial matrix in exchange for

aspartate Aspartic acid (symbol Asp or D; the ionic form is known as aspartate), is an α-amino acid that is used in the biosynthesis of proteins. The L-isomer of aspartic acid is one of the 22 proteinogenic amino acids, i.e., the building blocks of protein ...

transport to the

cytosol The cytosol, also known as cytoplasmic matrix or groundplasm, is one of the liquids found inside cells ( intracellular fluid (ICF)). It is separated into compartments by membranes. For example, the mitochondrial matrix separates the mitochondri ...

. Upon being transported by citrin from the mitochondrial matrix to the cytosol, aspartate is converted into

oxaloacetate 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 ...

, and then into

malate Malic acid is an organic compound with the molecular formula . It is a dicarboxylic acid that is made by all living organisms, contributes to the sour taste of fruits, and is used as a food additive. Malic acid has two stereoisomeric forms ( ...

, 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 The citric acid cycle—also known as the Krebs cycle, Szent–Györgyi–Krebs cycle, or TCA cycle (tricarboxylic acid cycle)—is a series of chemical reaction, biochemical reactions that release the energy stored in nutrients through acetyl-Co ...

. Citrin is also important because it supplies liver cells with aspartate that is used during the

urea cycle 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. The urea cycle converts highl ...

and

gluconeogenesis Gluconeogenesis (GNG) is a metabolic pathway that results in the biosynthesis of glucose from certain non-carbohydrate carbon substrates. It is a ubiquitous process, present in plants, animals, fungi, bacteria, and other microorganisms. In verte ...

Structure

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 The EF hand is a helix–loop–helix structural domain or ''motif'' found in a large family of calcium-binding proteins. The EF-hand motif contains a helix–loop–helix topology, much like the spread thumb and forefinger of the human hand, in ...

motifs and is responsible for the binding of a single calcium ion. The N-terminal domain is also responsible for the

dimerization In chemistry, dimerization is the process of joining two identical or similar molecular entities by bonds. The resulting bonds can be either strong or weak. Many symmetrical chemical species are described as dimers, even when the monomer is u ...

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 In chemistry, hydrophobicity is the chemical property of a molecule (called a hydrophobe) that is seemingly intermolecular force, repelled from a mass of water. In contrast, hydrophiles are attracted to water. Hydrophobic molecules tend to b ...

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

amphipathic In chemistry, an amphiphile (), or amphipath, is a chemical compound possessing both hydrophilic (''water-loving'', polar) and lipophilic (''fat-loving'', nonpolar) properties. Such a compound is called amphiphilic or amphipathic. Amphiphilic c ...

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.

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 The organic compound citrulline is an α-amino acid. Its name is derived from '' citrullus'', the Latin word for watermelon. Although named and described by gastroenterologists since the late 19th century, it was first isolated from watermelon in ...

to form

argininosuccinate Argininosuccinic acid is a non-proteinogenic amino acid that is an important intermediate in the urea cycle. It is also known as argininosuccinate. Reactions Some cells synthesize argininosuccinic acid from citrulline and aspartic acid and use ...

. 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.

References

External links

*
GeneReviews/NCBI/NIH/UW entry on Citrin Deficiency
* *
Citrin Foundation
non-profit funding research to cure citrin deficiency.
Citrin Foundation patient website
website with resources for citrin deficiency patients and families. Solute carrier family EF-hand-containing proteins {{membrane-protein-stub

Function

Structure

Diseases

See also

References

External links