Carboxyglutamic acid (or the conjugate base, carboxyglutamate), is an uncommon
amino acid
Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha ...
introduced into proteins by a
post-translational
Post-translational modification (PTM) is the covalent and generally enzymatic modification of proteins following protein biosynthesis. This process occurs in the endoplasmic reticulum and the golgi apparatus. Proteins are synthesized by ribosomes ...
carboxylation
Carboxylation is a chemical reaction in which a carboxylic acid is produced by treating a substrate with carbon dioxide. The opposite reaction is decarboxylation. In chemistry, the term carbonation is sometimes used synonymously with carboxylation ...
of
glutamic acid
Glutamic acid (symbol Glu or E; the ionic form is known as glutamate) is an α-amino acid that is used by almost all living beings in the biosynthesis of proteins. It is a non-essential nutrient for humans, meaning that the human body can syn ...
residues. This modification is found, for example, in
clotting factor
Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It potentially results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The mechanism ...
s and other proteins of the coagulation cascade. This modification introduces an affinity for
calcium ions
Calcium ions (Ca2+) contribute to the physiology and biochemistry of organisms' cells. They play an important role in signal transduction pathways, where they act as a second messenger, in neurotransmitter release from neurons, in contraction of ...
. In the blood coagulation cascade,
vitamin K
Vitamin K refers to structurally similar, fat-soluble vitamers found in foods and marketed as dietary supplements. The human body requires vitamin K for post-synthesis modification of certain proteins that are required for blood coagulat ...
is required to introduce γ-carboxylation of clotting factors II, VII, IX, X and
protein Z
Protein Z (PZ or PROZ) is a Protein in humans which is encoded by the ''PROZ'' gene.
Protein Z is a member of the coagulation cascade, the group of blood proteins that leads to the formation of blood clots. It is a glycoprotein. Protein Z functi ...
.
Synthesis
In the biosynthesis of γ-carboxyglutamic acid, the γ-proton on glutamic acid is abstracted, and CO
2 is subsequently added. The reaction intermediate is a γ-glutamyl carbanion.
This reaction is catalyzed by a carboxylase that requires vitamin K as its cofactor. It is not exactly known how vitamin K participates, but it is hypothesized that a free cysteine residue in the carboxylase converts vitamin K into an active strong base that in turn abstracts a hydrogen from glutamic acid's γ-carbon. Then CO
2 is added to the γ-carbon to form γ-carboxyglutamic acid.
Fig. 1.
γ-Carboxyglutamic acid-rich (GLA) domain
A number of γ-carboxyglutamate residues are present in the γ-carboxyglutamic acid-rich ("GLA") domain. This GLA domain is known to be found in over a dozen known proteins, including coagulation factors X, VII, IX, and XIV,
vitamin K-dependent protein S and Z,
prothrombin
Thrombin (, ''fibrinogenase'', ''thrombase'', ''thrombofort'', ''topical'', ''thrombin-C'', ''tropostasin'', ''activated blood-coagulation factor II'', ''blood-coagulation factor IIa'', ''factor IIa'', ''E thrombin'', ''beta-thrombin'', ''gamma- ...
,
transthyretin
Transthyretin (TTR or TBPA) is a transport protein in the plasma and cerebrospinal fluid that transports the thyroid hormone thyroxine (T4) and retinol to the liver. This is how transthyretin gained its name: ''transports thyroxine and retin ...
,
osteocalcin
Osteocalcin, also known as bone gamma-carboxyglutamic acid-containing protein (BGLAP), is a small (49-amino-acid) noncollagenous protein hormone found in bone and dentin, first identified as a calcium-binding protein.
Because osteocalcin has g ...
,
matrix Gla protein
Matrix Gla protein (MGP) is member of a family of vitamin K2 dependent, Gla-containing proteins. MGP has a high affinity binding to calcium ions, similar to other Gla-containing proteins. The protein acts as an inhibitor of vascular mineraliz ...
(MGP),
inter-alpha trypsin inhibitor heavy chain H2, and growth arrest-specific protein 6 (
GAS6
Growth arrest – specific 6, also known as GAS6, is a human gene coding for the GAS6 protein. It is similar to the Protein S with the same domain organization and 43% amino acid identity. It was originally found as a gene upregulated by growth ...
). The Gla domain is responsible for high-affinity binding of calcium ions (Ca
2+) to Gla proteins, which is often necessary for their conformation, and always necessary for their function.
Role in coagulation
γ-Carboxyglutamic acid residues play an important role in coagulation. The high-affinity calcium binding sites in the GLA domain of factor IX, which is a serine protease of the coagulation system, were found to partially mediate the binding of factor IXa to platelets and in factor-X activation. In addition, upon mechanical injury to the blood vessel wall, a cell-associated tissue factor becomes exposed and initiates a series of enzymatic reactions localized on a membrane surface generally provided by cells and accumulating platelets. Gla residues partly govern the activation and binding of circulating blood-clotting enzymes and zymogens to this exposed cell membrane surface. Specifically, gla residues are needed in calcium binding and in exposing hydrophobic membrane binding regions to the cell bilayer. Lack of these gla residues results in impaired coagulation or even anticoagulation, which may lead to bleeding diathesis or thrombosis.
In addition, removal of calcium ion from these proteins with an organic chelator, such as
citrate
Citric acid is an organic compound with the chemical formula HOC(CO2H)(CH2CO2H)2. It is a colorless weak organic acid. It occurs naturally in citrus fruits. In biochemistry, it is an intermediate in the citric acid cycle, which occurs in t ...
ion, causes their dysfunction, and prevents blood from coagulating. Thus, citrate addition to blood is the most common method of storing it in a liquid state between harvest and transfusion.
See also
*
Gamma-glutamyl carboxylase
Gamma-glutamyl carboxylase is an enzyme that in humans is encoded by the ''GGCX'' gene, located on chromosome 2 at 2p12.
Function
Gamma-glutamyl carboxylase is an enzyme that catalyzes the posttranslational modification of vitamin K-dependent p ...
References
{{DEFAULTSORT:Carboxyglutamic Acid
Amino acids
Post-translational modification
Tricarboxylic acids
Non-proteinogenic amino acids