Cofactor in carboxylation reactions
Vitamin K plays an essential role as a cofactor in the conversion of coagulation proteins into their coagulant forms. In this process, vitamin K is involved in the carboxylation-reaction to introduce a carboxyl group into an organic compound-of specific glutamic acid residues of vitamin K-dependent proteins to form gamma-carboxyglutamic acid (Gla) residues. The enzyme carboxylase required for this reaction is also vitamin K-dependent. As a result of the carboxylation of the glutamyl residues of the vitamin K-dependent proteins, the formation of:
- Proteins of hemostasis (hemostasis) – blood coagulation factor II (prothrombin), VII (proconvertin), IX (Christmas factor), and X (Stuart factor), as well as plasma protein C and S
- Proteins of bone metabolism – osteocalcin and bone Gla protein (BGP), matrix Gla protein (MGP), respectively, as well as protein S
- Growth regulation proteins – Growth arrest-specific gene 6 (Gas6).
- Proteins of unknown function – Proline-rich Gla protein 1 (RGP1) and 2 (RGP2) and protein Z – RGP1 and RGP2 are thought to play a role in cell signaling.
Furthermore, less well-characterized proteins are synthesized in kidney (nephrocalcin), spleen, pancreas, lung and other tissues. Mainly, the function of coagulation proteins and osteocalcin has been elucidated. The physiological significance of other calcium-binding proteins are still largely unknown.
Proteins of hemostasis-blood coagulation factor II, VII, IX, and X
Coagulation factors II, VII, IX, and X, which are formed during vitamin K-dependent carboxylation, as well as plasma proteins C and S, are exceedingly important in the process of normal blood coagulation. Vitamin K can therefore be described as a coagulation vitamin with an anti-hemorrhagic (anti-bleeding) effect. In addition, the blood coagulation proteins influence bone metabolism. The vitamin K-dependent factors VIIa and X of blood coagulation stimulate the synthesis of cysteine-rich protein 61 (hCYR61) and connective tissue growth factor (CTGF). As components of the extracellular matrix, hCYR61 and CTGF are essential for growth and angiogenesis (new blood vessel formation) of bone tissue and thus for bone development and in phases of repair and remodeling.
Proteins of bone metabolism-osteocalcin (BGP)
Osteocalcin, formed by carboxylation in osteoblasts, is of particular importance. It is a component of the extracellular matrix (ECM) of bone tissue and accounts for 2% of the total protein content of bone. Because the bone protein has been found to be at increased levels during increased remodeling and repair of bone, osteocalcin is essential for bone formation.
Regenerative cycle of vitamin K in protein carboxylation
While the ineffective acarboxy precursors of coagulation proteins, formerly PIVKA (protein induced by vitamin K absence or antagonist), are converted to their biologically active forms by the activity of vitamin K-dependent carboxylase, conversion of vitamin KH2 (hydroxylated vitamin K) to vitamin K-2,3-epoxide occurs. In order to be available again for the carboxylation of the coagulation precursors, vitamin K must be regenerated. For this purpose, the carboxylase now functions as a vitamin K epoxidase. Finally, epoxide reductase converts vitamin K-2,3-epoxide back into native vitamin K (quinone). The final step in the regeneration cycle of vitamin K is performed by vitamin K reductase. This results in the reduction of native vitamin K to hydroxylated vitamin K (vitamin KH2). In order for the entire carboxylation process to occur optimally at the membrane of the endoplasmic reticulum, vitamin K-2,3-epoxide must be continuously regenerated to vitamin KH2. Once the process of carboxylation is complete, proteins are transported in the endoplasmic reticulum (structurally rich cell organelle with a channel system of cavities surrounded by membranes) of the cell and subsequently secreted.
Sites of the carboxylation reaction
Carboxylation of vitamin K-dependent proteins is essential for their respective protein functions. It takes place in the liver on the one hand and in the osteoblasts of bone on the other.However, the proteins can also be carboxylated in other tissues by vitamin K-dependent carboxylase. For example, prothrombin is synthesized in muscle tissue.
Incomplete carboxylation
Incompletely carboxylated proteins may occur, for example, because of decreased vitamin K uptake or during treatment with vitamin K antagonists, such as coumarin or warfarin. In the case of low carboxylation (under carboxylation “UC”), the proteins cannot be secreted by the endoplasmic reticulum – accordingly, they accumulate to a greater extent. Undercarboxylation of the coagulation-active proteins ultimately leads to inhibition of the coagulation cascade and increased bleeding tendency (hemorrhagic diathesis). If the Gla proteins of bone (BGP, MGP) in particular are reduced in carboxylation, the increased excretion of calcium and hydroxyproline via the urine can result in disturbances in the mineralization of bone as well as malformations both during development and in adulthood. MGP is one of the most important proteins with an inhibitory effect on the calcification of tissues. MGP deficiencies can therefore lead to increased calcification in vessels and bones and thus promote the development of the two widespread diseases atherosclerosis (hardening of the arteries) and osteoporosis (bone loss). On the basis of studies, a low carboxylation of proteins was observed in osteoporosis patients.
