Gamma-glutamyl carboxylase

Last updated
GGCX
Identifiers
Aliases GGCX , VKCFD1, gamma-glutamyl carboxylase, Gamma-glutamyl carboxylase; GGCX
External IDs OMIM: 137167; MGI: 1927655; HomoloGene: 639; GeneCards: GGCX; OMA:GGCX - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_000821
NM_001142269
NM_001311312

NM_019802

RefSeq (protein)

NP_000812
NP_001135741
NP_001298241

NP_062776

Location (UCSC) Chr 2: 85.54 – 85.56 Mb n/a
PubMed search [2] [3]
Wikidata
View/Edit Human View/Edit Mouse

Gamma-glutamyl carboxylase is an enzyme that in humans is encoded by the GGCX gene, located on chromosome 2 at 2p12. [4]

Contents

Function

Gamma-glutamyl carboxylase is an enzyme that catalyzes the posttranslational modification of vitamin K-dependent proteins. Many of these vitamin K-dependent proteins are involved in coagulation so the function of the encoded enzyme is essential for hemostasis. [5] Most gla domain-containing proteins depend on this carboxylation reaction for posttranslational modification. [6] In humans, the gamma-glutamyl carboxylase enzyme is most highly expressed in the liver.

Catalytic reaction

Gamma-glutamyl carboxylase oxidizes vitamin K hydroquinone to Vitamin K-2,3-epoxide, while simultaneously adding CO2 to protein-bound glutamic acid (abbreviation = Glu) to form gamma-carboxyglutamic acid (also called gamma-carboxyglutamate, abbreviation = Gla). Presence of two carboxylate groups causes chelation of Ca2+, resulting in change in tertiary structure of protein and its activation. The carboxylation reaction will only proceed if the carboxylase enzyme is able to oxidize vitamin K hydroquinone to vitamin K epoxide at the same time; the carboxylation and epoxidation reactions are said to be coupled reactions. [7] [8]

Gamma-glutamyl carboxylase.svg
a [protein]-α-L-glutamate (Glu) + phylloquinol (KH
2
) + CO
2
+ oxygen → a [protein] 4-carboxy-L-glutamate (Gla) + vitamin K 2,3-epoxide (KO) + H+
+ H
2
O

No experimental structure is known for GGCX, limiting understanding of its reaction mechanism. Based on the fact that the two reactions are coupled, a computational study is able to propose how the reactants interact with each other to form the products. [9] Lys228 has been shown to be the residue responsible for starting the reaction. [10] How the enzyme holds the reactants in place to have them interact with each other remains poorly shown. 491-507 and 395-401 are probably responsible for propeptide and glutamate binding respectively. [11]

Clinical significance

Mutations in this gene are associated with vitamin K-dependent coagulation defect and PXE-like disorder with multiple coagulation factor deficiency. [5] [12]

See also

Related Research Articles

<span class="mw-page-title-main">Vitamin K</span> Fat-soluble vitamers

Vitamin K is a family of 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 coagulation or for controlling binding of calcium in bones and other tissues. The complete synthesis involves final modification of these so-called "Gla proteins" by the enzyme gamma-glutamyl carboxylase that uses vitamin K as a cofactor.

<span class="mw-page-title-main">Post-translational modification</span> Chemical changes in proteins following their translation from mRNA

In molecular biology, post-translational modification (PTM) is the covalent process of changing proteins following protein biosynthesis. PTMs may involve enzymes or occur spontaneously. Proteins are created by ribosomes, which translate mRNA into polypeptide chains, which may then change to form the mature protein product. PTMs are important components in cell signalling, as for example when prohormones are converted to hormones.

<span class="mw-page-title-main">Coagulation</span> Process of formation of blood clots

Coagulation, also known as clotting, is the process by which blood changes from a liquid to a gel, forming a blood clot. It results in hemostasis, the cessation of blood loss from a damaged vessel, followed by repair. The process of coagulation involves activation, adhesion and aggregation of platelets, as well as deposition and maturation of fibrin.

<span class="mw-page-title-main">Carboxyglutamic acid</span> Chemical compound

Carboxyglutamic acid, is an uncommon amino acid introduced into proteins by a post-translational carboxylation of glutamic acid residues. This modification is found, for example, in clotting factors and other proteins of the coagulation cascade. This modification introduces an affinity for calcium ions. In the blood coagulation cascade, vitamin K is required to introduce γ-carboxylation of clotting factors II, VII, IX, X and protein Z.

<span class="mw-page-title-main">Protein S</span>

Protein S is a vitamin K-dependent plasma glycoprotein synthesized in the liver. In the circulation, Protein S exists in two forms: a free form and a complex form bound to complement protein C4b-binding protein (C4BP). In humans, protein S is encoded by the PROS1 gene. Protein S plays a role in coagulation.

Transcobalamins are carrier proteins which bind cobalamin (B12).

<span class="mw-page-title-main">Vitamin K epoxide reductase</span> Class of enzymes

Vitamin K epoxide reductase (VKOR) is an enzyme that reduces vitamin K after it has been oxidised in the carboxylation of glutamic acid residues in blood coagulation enzymes. VKOR is a member of a large family of predicted enzymes that are present in vertebrates, Drosophila, plants, bacteria and archaea. In some plant and bacterial homologues, the VKOR domain is fused with domains of the thioredoxin family of oxidoreductases.

<span class="mw-page-title-main">Propionyl-CoA carboxylase</span>

Propionyl-CoA carboxylase (EC 6.4.1.3, PCC) catalyses the carboxylation reaction of propionyl-CoA in the mitochondrial matrix. PCC has been classified both as a ligase and a lyase. The enzyme is biotin-dependent. The product of the reaction is (S)-methylmalonyl CoA.

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, especially when applied to the reaction of carbanionic reagents with CO2. More generally, carbonation usually describes the production of carbonates.

Des-gamma carboxyprothrombin (DCP), also known as protein induced by vitamin K absence/antagonist-II (PIVKA-II), is an abnormal form of the coagulation protein, prothrombin. Normally, the prothrombin precursor undergoes post-translational carboxylation by gamma-glutamyl carboxylase in the liver prior to secretion into plasma. DCP/PIVKA-II may be detected in people with deficiency of vitamin K and in those taking warfarin or other medication that inhibits the action of vitamin K.

<span class="mw-page-title-main">Gla domain</span>

Vitamin K-dependent carboxylation/gamma-carboxyglutamic (GLA) domain is a protein domain that contains post-translational modifications of many glutamate residues by vitamin K-dependent carboxylation to form γ-carboxyglutamate (Gla). Proteins with this domain are known informally as Gla proteins. The Gla residues are responsible for the high-affinity binding of calcium ions.

<span class="mw-page-title-main">NAD(P)H dehydrogenase (quinone 1)</span> Protein-coding gene in the species Homo sapiens

NAD(P)H dehydrogenase [quinone] 1 is an enzyme that in humans is encoded by the NQO1 gene. This protein-coding gene is a member of the NAD(P)H dehydrogenase (quinone) family and encodes a 2-electron reductase (enzyme). This FAD-binding protein forms homodimers and performs two-electron reduction of quinones to hydroquinones and of other redox dyes. It has a preference for short-chain acceptor quinones, such as ubiquinone, benzoquinone, juglone and duroquinone. This gene has an important paralog NQO2. This protein is located in the cytosol.

<span class="mw-page-title-main">Matrix Gla protein</span>

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 mineralization and plays a role in bone organization.

<span class="mw-page-title-main">VKORC1</span> Protein-coding gene in the species Homo sapiens

The human gene VKORC1 encodes for the enzyme, Vitamin K epOxide Reductase Complex (VKORC) subunit 1. This enzymatic protein complex is responsible for reducing vitamin K 2,3-epoxide to its active form, which is important for effective clotting (coagulation). In humans, mutations in this gene can be associated with deficiencies in vitamin-K-dependent clotting factors.

<span class="mw-page-title-main">LCOR</span> Protein-coding gene in the species Homo sapiens

Ligand-dependent corepressor is a protein that in humans is encoded by the LCOR gene.

Vitamin K deficiency results from insufficient dietary vitamin K1 or vitamin K2 or both.

<span class="mw-page-title-main">Chlorophacinone</span> Chemical compound

Chlorophacinone is a first-generation anticoagulant rodenticide. The mechanism of action results in internal bleeding due to non-functional clotting factors. It was used as a toxin to control rodent populations. It is classified as an extremely hazardous substance in the United States as defined in Section 302 of the U.S. Emergency Planning and Community Right-to-Know Act and is subject to strict reporting requirements by facilities which produce, store, or use it in significant quantities.

Vitamin K<sub>2</sub> Group of vitamins and bacterial metabolites

Vitamin K2 or menaquinone (MK) is one of three types of vitamin K, the other two being vitamin K1 (phylloquinone) and K3 (menadione). K2 is both a tissue and bacterial product (derived from vitamin K1 in both cases) and is usually found in animal products or fermented foods.

<span class="mw-page-title-main">Gamma-glutamyl hydrolase</span> Protein-coding gene in the species Homo sapiens

Ghk.

Peptidyl-glutamate 4-carboxylase (EC 4.1.1.90, vitamin K-dependent carboxylase, gamma-glutamyl carboxylase) is an enzyme with systematic name peptidyl-glutamate 4-carboxylase (2-methyl-3-phytyl-1,4-naphthoquinone-epoxidizing). This enzyme catalyses the following chemical reaction

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000115486 Ensembl, May 2017
  2. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  3. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. Wu SM, Cheung WF, Frazier D, Stafford DW (December 1991). "Cloning and expression of the cDNA for human gamma-glutamyl carboxylase". Science. 254 (5038): 1634–6. Bibcode:1991Sci...254.1634W. doi:10.1126/science.1749935. PMID   1749935.
  5. 1 2 "Entrez Gene: GGCX".
  6. Brenner B, Tavori S, Zivelin A, Keller CB, Suttie JW, Tatarsky I, Seligsohn U (August 1990). "Hereditary deficiency of all vitamin K-dependent procoagulants and anticoagulants". Br. J. Haematol. 75 (4): 537–42. doi:10.1111/j.1365-2141.1990.tb07795.x. PMID   2145029. S2CID   24679257.
  7. Suttie JW (1985). "Vitamin K-dependent carboxylase". Annu. Rev. Biochem. 54 (1): 459–77. doi:10.1146/annurev.bi.54.070185.002331. PMID   3896125.
  8. Presnell SR, Stafford DW (2002). "The vitamin K-dependent carboxylase". Thromb. Haemost. 87 (6): 937–46. doi:10.1055/s-0037-1613115. PMID   12083499. S2CID   27634025.
  9. Silva PJ, Ramos MJ (2007). "Reaction mechanism of the vitamin K-dependent glutamate carboxylase: a computational study". J Phys Chem B. 111 (44): 12883–7. doi:10.1021/jp0738208. PMID   17935315.
  10. Rishavy MA, Hallgren KW, Yakubenko AV, Shtofman RL, Runge KW, Berkner KL (7 November 2006). "Brønsted analysis reveals Lys218 as the carboxylase active site base that deprotonates vitamin K hydroquinone to initiate vitamin K-dependent protein carboxylation". Biochemistry. 45 (44): 13239–48. doi:10.1021/bi0609523. PMID   17073445.
  11. Parker CH, Morgan CR, Rand KD, Engen JR, Jorgenson JW, Stafford DW (11 March 2014). "A conformational investigation of propeptide binding to the integral membrane protein γ-glutamyl carboxylase using nanodisc hydrogen exchange mass spectrometry". Biochemistry. 53 (9): 1511–20. doi:10.1021/bi401536m. PMC   3970815 . PMID   24512177.
  12. Vanakker OM, Martin L, Gheduzzi D, Leroy BP, Loeys BL, Guerci VI, Matthys D, Terry SF, Coucke PJ, Pasquali-Ronchetti I, De Paepe A (March 2007). "Pseudoxanthoma elasticum-like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity". J. Invest. Dermatol. 127 (3): 581–7. doi: 10.1038/sj.jid.5700610 . PMID   17110937.

Further reading

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