Gamma-glutamyl carboxylase

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

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
Gene location (Human) Chr. Chromosome 2 (human)[1] Band 2p11.2 Start 85,544,720 bp[1] End 85,561,532 bp[1]
RNA expression pattern Bgee Human Mouse (ortholog) Top expressed in buccal mucosa cell tendon of biceps brachii liver right lobe of liver endothelial cell stromal cell of endometrium internal globus pallidus saphenous vein body of pancreas parotid gland n/a More reference expression data BioGPS More reference expression data
Gene ontology Molecular function gamma-glutamyl carboxylase activity lyase activity Cellular component integral component of membrane endoplasmic reticulum membrane membrane endoplasmic reticulum Biological process peptidyl-glutamic acid carboxylation blood coagulation Sources:Amigo / QuickGO
Orthologs Species Human Mouse Entrez 2677 56316 Ensembl ENSG00000115486 ENSMUSG00000053460 UniProt P38435 Q9QYC7 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

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]

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
₂O

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

• Carboxyglutamate