Vitamin K-dependent gamma-carboxylase

Function

Mediates the vitamin K-dependent carboxylation of glutamate residues to calcium-binding gamma-carboxyglutamate (Gla) residues with the concomitant epoxidation of vitamin K hydroquinone to vitamin K epoxide. Couples epoxidation and carboxylation in the same active site. Catalyzes gamma-carboxylation of blood coagulation factors (F2, F7, F9 and F10) and anticoagulants such as PROC, which are essential for thrombosis. Catalyzes gamma-carboxylation of osteocalcin/BGLAP, which is essential for bone metabolism. Catalyzes gamma-carboxylation of matrix Gla protein (MGP) and other transmembrane gamma-Gla proteins such as PRRG2, which are essential for calcium homeostasis and haemostasis.

Classification

Family (Pfam)

PF05090 HTTM, PF22777 VKGC_lumenal_dom

InterPro

HTTM-like, HTTM_dom, RmlC-like_jellyroll, RmlC_Cupin_sf, VKG_COase, VKGC_lumenal_dom

Functional cluster

Membrane Channels & Lipid-Anchored Proteins

Experimental structures · PDB · 23

• 9BUM EM 3.63A
• 9BUR EM 2.95A
• 9BUX EM 3.06A
• 9BVK EM 3.60A
• 9BVL EM 3.40A
• 9BVM EM 3.40A
• 9BVO EM 4.40A
• 9BVP EM 3.30A
• 9BVQ EM 3.30A
• 9BVR EM 3.50A
• 9L1Y EM 3.46A
• 9L20 EM 2.82A
• … and 11 more

A predicted model is available from AlphaFold.

Gene Ontology · 14

• GO:0005788 endoplasmic reticulum lumen
• GO:0005789 endoplasmic reticulum membrane
• GO:0016020 membrane
• GO:0008488 gamma-glutamyl carboxylase activity
• GO:0008289 lipid binding
• GO:0019842 vitamin binding
• GO:0007596 blood coagulation
• GO:1903011 negative regulation of bone development
• GO:0046929 negative regulation of neurotransmitter secretion
• GO:2000225 negative regulation of testosterone biosynthetic process
• GO:0017187 peptidyl-glutamic acid carboxylation
• GO:0051604 protein maturation
• GO:0036211 protein modification process
• GO:0042373 vitamin K metabolic process

Disease associations

• vitamin K-dependent clotting factors, combined deficiency of, type 1 MONDO:0010187
• body skin hyperlaxity due to vitamin K-dependent coagulation factor deficiency MONDO:0012570

Drugs targeting this protein · 1

• ANISINDIONE inhibitor

Related proteins · sequence + function similarity

• Vitamin K-dependent gamma-carboxylase 1.00
• Vitamin K-dependent gamma-carboxylase 0.99
• Vitamin K-dependent gamma-carboxylase 0.99
• Vitamin K-dependent gamma-carboxylase 0.99
• Vitamin K-dependent gamma-carboxylase 0.98
• Vitamin K-dependent gamma-carboxylase 0.98
• Lipase maturation factor 2 0.69
• Lipase maturation factor 1 0.69
• Lipase maturation factor 1 0.69
• Lipase maturation factor 2 0.69
• Lipase maturation factor 2 0.68
• Lipase maturation factor 2 0.67

Co-cited proteins · studied together in the literature

• Vitamin K-dependent gamma-carboxylase 1 shared papers
• Osteocalcin 1 shared papers
• Vitamin K-dependent protein C 1 shared papers
• Transmembrane gamma-carboxyglutamic acid protein 2 1 shared papers
• Coagulation factor IX 1 shared papers
• Coagulation factor X 1 shared papers

Literature · 21 cited papers

• Structure and mechanism of vitamin-K-dependent gamma-glutamyl carboxylase. Nature · 2025
• Molecular basis of vitamin-K-driven gamma-carboxylation at the membrane interface. Nature · 2025
• An enzyme assisted RP-RPLC approach for in-depth analysis of human liver phosphoproteome. J. Proteomics · 2014
• System-wide temporal characterization of the proteome and phosphoproteome of human embryonic stem cell differentiation. Sci. Signal. · 2011
• Lys-N and trypsin cover complementary parts of the phosphoproteome in a refined SCX-based approach. Anal. Chem. · 2009
• Glycoproteomics analysis of human liver tissue by combination of multiple enzyme digestion and hydrazide chemistry. J. Proteome Res. · 2009
• Pseudoxanthoma elasticum-like phenotype with cutis laxa and multiple coagulation factor deficiency represents a separate genetic entity. J. Invest. Dermatol. · 2007
• Bronsted analysis reveals Lys218 as the carboxylase active site base that deprotonates vitamin K hydroquinone to initiate vitamin K-dependent protein carboxylation. Biochemistry · 2006
• The vitamin K-dependent carboxylase. Annu. Rev. Nutr. · 2005
• Generation and annotation of the DNA sequences of human chromosomes 2 and 4. Nature · 2005
• The status, quality, and expansion of the NIH full-length cDNA project: the Mammalian Gene Collection (MGC). Genome Res. · 2004
• Compound heterozygous mutations in the gamma-glutamyl carboxylase gene cause combined deficiency of all vitamin K-dependent blood coagulation factors. Br. J. Haematol. · 2004
• … and 9 more in the literature graph