Metabolism of vitamin K

Stable Identifier
Homo sapiens
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Vitamin K is a required co-factor in a single metabolic reaction, the gamma-carboxylation of glutamate residues of proteins catalyzed by GGCX (gamma-carboxyglutamyl carboxylase). Substrates of GGCX include blood clotting factors, osteocalcin (OCN), and growth arrest-specific protein 6 (GAS6) (Brenner et al. 1998). Vitamin K is derived from green leafy vegetables as phylloquinone and is synthesized by gut flora as menaquinone-7. These molecules are taken up by intestinal enterocytes with other lipids, packaged into chylomicrons, and delivered via the lymphatic and blood circulation to tissues of the body, notably hepatocytes and osteoblasts, via processes of lipoprotein trafficking (Shearer & Newman 2014; Shearer et al. 2012) described elsewhere in Reactome.

In these tissues, menadiol (reduced vitamin K3) reacts with geranylgeranyl pyrophosphate to form MK4 (vitamin K hydroquinone), the form of the vitamin required as cofactor for gamma-carboxylation of protein glutamate residues (Hirota et al. 2013). The gamma-carboxylation reactions, annotated elsewhere in Reactome as a part of protein metabolism, convert MK4 to its epoxide form, which is inactive as a cofactor. Two related enzymes, VKORC1 and VKORCL1, can each catalyze the reduction of MK4 epoxide to active MK4. VKORC1 activity is essential for normal operation of the blood clotting cascade and for osteocalcin function (Ferron et al. 2015). A physiological function for VKORCL1 has not yet been definitively established (Hammed et al. 2013; Tie et al. 2014).

Literature References
PubMed ID Title Journal Year
24085302 Menadione (vitamin K3) is a catabolic product of oral phylloquinone (vitamin K1) in the intestine and a circulating precursor of tissue menaquinone-4 (vitamin K2) in rats

Suhara, Y, Tsugawa, N, Okano, T, Wada, A, Kamao, M, Uchino, Y, Sawada, N, Nakagawa, K, Tanaka, K, Takeuchi, A, Hirota, Y, Okitsu, T

J. Biol. Chem. 2013
24489112 Recent trends in the metabolism and cell biology of vitamin K with special reference to vitamin K cycling and MK-4 biosynthesis

Shearer, MJ, Newman, P

J. Lipid Res. 2014
22516726 Vitamin K nutrition, metabolism, and requirements: current concepts and future research

Booth, SL, Shearer, MJ, Fu, X

Adv Nutr 2012
9845520 A missense mutation in gamma-glutamyl carboxylase gene causes combined deficiency of all vitamin K-dependent blood coagulation factors

Wu, SM, Stafford, DW, Sanchez-Vega, B, Lanir, N, Solera, J, Brenner, B

Blood 1998
23928358 VKORC1L1, an enzyme rescuing the vitamin K 2,3-epoxide reductase activity in some extrahepatic tissues during anticoagulation therapy

Matagrin, B, Lattard, V, Prouillac, C, Spohn, G, Hammed, A, Benoit, E

J. Biol. Chem. 2013
25753038 GGCX and VKORC1 inhibit osteocalcin endocrine functions

Oury, F, Germain, A, Lacombe, J, Ferron, M, Karsenty, G

J. Cell Biol. 2015
24532791 Conserved loop cysteines of vitamin K epoxide reductase complex subunit 1-like 1 (VKORC1L1) are involved in its active site regeneration

Stafford, DW, Jin, DY, Tie, JK

J. Biol. Chem. 2014
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