Vitamin K -dependent protein carboxylation is a process that involves all tissues and regulates processes like coagulation, apoptosis, signal transduction and arterial calcification.
The reaction takes place in the endoplasmic reticulum leading to the formation of GLA domains, rich in gamma-carboxyglutamate (Gla), in the target proteins.
The reaction requires different steps:
- Vitamin K oxidation and protein reduction
- CO2 incorporation as carboxyl group
- recycling of the oxidized vitamin K back to the reduced form, by action of a Vitamin K Oxidoreductase (VKOR) that is the target of the anticoagulant drug Warfarin
Vitamin K Dependent (VKD) proteins
The Vitamin K–Dependent Carboxylase 2000
Synthesis of vitamin K-dependent proteins 1993
Google Books VKD proteins
VKD-γ-glutamyl carboxylase
Hypothetical model of the vitamin K-dependent γ-carboxylation system.
VKD-γ-glutamyl carboxylase activity regulation
Enhanced Renal Vitamin-K- Dependent Gamma-Glutamyl Carboxylase Activity in Experimental Rat Urolithiasis 1998
Open Questions
naturally-occurring human mutations in the carboxylase cause two distinctly different diseases
- pseudoxanthoma elasticum that is associated with dermal defects
- VKCFD1 (for combined deficiency of vitamin K-dependent coagulation factors) that is associated with serious bleeding.
The carboxylase is regulated by self-carboxylation
how the secretory machinery impacts carboxylation, which occurs in the endoplasmic reticulum during vitamin K-dependent protein secretion.
VKOR reduction of vitamin K may be the limiting step in carboxylation,
VKOR and the carboxylase, which are both integral membrane proteins, exist in a complex to cycle vitamin K ?
Roles of Vitamin K
Natural Vitamin K inibitors
Natural prenylquinones inhibit the enzymes of the vitamin K cycle in vitro. 1996
Quinones with a redox potential exceeding that of vitamin K1 (eg Ubiquinone10 = E(mv) 122) , showed strong inhibition of the KH 2 mediated carboxylation reaction, whereas the anthraquinone derivative (eg Menadione = E(mv) 2), with a relatively low redox potential, had no effect.
Fulltext
Vitamin K-antagonistic effect of plastoquinone and ubiquinone derivatives in vitro. 1994
Idem on Science Direct Fulltext