The vitamin K cycle

@article{Stafford2005TheVK,
  title={The vitamin K cycle},
  author={D. Stafford},
  journal={Journal of Thrombosis and Haemostasis},
  year={2005},
  volume={3}
}
  • D. Stafford
  • Published 2005
  • Chemistry, Medicine
  • Journal of Thrombosis and Haemostasis
Summary.  Post‐translational modification of glutamate to gamma carboxyl glutamate is required for the activity of vitamin K‐dependent proteins. Carboxylation is accomplished by the enzyme gamma glutamyl carboxylase (GGCX) which requires the propeptide‐containing substrate and three co‐substrates: reduced vitamin K, CO2, and O2. Most propeptides bind tightly to GGCX and all of the Glu residues that will be modified are modified during one binding event. Complete carboxylation is thus dependent… Expand
Vitamin K-dependent gamma-glutamylcarboxylation: an ancient posttranslational modification.
TLDR
The suggestion that gamma-carboxylation is an extracellular posttranslational modification that antedates the divergence of molluscs, arthropods, and chordates is suggested. Expand
Disulfide-dependent Protein Folding Is Linked to Operation of the Vitamin K Cycle in the Endoplasmic Reticulum
TLDR
The energy required for γ-carboxylation of proteins is provided by dithiol-dependent oxidative protein folding in the ER and thus is linked to de novo protein synthesis. Expand
Structure and function of vitamin K epoxide reductase.
TLDR
The recent identification of the gene encoding VKOR allows us to study its structure and function relationship at the molecular level and it is proposed that an active site disulfide needs to be reduced for the enzyme to be active. Expand
Key Pathways and Regulators of Vitamin K Function and Intermediary Metabolism.
TLDR
Novel molecular biological approaches are providing new insights into the pathophysiological mechanisms caused by rare mutations of both GGCX and VKOR, and other protein regulators influence the intermediary metabolism of VK. Expand
A hetero-dimer model for concerted action of vitamin K carboxylase and vitamin K reductase in vitamin K cycle.
TLDR
A hetero-dimeric form of VKC and VKOR is proposed that may explain the efficient oxidation and reduction of vitamin K during the vitamin K cycle. Expand
Vitamin K epoxide reductase complex and vascular calcification: is this the important link between vitamin K and the arterial vessel wall?
TLDR
Four key components are involved in the proper biosynthesis of the vitamin K–dependent proteins: the enzymes γ-glutamyl carboxylase and vitamin K epoxide reductase complex (VKORC1), vitamin K, and a precursor protein. Expand
VKORC1 and the vitamin K cycle.
TLDR
Screening for VKORC1 polymorphisms that affect warfarin dosage could be helpful to tailor dosage at the onset of oral anticoagulant treatment in order to lower thrombosis and bleeding risks. Expand
The conversion of vitamin K epoxide to vitamin K quinone and vitamin K quinone to vitamin K hydroquinone uses the same active site cysteines.
TLDR
It is reported here that C132 and C135 of the CXXC motif are essential for both the conversion of vitamin K epoxide to vitamin K and the conversionof vitamin K to vitaminK hydroquinone. Expand
A cellular system for quantitation of vitamin K cycle activity: structure-activity effects on vitamin K antagonism by warfarin metabolites.
TLDR
A sensitive assay is described that enables quantitative analysis of γ-glutamyl carboxylation and its antagonism in live cells and predicts 10-hydroxywarfarin and warfarin alcohols were predicted to be the most potent inhibitory metabolites in vivo. Expand
Quinone oxidoreductases and vitamin K metabolism.
TLDR
Quinone oxidoreductases metabolically detoxifies vitamin K3 and protects cells against oxidative stress and other adverse effects, and future studies are also required to identify the enzymes that catalyze high affinity reduction of vitamin K1 and K2 to hydroquinone for use in gamma-carboxylation reactions. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 45 REFERENCES
A new model for vitamin K-dependent carboxylation: the catalytic base that deprotonates vitamin K hydroquinone is not Cys but an activated amine.
TLDR
The identity of the catalytic base is critical to understanding carboxylase mechanism and this work will therefore impact both reinterpretation of previous studies and future ones that define how this important enzyme functions. Expand
Processive Post-translational Modification
TLDR
Kinetic experiments and arguments were used to show that the vitamin K-dependent carboxylase is not distributive but rather is one of the first well documented examples of an enzyme that catalyzes a processive post-translational modification. Expand
Identification and purification to near homogeneity of the vitamin K-dependent carboxylase.
TLDR
The bovine vitamin K-dependent carboxylase is identified and purified it to near homogeneity by an affinity procedure that uses the 59-amino acid peptide FIXQ/S. Expand
Amino acids responsible for reduced affinities of vitamin K-dependent propeptides for the carboxylase.
TLDR
The identification of a new, naturally occurring mutation at this position in factor IX which causes a warfarin-sensitive hemophilia B phenotype is identified and it is found that propeptides with mutations found in warfarinsensitive patients have reduced affinity for the carboxylase, suggesting a physiological relevance of propeptide binding affinity. Expand
Assembly of the Warfarin-sensitive Vitamin K 2,3-Epoxide Reductase Enzyme Complex in the Endoplasmic Reticulum Membrane*
TLDR
An in vitro γ-carboxylation test system is designed and it is proposed that formation of VKOR in the endoplasmic reticulum membrane resembles formation of the lipoxygenase enzyme complex where the glutathioneS-transferase-related FLAP protein binds cytosolic lip oxygengenase to form a membrane enzyme complex. Expand
Chemical Modification of Cysteine Residues Is a Misleading Indicator of Their Status as Active Site Residues in the Vitamin K-dependent γ-Glutamyl Carboxylation Reaction*
TLDR
It is concluded that cysteine residues are not directly involved in carboxylase catalysis, but chemical modification of Cys323 and Cys343 may disrupt the three-dimensional structure, resulting in inactivation. Expand
A new carboxylation reaction. The vitamin K-dependent incorporation of H-14-CO3- into prothrombin.
TLDR
Hydrolysis of the purified radioactive prothrombin resulted in a loss of 50% of the radioactivity and subsequent chromatography of the amino acid hydrolyzate demonstrated that the remaining radioactivity was entirely in glutamic acid, consistent with the hypothesis that all of the H-14-CO3- minus was incorporated into the carboxyl groups of gamma-carboxyglutamic acid residues. Expand
Stimulation of the dithiol-dependent reductases in the vitamin K cycle by the thioredoxin system. Strong synergistic effects with protein disulphide-isomerase.
TLDR
Data suggest that in the vitro system the formation of disulphide bonds is somehow linked to the vitamin K-dependent carboxylation of glutamate residues, and the possibility that the reactions are also coupled in vivo is discussed. Expand
A topological study of the human γ-glutamyl carboxylase
TLDR
In vitro translation and in vivo mapping were used to study the structure ofγ-Glutamyl carboxylase, a polytopic membrane protein found in the endoplasmic reticulum (ER), and it was demonstrated that the amino-terminus of the GC is on the cytoplasmic side of the ER, while the carboxy-terminal side are on the lumenal side. Expand
A topological study of the human gamma-glutamyl carboxylase.
TLDR
In vitro translation and in vivo mapping were used to study the structure of gamma-Glutamyl carboxylase, and it was demonstrated that the amino-terminus of the GC is on the cytoplasmic side of the ER, while the carboxyles are on the lumenal side. Expand
...
1
2
3
4
5
...