Vitamin K

Micronutrients Prof. Kathleen Axen HNS 7211 Spring 2014

Forms of Vitamin K
Phylloquinones
K1 green plants

Menaquinones
K2 animal sources bacterial synthesis, GI tract

Menadione
K3 synthetic must be converted to K2 in liver in order to be active

1,4-Napthoquinone (core of the structure)

Phylloquinone
2 methyl 1,4 napthoquinone 3 repeating units (single bonds)in side chain Bacteria in gut can remove side chain Resulting menadione is then converted to menaquinone-4 (MK4) in tissues ~20% catabolized and excreted/day

Menaquinone
Double bonds in repeating side chain MK4 has 4 sets of side chain units concentrated in brain Synthesized by GI bacteria Human liver: K1:K2::1:10 MK 4 and 5 most active, MK7 high in legumes
MK4

Menadione
synthetic Water-soluble salts in supplements Converted to MK4 in liver Can produce toxicity: liver damage Unstable in UV, alkali; degraded faster than K or MK

standard

Max activity

Absorption and Excretion

Requires bile K1-active transport in proximal SI K2 & K3 passive diffusion Incorporated into lipoprotein particles Go to liver in Chylomicrons (lymph first) VLDLLDL, HDL transport it to tissues Liver storage Poor placental transport Excretion via bile (feces); coprophagia provides vitamin water-soluble urinary metabolites

Coenzyme form

What does vitamin K do?

Coenzyme form: KH2

Vitamin K-dependent gammacarboxylation

Post-translational modification of proteins Acts on glutamic acid residues (9-12 sites) of the peptide chain Microsomal (ER bound) Formation of GLA proteins

Rest of peptide--C

Nrest of peptide

Coenzyme form: KH2

KH2

Gene-nutrient interactions
Mutations (Single Nucleotide Polymorphisms) observed in population for: Vit K gamma glutamyl carboxylase Vit K epoxide reductase (recycles vitamin) Vit K quinone reductase (forms coenzyme) Warfarin resistance

Clotting Factors
Synthesized in liver Undergo vit K dependent gamma carboxylation (GLA proteins) in liver Can bind to Ca 2+ Activated in plasma as needed Cascade activation Self-limiting

insoluble soluble

Protein C
GLA protein Activated when it binds to thrombin (so activated during clotting) Activation promoted by thrombomodulin Binds to endothelial cells Inactivates factors V and VIII So functions as an anti-coagulant (limits coagulation)

*
fibrinolytic

GLA proteins C and S limit the clotting cascade

Some other GLA proteins

Osteocalcin
(bone) affects bone mineralization? Influences bone microstructure? increases adipocyte tissue development

Matrix GLA protein (MGP)

chondrocytes, osteoblasts vascular smooth muscle Inhibits calcification of vessels( in MGP ko)

Gas6 Growth arrest gene 6 --brain

Increases growth, migration, cell survival, myelination (low in Alzheimers)

Bone
Some studies show vit K supplementation to decrease bone loss and/or fractures Osteocalcin produced by osteoblasts (transcription and translation regulated by calcitriol)a GLA protein.
Effect on bone architecture?

Bone GLA-rich Protein (GRP) involved?

Other vit K effects

Anti-inflammatory effects through decreased expression of IL-6 Regulation of adipose tissue development, prevention of insulin resistance Dietary requirements may differ for the various functions of vit K DRI 90-120 micrograms

Warfarin
aka coumadin Structurally similar to vit K Competitive inhibitor

Effect of Warfarin during pregnancy

Vitamin K deficiency
Newborns hemorrhagic disease
Sterile GI tract, poor placental transport Intracranial hemorrhage 1 mg vit k given im at birth

Chronic lipid malabsorption

cystic fibrosis Obstructive jaundice (no bile) Ileitis Chronic antibiotics, excess coumarin therapy

Indices of deficiency (biomarkers)

Des--carboxyglutamyl prothrombin plasma prothrombin

clotting time (excess bleeding) other GLA proteins

% uncOC is sensitive biomarker of vitK deficiency