Vitamin K exists in two naturally occurring forms, K1 and K2. It plays an essential role in blood clotting by allowing the conversion of prothrombin to thrombin through γ-carboxyglutamic acid residues on prothrombin that can bind calcium. Vitamin K is a cofactor for the enzyme γ-glutamyl carboxylase, which mediates the carboxylation of glutamate to γ-carboxyglutamate in clotting factors and osteocalcin. Vitamin K deficiency is rare in adults but dangerous in newborns, while the drug warfarin is an antagonist that blocks the activation and recycling of vitamin K to inhibit coagulation and bone mineralization

1. ENZYMES
A protein with catalytic properties
due to its power of specific
activation
© 2007 Paul Billiet ODWS

2. Vitamin

3. Objectives
• By the end of this lecture You should be able to know:
• What are vitamins and how they are classified
• Distinguish fat soluble vs water soluble
• Characteristic features of Fat soluble vitamins
• The principal role of vitamin K in coagulation
• A) formation of Y-carboxyglutamate
• B) interaction of prothrombin with platelets
• C) role of vit. K in other proteins
• Identify food sources and daily requirement of vit. K
• The deficiency in the newborn and in adults
• The toxicity of vitamin K.

4. Characteristics of Vitamins
• Vitamins are micronutrients
– Very small amounts are needed by the body (>1
gm)
– Very small amounts are contained in foods.
• Vitamins are essential.
– The roles they play in the body are very
important.
– Most vitamins are obtained from the foods we eat.
– Some are made by bacteria in the intestine
– One is made in the skin.

5. • Vitamins are non-energy producing
– They do not contain kcalories.
– They are involved in extracting
energy from the macronutrients.
• Vitamins are classified according to
how soluble they are in fat or water.

6. Classification of Vitamins

7. 14 Essential Vitamins For Human Being
vitamins
water -soluble lipid-soluble
Vit C Vit B A,D,E,K
B1, B2, B6, B12, PP, patothenic
acid ， folic acid,biotin ,lipoic acid

8. Fat versus water soluble
vitamins
Fat-soluble vitamins
• Dissolve in fat
• Require bile acids to be
dissolved and then
absorbed.
• Can be stored in body:
liver, adipose tissue.
• Toxicity is possible.
Water-soluble vitamins
• Dissolve in water.
• Easily absorbed.
• Not stored in large
quantities.
• Execrated via urine.
• Generally non-toxic.

9. Lipid-soluble Vitamins
Common features
﹡nonpolar (hydrophobic) isoprene derivative
﹡poorly soluble in water ， but good in fat and fat
solvents
﹡existing with the lipids in food products and
absorbing with the lipids
﹡ specifically binding to lipoprotein and certain
binding-protein in blood and transportation
Stored in liver and body fat and can become toxic if
large amounts are consumed.

11. FORMS OF Vitamin K
K1, phylloquinone
 Chloroplasts in plants
K2, menaquinone
 Bacterial synthesis
K3, menadione
 Synthetic, water soluble form
 Complexed to improve stability

12. Vitamin K1
Vitamin K2
Vitamin K
• Vitamin K1(phylloquinon) –
plant origin
• Vitamin K2 (menaquinon) –
normally produced by
bacteria in the large
intestine
• K1 a K2 are used differently
in the body
– K1 – used mainly for blood
clotting
– K2 – important in non-
coagulation actions - as in
metabolism and bone
mineralization, in cell growth,
metabolism of blood vessel
walls cells. Synthetic derivatives of Vit.K

13. • Significant sources
–Bacterial synthesis
in the digestive tract
– Leafy green vegetables,
cabbage-type
vegetables
–Liver
–Milk
– Dietary Recommendation:
• 120 and 90 µg a day for
adult males and females

14. 14
Absorption, Transport and Excretion of
Vitamin K
• Vitamin k is taken in the diet or
synthesized by the intestinal bacteria.
• Absorption and Transportation
– Absorbed in small intestine, via
chylomicrons in lymphatic system.
– Transported via lipoproteins and stored in
the liver
• Excretion
– Primarily bile, small amount urine

15. Vitamin K Dependent Coagulation
• Certain clotting factors/proteins require calcium to
bind for activation
• Calcium can only bind after gamma carboxylation
of specific glutamic acid residues in these proteins
• The reduced form of vitamin K2 (vitamin KH2) acts
as a cofactor for this carboxylation reaction.
• These proteins are known as “Vitamin K
dependent” proteins

16. Vitamin K - function
• Cofactor of liver microsomal carboxylase
which carboxylates glutamate residues to γ-
carboxyglutamate during synthesis of
prothrombin and coagulation factors VII, IX a
X (posttranslation reaction).
• Carboxylated glutamate chelates Ca2+
ions,
permitting the binding of blood clotting
proteins to membranes.
• Forms the binding site for Ca2+
also in other
proteins – osteocalcin.

17. Biochemical functions
Vitamin K act as a Coenzyme for the
carboxylation of glutamic acid residues present in
the proteins and this reaction is catalysed by a
carboxylase (microsomal).
It involves the conversion of glutamate (Glu) to
carboxyglutamate is inhibited by dicumarol
(natural), an anticoagulant.
Warfarin is a synthetic analogue that can inhibit
vitamin K action.

18. Role of Gla in clotting
The –carboxyglutamic acid (Gla ) residues
Of clotting factors are negatively charged (COO) and
they combine with positively charged calcium ions
(Ca2+) to form a complex.
The prothrombin Ca complex binds to the
phospholipids on the membrane surface of the
platelets.
This lead to the increased conversionof prothrombin
to thrombin.

19. Vitamin K - Carboxyglutamate

20. Interaction of prothrombin with platelets
1. γ -carboxylates chelate calcium and allow prothrombin to
associate with
membrane phospholipids in platelets
2. conversion to thrombin is stimulated

24. Fig. 10-23, p. 364
Vitamin K cycle
Needed for protein
carboxylation
Vit. K usually only present
in this form in the body
Osteocalcin or Bone Gla protein
Matrix Gla protein

25. What does Vitamin K do?
• Carboxylated Prothrombin can bind
Ca2+; which is essential for its
activation to Thrombin.
• Abnormal Prothrombin cannot bind
Ca2+; prohibiting the clotting cascade.

26. Why does the body recycle
Vitamin K?
• Very minimal body stores
• Must have regular dietary intake
• Recycles so that the same vitamin K can be
cycled and re-used many times (decreasing
need in dietary intake)

27. Warfarin and Vitamin K
• Warfarin blocks vitamin K recycling
and activation (by inhibiting 2
reductase) therefore, carboxylation of
glutamic acid cannot occur at a normal
rate
• This decreases blood coagulation.
 anticoagulant.
• Warfarin is a Vitamin K antagonist.

28. VITAMIN K DICOUMAROL
WARFARIN
Structures of the
Coumarin Drugs
(Vitamin K analogs)

29. Warfarin Blocks 2 Pathways
(1) Blocks Quinone
Reductase
 Vitamin K’s
activation to
Vitamin K
hydroquinone
(2) Blocks Vitamin K-
epoxide reductase
 Vitamin K (epoxide)
recycling to Vitamin K

30. Role of Vitamin K in Bone Formation
• Vitamin K is a cofactor for the γ-
carboxylation of osteocalcin, a protein found
in bone tissue
• Osteocalcin is involved in the mineralization
of bone matrix
• γ-carboxylation of Glu residues to Gla gives
each osteocalcin molecule the ability to bind
Ca2+
and form part of the mineralizing bone
matrix
• Non-carboxylated osteocalcin cannot form
bone
• Serum osteocalcin is used as a biochemical
marker of bone formation

31. Vitamin K antagonists disrupt bone mineralization

32. Vitamin K Deficiency
Results in impaired blood clotting and, potentially,
bleeding.
• Rare in adults
– Newborns – higher risk
Vitamin K deficiency can result from:
• a lack of vitamin k in the diet
• disorders that reduce fat absorption
• Taking certain drugs, including some antibiotics
• Use of coumarin anticoagulants
• Salicylates
• Hepatic insufficiency

33. Vitamin K Deficiency in Infants
Newborns are prone to vitamin K
deficiency because…
1. Vitamin K and lipids are not easily
transported across the placental
barrier
2. Prothrombin synthesis in the liver is
an immature process in newborns,
especially when premature.
3. The neonatal gut is sterile, lacking
the bacteria that is necessary in
menaquinone synthesis.
4. Breast milk is not a good source of
vitamin K
Results in a hemorrhagic disease called
vitamin K deficiency bleeding (VKDB)

34. Vitamin K - Toxicity
• Not common except with over supplementation
– Phylloquinone and menaquinone are relatively
nontoxic
• Jaundice; brain damage
– Menadione toxic to skin and respiratory tract in high
doses

35. SUMMARY SLIDE
• The two naturally-occurring types of Vitamin K are K1 & K2, synthesized by plants and
gastrointestinal bacteria, respectively.
• Vitamin K deficiency is rare in healthy adults but is dangerous in infants where it can
cause hemorrhaging in vital organs such as the brain
• Vitamin K is essential for the synthesis of factors VII, IX, X and for the conversion of
prothrombin to thrombin
• The γ-carboxyglutamic acid on prothrombin can bind Ca2+ allowing for the conversion to
thrombin
• Vitamin K Hydroquinone (active form), is a cofactor of the enzyme γ -glutamyl
carboxylase; leads to carboxylation of Glu to Gla
• The vitamin K is recycled
• Warfarin is a vitamin K antagonist in btoh bone mineralization and coagulation
– Blocks the acitvation and recycling of vitamin K
• Vitamin K is needed for γ-carboxylation of Glu→Gla residues on osteocalcin; Gla binding
Ca2+ helps osteocalcin incorporate into mineralizing bone

37. Thank you!