Fat soluble vitamins

(K, E, A & D)
Lecture 1 (40 slides)

Dr. Eman Shaat

Professor of Biochemistry & Molecular biology

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 Vitamins
• Organic compounds
• Cannot be synthesized in ample amounts in the body. Required in
small amounts
• Deficiencies can result in potentially serious consequences.
 Provitamin (precursor) vs Preformed vitamin (vitamins found in
foods in their active form)
• vitamins can be destroyed by: Heat, Light (ultraviolet), Oxygen.
 Fat-soluble vitamins tend to be more stable.
• Whole foods: Fruits, vegetables, and whole grains.
 Vitamins from animal foods are generally more bioavailable than
those in plant foods.
• Vitamins grouped into two major categories:
– Fat-soluble (4 fat soluble) Vitamin A, D, E, K.
– Water-soluble (9 water soluble)

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 Vitamins
 Water-soluble vitamins – Fat-soluble vitamins
 Found in watery parts of • Found in fats and oils of
foods (hydrophilic) foods (hydrophobic).
 After absorbed move directly
• After absorbed enter
into blood
 Transported freely in blood.
lymph, then blood
Some Vits require carrier . • Protein carriers for
 Not stored transport
 Needed more regularly – • Stored (fatty tissue/liver)
every 1-3 days; because not
stored
• Doesn’t need as regularly -
 Deficiencies fast to develop; weekly, monthly; because
because not stored stored.
 Toxicities less likely • Deficiencies slow to
 Usually no precursors develop; because stored
 Urine excretion • Toxicities more likely;
3 because stored
 Digesting and absorbing vitamins

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 FAT SOLUBLE VITAMINS
• They are non polar.
• All of them are isoprene derivatives.
• require micelles to be absorbed.
• are transported to the liver in chylomicrons.
• They are stored either in the liver (A, D and K) or in adipose tissue
(E) for varying periods of time.
• In blood they are transported by lipoproteins or specific binding
proteins.
• They are mainly excreted in feces.
• Toxicity occurs from over dosage.
• No specific coenzyme function has yet been found for the fat
soluble vitamins EXCEPT vitamin K.

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 Fat soluble vitamins

Vitamin K

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Vitamin K: chemical structure, Sources & function
• Vitamin K1 is abundant in vegetable oils and green
leafy vegetables e.g. Spinach, also in cabbage,
cauliflower and peas.
• Vitamin K2 is synthesized by intestinal flora and is
found in animal tissues. Putrefied fish meal is a
rich source.
• Good sources of vitamin K include tomatoes,
cheese, egg yolk, and liver. Breast milk is NOT a
good source of vitamin K.
• Vitamin K is required for post translational
modifications of several proteins required in the
coagulation cascade. It converts blood clotting
factors (II, VII, IX and X) to the active state.
• All these factors are proteins synthesized in the
liver in an inactive precursor form.
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Vitamin K: Mechanism of vitamin K-dependent
activation for prothrombin
1. Prothrombin is synthesized in the liver in an inactive precursor
form called Pre-prothrombin.
2. Pre-prothrombin (prothrombin precursor) to prothrombin
Requiring vitamin K-dependent carboxylation (of specific
glutamic acid residues to -carboxyglutamic)
Pre-prothrombin Prothrombin
(Glutamate) (g caboxyglutamate)

g
b
a Vit. K-dependent
carboxylase
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 Vitamin K: Mechanism of vitamin K-dependent
activation for prothrombin
3. The γ-carboxygulatmic acid residues are good chelators
Ca++
which allow prothrombin (active) to bind (chelate)
calcium.
4. Prothrombin-Ca++-complex binds to Phospholipid
membrane where proteolytic conversion to thrombin
can occur.
Summary of function:
• Vitamin K is an essential cofactor for the carboxylase
enzyme in specific protein molecules such as:
 Blood clotting factors (II,VII, IX, X).
 Bone calcium-binding proteins as Osteocalcin.
 The product of Growth arrest specific gene Gas6 which
is involved in differentiation & development of nervous
system.
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 Vitamin K cycle
Role of liver in blood clotting:
1. Site of clotting factors synthesis.
2. Site of bile salts synthesis (to help vit. K absorption).
• Liver failure: results in severe bleeding problems.

,,,

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Vitamin K: Anti-coagulants
• Dicumarol & warfarin are antagonists of vitamin K (anti-coagulants).
• Are used to reduce blood coagulation in patients at risk of thrombosis.
• Thus, vitamin K is the antidote to an overdose of warfarin.

Deficiency
Causes:
• Primary deficiency: rare
• Secondary deficiency:
 In newborn who lack bacterial colonization.
 Anticoagulant Therapy.
 Fat malabsorption.
 in patients suffering from Liver diseases (obstructive jaundice).
 long-term or high-dose administration of antibiotics (they kill the bacteria
in large intestine).

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Vitamin K: Deficiency
Manifested by:
• Bleeding tendency (GIT, ecchymoses) from minor
wounds. . Nose & gum bleeding. Heavy menstrual bleeding.
• Increased risk for osteoporosis.
Diagnosed by:
• prolonged blood coagulation time: prolonged
prothrombin time (↑↑ PT). [ blood takes 10-13.5
sec to clot].
• Prevention: single shot of vit. K at birth in newborn.

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 Fat soluble vitamins

Vitamin E

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 Vitamin E: Chemical structure & sources
• Vitamin E is a family of a-,
b-, g-, d- tocopherols which
are derivatives of an alcohol.
• The highest biological activity
has a-tocoferol.
Plant sources:
• Vegetable oils
• Nuts
• Whole grains
• Leafy green vegetables as green lettuce leaves .
Animal sources:
• Egg yolk, liver, meat, fish.
[Freezing may destroy Vitamin E]
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 Metabolism of vitamin E
• Absorption of vitamin E from the intestine depends on micelle
formation.
• Vitamin E is transported in the blood by the plasma
lipoproteins. Chylomicrons carry tocopherol from the
enterocyte to the liver.
• Upon reaching the liver, alpha-tocopherol is preferentially
taken up by alpha-tocopherol transfer protein. Then either
sulfated or glycuronidated. This renders the molecules water-
soluble and leads to excretion via urine.
• Unabsorbed vitamin E is excreted via feces.

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Vitamin E: Functions
• Tocopherols have antioxidant activity i.e. they react very
readily with molecular oxygen and free radicals, thus prevent
autoxidation of tissues.
• Vit E acts as lipid-soluble antioxidant in cell membranes.
• Vitamin E prevents oxidation of :
 PUFAs in all membranes. This prevents hemolysis of RBCs by
H2O2 .
 LDL (low density lipoprotein). Oxidized LDL may be more
atherogenic (Vit.E may protect against coronary heart
disease).
 DNA. (may help prevent DNA damage & cancer).

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 Free Radicals
• Free Radicals are By-products of the body’s metabolic reactions.
• Cells contain many potentially oxidizable substrates such as
polyunsaturated fatty acids (PUFAs), proteins, and DNA.
• Anti-oxidants: Group of compounds that neutralizes free radicals,
helping to counteract the oxidation that takes place in cells. E.g.
 Vitamins E: it is an example of a phenolic antioxidant. They donate the
hydrogen from the hydroxyl (-OH) group on the ring structure to free
radicals, which then become un-reactive. On donating the hydrogen, the
phenolic compound itself becomes a relatively free radical.
 Vitamins C.
 Selenium.
 Carotenoids as beta carotene
• If exposure to free radicals exceed the protective capacity of the
antioxidant defense system, a phenomenon often referred to as oxidative
stress.
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Vitamin E: deficiency
Causes:
• Severe malabsorption.
• Chronic liver disease. [They suffer deficiency because they are
unable to absorb the vitamin or transport it.]
• Premature infants are born with inadequate reserve of the
vitamin.
Manifestations:
• Muscle weakness & neurological problems. Due to nerve and
muscle membrane damage. Ataxia (unstable gait).
• Hemolytic anemia. The RBC membranes are abnormally fragile
as a result of lipid peroxidation. It can be corrected by vitamin E
supplementation.

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End of vitamin E
 Fat soluble vitamins

Vitamin A

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Vitamin A: Chemical structure
• 3 forms of vitamin A:

 Retinol.

 Retinal.
All-trans-retinal 11-cis-retinal

 Retinoic acid

• β-carotene.

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Vitamin A:
Sources
1. Vitamin A is supplied by foods of animal
origin e.g. liver, egg yolk, butter, whole
milk and fish liver oil.
2. Carotenes (provitamin A): plant origin:
dark green and yellow vegetables and
fruits are good sources e.g. carrots,
sweet potatoes, spinach, apricots and
green leafy vegetables.

Synthesis & storage: Synthesis of vitamin A

from α , β , and γ carotenes by
carotenase (dioxygenase) enzyme occurs
in the intestinal mucosa and the liver.

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 Absorption and Storage
 Retinyl esters and carotenoids are incorporated into micelle.
Phospholipids, and bile salts are essential for the efficient
solubilization of retinol.
 Retinyl esters together with other lipids are incorporated into
chylomicrons, excreted into intestinal lymphatic channels,
and delivered to the blood.
• most retinyl esters are taken by liver cells.
• Following hydrolysis of stored retinyl esters, retinol combines
with a plasma-specific transport protein, retinol-binding
protein (RBP).
• The RBP-retinol complex associates with transthyretin. The
transthyretin-RBP-retinol complex circulates in the blood,
delivering the retinol to tissues.
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Vitamin A: Metabolism

Reduction Oxidation

Light

11-cis-retinal
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Dark
Vitamin A: Function and Physiological Role
I. Antioxidant: Vitamin A (retinol and retinoic acid) reduce the risk of:
 cancers e.g. lung cancer in heavy smokers. (Anticancer agent)
 Protecting from heart disease.
II. Role in cell growth and differentiation:
· The mechanism of vitamin A action is mediated through specific
nuclear receptors. These receptors are activated by binding with
retinoic acid. Activated receptors bind to DNA response elements
located upstream of specific genes to regulate the level of
expression of those genes. Those proteins will be involved in
regulation of cell growth and differentiation.
III. Role in Epithelial Tissue:
 Vitamin A is essential for health and integrity of the epithelial tissues.
 Retinal also inhibits the synthesis and deposition of keratin by
epithelial cells.
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Vitamin A:
IV. Role in Vision:
• The retinal rod cells are adapted for vision in low light
intensities (night vision).
• Rhodopsin; conjugated protein, is formed in the retinal-rods
by binding of opsin to 11-cis-retinal during dark.
• When rhodopsin is exposed to light, the bound 11-cis-retinal
is transformed into all trans retinal (change in configuration;
non enzymatic).
• Dissociation of the bleached rhodopsin to yield free opsin
and all trans retinal initiates the nerve impulse which will be
perceived by the brain.
• Rhodopsin must be reconstituted for continued vision in dim
light.

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Vitamin A: Summary of function

I. Antioxidant: Vitamin A (retinol and retinoic acid) & b-

carotene (Anticancer agent).
II. Role in cell growth and differentiation (retinoic acid).
III. Role in Epithelial Tissue.
IV. Role in Vision (retinal).
V. Support reproduction and growth. (retinol and retinoic acid)
VI. Support immunity (retinoic acid and carotenoids). Vitamin
A plays a role in T cell differentiation, and can increase IgA
secretion.

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Vitamin A: Deficiency
Deficiency: is characterized by:
• Night blindness: The earliest sign of vit A deficiency is a loss of sensitivity
to green light, followed by impairment to adapt to dim light.
• Follicular hyperkeratosis (rough and dry skin with keratinization of
hair follicles).
• Xerophthalmia (dry eye due to keratinization
of the epithelium of lacrimal glands and loss of
tears). Collection of keratin in conjunctiva are
known as Bitot’s spots.
• Keratomalacia (keratinization of the cornea).
• Abnormal skeletal development.
• Immune dysfunction.
• Reproductive disorders: as Increased abortions ,
Neonates born dead.
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 Toxicity (Hypervitaminosis A)
 Large doses over a period of months or years as in treatment
of acne can be toxic.
· Toxic symptoms include:
 Symptoms affects CNS (headache, nausea, ataxia, anorexia).
 Enlargement of liver (hepatomegaly).
 Calcium homeostasis (calcification of soft tissues), bone pain.
 Skin (dryness, desquamation, alopecia).

• It is virtually impossible to develop vit.A toxicity by ingesting

natural foods.

End of vitamin A
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 Fat soluble vitamins
Vitamin D

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Vitamin D: Introduction
• Vitamin D is not strictly a vitamin since it can be synthesized
in the skin.
• Only when sunlight exposure is inadequate, is a dietary source
required.

Chemical structure:
• D vitamins are a group of sterol compounds:
 Vitamin D2 (ergocalciferol) is generated from ergosterol (pro-
vitamin D2) by ultraviolet irradiation.
 Vitamin D3 (cholecalciferol) is derived from 7-dehyro
cholesterol (pro-vitamin D3) by ultraviolet irradiation.
• Vitamins D2 and D3 are of equal biologic potency and are
metabolized identically.
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Vitamin D: Sources
• Cholecalciferol is produced in the skin by U.V. (the cheapest source of
vitamin D3).
• Preformed vitamin D3 from fish-liver oils, flesh of oily fish, egg yolk and
liver.
Activation:
• Activation of vitamin D starts in liver cells, where it is hydorxylated on the
25 position by specific microsomal enzyme.
• 25-hydroxy D can be further hydroxylated in kidney by a mitochondrial
enzyme to produce 1,25 dihyroxy D3 (calcitriol) which is the metabolically
active form of the vitamin.
• 24,25-dihydroxy-D is another active form isolated. However, it is less
active than 1,25 dihydroxy D3.
 25-OH D3 = storage form
 1,25-(OH)2 D3 (calcitriol) = active form

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Vitamin D: Activation Diet

25-hydroxylase

1-hydroxylase

Calcitriol
36 Steroid hormone
Vitamin D: Function
I. Calcium homeostasis: The mechanism of action of 1,25 dihyroxy D:

 In the intestine: it increases the absorption of calcium and

phosphorus from the intestine (it induces the synthesis of specific
mRNA responsible for synthesis of intestinal calcium binding protein).
 In the bone: It promote bone resorption (mobilization of calcium
from bone) at low Ca level. In moderate amount 1,25 dihydroxy D
enhance deposition of calcium in bone.
It promotes synthesis of osteocalcin which is needed for bone
mineralization. It also promotes bone collagen synthesis.
 In the kidney: It enhances reabsorption of filtered tubular calcium &
phosphate.

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 Function
II. Reduce risk of:
 insulin resistance, obesity , metabolic syndrome: it is lower
in obese individuals who are more likely to develop diabetes
mellitus.
 Cancer: 1,25(OH)2D can prevent cancer development or
retard its progress/metastasis once developed by inhibition
of the cell cycle, inducing apoptosis, prevention of tumor
angiogenesis, and inhibition of metastasis.
 Vitamin D also affects immunity. vitamin D derivatives are
now used successfully in the treatment of psoriasis.
 Cardiovascular system: Severe vitamin D deficiency in
humans is associated with cardiomyopathy

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Vitamin D: Deficiency
Causes:
 insufficient exposure to sunlight.
 inadequate dietary intake.
 GIT disorder (malabsorption) &
obstructive jaundice.
Manifestations:
In children:
 Rickets is due to defective mineralization secondary to calcium
deficiency: -delayed closure of fontanelles.
- soft bones. - “bowed” legs. - knobs on ribs.
 Rickets is due to defective mineralization secondary to:
1. Type I vit D dependent rickets: caused by an inherited defect in the
conversion of 25(OH)- D3 to calcitriol (1-hydroxylase).
2. Type II: Is a vitamin D-resistant rickets caused by absence of calcitriol
receptor.
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Vitamin D: Deficiency
Manifestations:
In adults: Osteomalacia due to decreased absorption of calcium
and phosphorous → low plasma calcium level → resulting in
demineralization of preexisting bone → causing the bone to
become softer and more susceptible to fracture.
Toxicity (Hypervitaminosis D)
 Hypercalcemia.
 Hypercalcuria which predisposes to formation of renal stones.
• Although Excess vit.D intake is toxic, excessive exposure to
sunlight does not lead to toxicity because a limited capacity to
form a precursor (7-dehydrocholesterol) and prolonged
exposure leads to formation of inactive compounds.
Thank you & Best wishes
Dr. Eman Shaat
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