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8/7/2019 Lipid Soluble Vitamins
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BIOCHEMISTRY: FAT SOLUBLE VITAMINS (VITAMINS A, D, E, K) Page 1
FAT SOLUBLE VITAMINS (VITAMINS A, D, E, K)
- Depend on lipoproteins to be stored in the liver
and fatty tissues
- They are eliminated much more slowly than water
soluble vitamins.
- Megadoses of these vitamins lead to toxicity,
unlike water soluble vitamins that get flushed out
of the system.
There are only 4 kinds of vitamins that are soluble to lipids
namely:
- Vitamin A (Retinol)
o Part of the visual pigment
- Vitamin D
o Calcium metabolism and bone grwoth
- Vitamin E
o antioxidant
- Vitamin K
o Blood clotting factor
**One of the major differences between water solublevitamins and lipid soluble vitamins is that lipid soluble
vitamins are most often stored in the body. On the other
hand, water soluble vitamins are constantly excreted in our
system.
- With the exception of Vitamin B12 which is stored
in the liver
VITAMIN A
- Vitamin A has two distinct roles in humans:
o Maintenance of vision
o Differentiation and growth of epithelial
cells at a genetic level
Also aids in growth and health of
skin and mucus membranes
Promotes normal development of
teeth and skeletal muscle
- Adult RDA: 1000 μg RE
- Active forms of Vitamin A:
o Retinol (OH)
Alcohol as functional group
o Retinal (HC=O)
Aldehyde as the functional group
o Retinoic acid (CO2H)
Carboxyl as the functional group
- Sources of Vitamin A
o Carotenoids
Precursor synthesized by plants
which are cleaved, reduced,
esterified and stored in the liver
as RETINOL PALMITATE
Retinol Palmitate is akind of RETINOL ESTER
which is simply Retinol
esterified with a fatty
acid (palmitate)
Palmitatemost
common lipid in the
human body
Good sources of carotinoids
include: dark green, leafy
vegetables, orange/ yellow
vegetables, fruits
o Retinol
Sources of retinol include: liver,
egg yolk, butter and whole milk
** Carotenoids and retinol absorbed along with other
lipids in the diet along the GIT.
** Fatty acid absorption diseases can also affect
absorption of lipid soluble vitamins.
- Deficiency of Vitamin A can cause:
o Night blindness
when liver stores are nearly
exhausted
o Keratinization of epithelial tissue
eyes
lungs
GIT
o Xerophthalmia
corneal dryness
loss of reflective power
DIOPTERmeasure of curvature of
lens or mirror for reflective power
SUBJECT: BIOCHEMISTRY
TOPIC: FAT SOLUBLE VITAMINS (VITAMINS A, D, E, K)
LECTURER: DR. LAYGO
DATE: FEBRUARY, 2011
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BIOCHEMISTRY: FAT SOLUBLE VITAMINS (VITAMINS A, D, E, K) Page 2
Corneal cells should always be wet to
prevent lens opacity due to corneal
dryness
Tears that provide lubrication are from
the lacrimal duct
o Blindness
o Keratomalacia
perforation of the cornea followed by
bacterial invasion
Softening of eyeballs
Lysozomes found in tears thatprevents bacterial invasion/ infection
o Death
METABOLISM OF BETA-CAROTENE
(Pls. refer to Figures 1 and 2 at the later pages of the tranx.)
FIGURE 1: Beta- carotene is a symmetrical structure. The
enzyme BETA-CAROTENE DEOXYGENASE in the intestines
will form 2 retinaldehyde molecules. One of the
retinaldehyde molecules, through the enzyme RETINOL
DEHYDROGENASE will form retinol (vitamin A
). This utilizes
an oxidation reaction (utilizing NADPH+) and this functional
retinol will be converted to retinol palmitate through
ESTERIFICATION. The other retinaldehyde molecule will
form an all-trans retinoic acid through IRREVERSIBLE
OXIDATION (this time, using NAD and FAD). This all-trans
retinoic acid is important in maintaining the skin especially
one a person is suffering from acne. The enzyme RETINOIC
ACID ISOMERASE will then convert the all-trans retinoic acid
into 11-cis retinoic acid.
In summary:
1. Beta-carotene will form 2 molecules of retinaldehyde through the enzyme beta-carotene
deozygenase
o Oxidation reaction
2. One retinaldehyde will yield retinol (vitamin A)
through the enzyme retinol dehydrogenase
o Retinol will be converted to retinol palmitate
through esterification
3. The other retinaldehyde will be converted to an all-
trans retinoic acid through irreversible oxidation
o
This will then be converted to 11-cis retinoic
acid through the enzyme retinoic acidisomerise.
ROD CELLS AND CONE CELLS OF THE RETINA
- Scotopsin protein in the retinal rods that combines
with retinal to form rhodopsin
o A kind of opsin protein
o involved in night vision;
o can absorb photon of light so that in the dark
we can see
** Rod cells dark vision; black and white vision
** Cone cells light vision, color vision
o depends on visual spectrum, and absorbs light
maximally
**Inherently Photo-sensitive ganglion cells cells among
those who have no cones or rods in their retina and yet they
can still respond to light stimulus.
PHOTORECEPTOR CELLS:
The Photoreceptor cell is composed of two segments: the
outer and the inner segment. The outer segment is likestacks of flattened discs with visual pigments, while the
inner segment contains the different organelles of a normal
cell. Closest to the visual field is the synaptic body that
synapses to the bipolar cell with the release of the
neurotransmitter glutamate.
Is glutamate excitatory or inhibitory?
Glutamate is both! The effect of glutamate depends on the
nature of the receptor found in the bipolar cells found on
the visual field. Absorption of photons results to the release
of glutamate at their axon terminals (which are the
presynaptic terminals to bipolar cells which are the postsynaptic terminals in this case). Note, that the
photoreceptor cells are DEPOLARIZED in the DARK.
Therefore, it releases high amounts of glutamate during the
dark, and during the DAY when there is more light available,
the photoreceptor cells are HYPERPOLARIZED and LESS
glutamate is released.
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BIOCHEMISTRY: FAT SOLUBLE VITAMINS (VITAMINS A, D, E, K) Page 3
The nature of receptors found in the bipolar cells’
membranes can be ionotropic or metabotropic. In
ionotropic cells, the binding of glutamate DEPOLARIZES the
bipolar cell. This means that at night when more glutamate
is released by rods or cone cells, the glutamate-receptor
complex induces depolarization. In contrast, during the DAY,
ionotropic receptors will HYPERPOLARIZE the bipolar cell.
The opposite happens in metabotropic cells.
So for example, glutamate is released, some bipolar cells
are excited, while others get inhibited. This property of the
receptors allows for detecting color, contrast, otherproperties for vision.
o Iodopsin prosthetic group of cone cells
o Rhodopsin prosthetic group of rod cells
** Responsible for circadian rhythm CORTISOL
o The cortisol level goes down at night and goes
up during the day.
o This the reason why people wake up during the
day and sleep at night, even without knowing
the time.
- Each cone cell contains only type of opsin which is
sensitive to only one color
- 3 pigments that depend on the visual spectrum (found
in cone cells)
o Cyanopsin
Pigment for blue color
(~420nm)
o Iodopsin
Pigment for green color
(~535nm)
o Porphyropsin
Pigment for red color
(~565 nm)
RHODOPSIN MOLECULE:
- 7-transmembrane helices/serpentine receptor
- 11-cis retinal will bind with the amino acid receptor,
LYSINE 296 which is found at the 7th helix forming a
protonated Schiff base.
- 11-cis retinal + opsin = rhodopsin
o Rhodopsin will interact with a cytoplasmic G-
protein, classic type .
** Classic type: with alpha, beta and gamma side chains
This will cause a formational change
in the molecular rhodopsin
Movement can be
transmitted to G-protein
molecule (G- transducin GT)
so that transducin is
subsequently activated
Inactive transducin has 3
subunits that are associated
with one another.
If alpha is bound to GDP
inactive form
When it is activated by
rhodopsin, there will be a
NUCLEOTIDE EXCHANGE.
**Activated G-protein moleculethe GTP bound to the
alpha subunit will exchange with a GDP molecule which
causes the dissociation of the beta and gamma subunits.
INACTIVE GT: alpha, beta, gamma sub-unit + GDPACTIVE GT: alpha sub-unit + GTP only (beta and gamma
dissociates)
**Schiff base formed by association of 11-cis retinal to
lysine of opsin which converts inactive rhodopsin to active
form METARHODOPSIN-2 which can in turn activate the G-
transducin.
**BARTHORHODOPSIN is an intermediate in forming
metarhodopsinII.
In summary:
(FIGURE 3: The participation of retinal in the visual cycle)
In the pigment epithelium retina, all-trans-retinol is
isomerized to 11-cis-retinol and oxidized to 11-cis-
retinaldehyde. It will react with lysine group in opsin forming
a protonated Schiff base, rhodopsin. The absorption of light
causes isomerisation of retinaldehyde from 11-cis-to all-
trans, and a conformational change in opsin, therefore
converting it to the intermediate, barthorhodopsin
, then a
series of conformational changes will give rise to
metarhodopsin II (the activated form) which initiates a
guanine nucleotide amplification cascade. The final step is
hydrolysis to release all-trans-retinaldehyde and opsin.
Therefore, there is a continuous supply of 11-cis retinal.
IMPORTANCE OF GMP:
- Signals should be transformed to electrical impulses
for the brain to understand these electrical impulses
- For rod cell and cone cells -30mV resting membrane
potential(RMP)
o RMP is determined by the influx and efflux of
Na+, Ca++, and K-
o Muscle RMP -60mV
2 ion channels maintaining the RMP:
o Na+-Ca++ ion channel
A ligand-gated ion channel
If opened will allow entry of sodium
and calcium ions to DEPOLARIZE rod
cells and cone cells (polarizing current)
Ligand: cGMP
PHOTORECEPTOR
CELLS (RODS and
CONES)
IONOTROPIC METABOTROPIC
DAY
(light)
HYPERPOLARIZE
LESS glutamate
released
HYPERPOLARIZE DEPOLARIZE
NIGHT
DEPOLARIZE
MORE glutamate
released
DEPOLARIZE HYPERPOLARIZE
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BIOCHEMISTRY: FAT SOLUBLE VITAMINS (VITAMINS A, D, E, K) Page 4
o Na+-Ca++-K- Exchanger
Always open (whether or not cGMP
levels are enough)
Not ligand gated
Brings out Na+ and Ca++ in exchange
for K- ions
When there is light:
- The activated GT activates Phosphodiesterase (an
enzyme which converts cGMP to 5’-GMP)
- Thus, cGMP concentration is reduced and the Na-Ca
ion channel has no ligand to activate it.
- Now, Na+ and Ca++ decreases inside because Na-K-Ca
exchanger is ALWAYS open HYPERPOLARIZATION
- Hyperpolarization is responsible for electrical impulse/
action potential
o -30 to -35mV
o Depolarization is NOT responsible for the
impulse
- When the level of Ca becomes too low inside, guanylylcyclase will be activated
o Guanylyl cyclase synthesizes GTP back to
cGMP to open the Na-Ca ion channels again
- Depolarization allows the entry of Na and Ca ions
** Photon activated rhodopsin activate transduction.
o It will activate phosphodiesterase
Na-Ca ion channels will be the first
one to close. This will cause the
decrease of Na and Ca inside
because Na-Ca-K exchangers stillwork.
FIGURE 4:
In the presence of light:
Activate rhodopsin (Metarhodopsin II) activate
transduction activate phosphodiester bond cGMP
converted to 5’-GMP closes Na-Ca ion channel Na
and Ca levels are lowered because of always open Na-Ca-K
exchanger hyperpolarization will occur AP is produced
Neurotransmitter: Glutamate is released if the level of
Ca inside drops, GTP will bind with guanylyl cyclase (GTP to
cGMP) Na-Ca ion channels will open again [darkness!!]
VITAMIN A TOXICITY
- Being a fat soluble vitamin, excess cannot be easily
excreted as in the case of water soluble vitamins
- This is very rare because it will happen only in mega-
mega amounts
- Occurs when the capacity of renal blood pressure has
been exceeded and the cells are exposed
SYMPTOMS
- Bone pain
o Craniofacial and neuro tube malformation
regulation of gene expression via induction
and repression goes hay-wire.
- Dermatitis (shedding of epithelial cells)
- Enlargement of liver and spleen
- Diarrhea (because of shedding of epithelial cells)
** Nuclear receptors in the gonads increase gene
expression and maintain reproductive tissues while nuclear
receptors in the epithelial cells regulate cell differentiation.
1 photon of light can...
- affect 1 mol of rhodopsin
- 1 metarhodopsin can activate 500 transducin
VITAMIN D
- 1,25-(OH)2-Cholecalciferol or Calcitriol (activated
Vitamin D)
- In the skin, 7-dehydrocholesterol + UV rays
cholecalciferol In the liver, becomes 25-OH-
cholecalciferol In the kidney, converted to 1,25
(OH)2 cholecalciferol or Calcitriol by α-1-hydroxylase
- Function: Synergistic to PTH by increasing GIT
absorption of dietary Calcium to help the function of
parathyroid hormone (resorption of bone)
- Considered as a steroid hormone.
o As a steroid hormone, Calcitriol can easily
enter the cell and binds to the intracellular
nuclear receptor. The Calcitriol-Receptor
complex binds to the DNA segment known as
the Calcitriol Response Element (CRE) which
forms new mRNA. After post-transcriptional
modification, it will go out to cytoplasm which
will be used to synthesize new protein
molecules.
o Protein molecules synthesized:
Calcium ATPase pump
Calcium binding proteins
**These help increase calcium absorption will lead to
correction of low serum Ca levels
VITAMIN E
- Contains isoprenes
- With several forms depending on the methyl groups
attached
o Alpha tocopherol
Beta
- Gamma
o Delta tocopherol
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BIOCHEMISTRY: FAT SOLUBLE VITAMINS (VITAMINS A, D, E, K) Page 5
most potent because there are more
methyl groups attached
- Vitamin E has anti-oxidant properties due to methyl
groups
o Methyl group will get lone pairs of radicals
Has 3 bonds; hence, there will be
available paring
Gets the lone pairs of radicals
o Prevents damages caused by lipid
peroxidation- Vitamin E is also transformed to a radical in the
process
o Why is vitamin E not harmful to us even if it is
a radical? Because it works in synchrony with
Vitamin C which also acts with glutathione.
Glutathione converts vitamin E radicals and
vitamin C radicals to their original form.
- Will function optimally in the presence of selenium
VITAMIN K
-“K” derived from the german word “koagulation”
- Function of Vitamin K
o To be able to carry on the carboxylation of
glutamate residues in liver to form GLA
residues
Quinone form is needed for the
carboxylation of glutamate.
o Why is it carried out?? Binding of sites for
calcium ions to form PROTHROMBIN
Activated prothrombin will act onfibrinogen to form FIBRIN. Soluble
fibrin will harden and form a clot.
Given to newborns because the
infant’s liver is not yet well developed.
Phospholipids are also important in
clotting co-factors, and they cannot be
used by the liver if it still immature.
Newborns have sterilized guts and no
flora is found yet in their intestines.
This bacterial flora can also produce
Vitamin K.
Vitamin K affect clotting factor II, VII, IX, X
3 types of vitamin K:
- Vitamin K3 phylloquinone (in plants)
- Vitamin K2menaquinone (in intestinal bacteria)
- Vitamin K1menadione
** Warfarrin transforms epoxide back to quinine for the
carboxylation of glutamate
--------------------------------END OF TRANX--------------------------------
FIGURE 1:
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BIOCHEMISTRY: FAT SOLUBLE VITAMINS (VITAMINS A, D, E, K) Page 6
FIGURE 2:
FIGURE 3:
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BIOCHEMISTRY: FAT SOLUBLE VITAMINS (VITAMINS A, D, E, K) Page 7
FIGURE 4: