lipid soluble vitamins

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BIOCHEMISTRY: FAT SOLUBLE VITAMINS (VITAMINS A, D, E, K)

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




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.




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




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




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--------------------------------

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lipid soluble vitamins

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