Transcript Slide 1

TUMS
Dr. Azin Nowrouzi, PhD
Tehran University of Medical Sciences
1
History
 Dumas (1871) individuals fed on pure minerals, water,
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proteins, fats and carbohydrates did not maintain good
health.
Lunin (1880) similar finding in animals, milk restored
them to normal
Eijkman (1897) Beri-beri occurred in those fed on
polished rice. Rice-polishings cured them. ..toxin in
polished rice and antitoxin in rice polishings!
Grijns (1901) tried to isolate toxin but did not find any.
There may be a protective substance in rice polishing.
Pokelharing, McCollum, Hopkins (1911)
Corroborated the findings of Lunin. The protective
substance present in milk were named “accessory factors”
by Hopkins.
Funk (1911-1912) isolated crystalline substance from
rice polishings that could cure polyneuritis in pigeons.
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Origin of the word VITAMIN
Casimir Funk, a Polish biochemist, isolated an antiberberi substance from rice polishing.
 Named it vitamine
 An amine
 Vital for life
Originally, it was thought these necessary
compounds were all amines. Since they were vital
to our health they became known as
“vital amines”, ie. vitamines.
When it was discovered that some were not amines,
i.e., not ' --ines', the name was changed to:
vitamins
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What are Vitamins?
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Vitamins are micronutrients:
Nutritionally important organic compounds
Required in very small amounts.
Cannot be synthesized by the human body.
Do not enter into tissue structures unlike proteins.
Do not undergo degradation for providing energy unlike
carbohydrates and lipids.
Plants and animals synthesize vitamins.
– Vitamins form through biochemical life processes of the plants and
animals we eat.
Examples:
1. Most mammals can synthesize vitamin C; not humans and primates.
2. No mammal can synthesize B vitamins but rumen bacteria do.
3. Some function as vitamins after undergoing a chemical change:
Provitamins (e.g., β-carotene to vitamin A).
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Coenzymes, Cofactors, and
Prosthetic groups
Vitamins bind the enzyme either loosely
or tightly:
 Coenzymes are lost upon dialysis because
they bind the enzyme loosely.
 When they bind enzymes tightly, they are
considered prosthetic group.
 The term cofactor includes such
compounds but also includes other
molecules such as metal ions that may be
necessary for enzyme activity.
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Classification
Fat-soluble vitamins are much more
soluble in fats, hydrocarbons and similar
solvents than in water
 Vitamins A, D, K, E
Water-soluble vitamins are much more
soluble in water than in “organic solvents”.
 C, B complex
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Classification, Requirements, Absorption
Water-soluble
Name(Letter)
RDA
(mg)
Thiamin (B1)
Riboflavin (B2)
Niacin (B3)
1.5
1.7
2
Pantothenic acid (B5)
Pyridoxine (B6)
Biotin (B7)
Folic acid (B9)
10
2
0.3
0.4
Cobalamin (B12)
Ascorbic acid (C)
6 g
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 Absorption: at the small
intestine.
 Regulation of absorption: by
either other vitamins or
binding proteins in the small
intestine.
 Transported away from
small intestine in blood.
 Typically not stored; instead,
kidney filters excess into
urine
 Thus, important to get these
vitamins daily.
 Toxicities almost unheard of.
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Classification, Requirements, Absorption
Oil-soluble
Name (Letter)
RDI
Retinol (A)
5000 IU
Calciferol (D)
400 IU
Tocopherol (E)
30 IU
Phylloquinone (K)
70 g
 Absorption: Along with dietary fat in small intestine.
 40-90% absorption efficiency.
 Absorption typically regulated by need:
need absorption
 Transported away from small intestine in chylomicra via
blood and lymph (depending on size).
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B Complex Vitamins
Vitamin Chemical name
B1
B2
B3
B4
B5
B6
B7
B8
B9
B10
B11
B12
Thiamine
Riboflavin
Nicotinamide (niacin)
Adenine (no longer considered a vitamin)
Pantothenic acid
Pyridoxine
Biotin
Inositol
Folacin (folic acid)
p-aminobenzoic acid (PABA) / H1
L-carnitine / b-hydroxy-g-trimethylammonium butyrate
Cyanocobalamin
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B Complex - General features
1.
Present in all plant and animal cells.
2.
Generally act as components of coenzymes in
metabolism of carbohydrates, lipids and proteins,
especially in energy-yielding reactions.
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Dietary requirement is closely linked to metabolic rate.
3.
Absorbed by passive diffusion (except B12) in small
intestine and any excess is excreted in urine i.e. there
is little or no tissue storage (except B12, some folic
acid).
4.
Must be continually supplied in diet (or by ruminal
synthesis).
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Vitamin B1 - Thiamine
 Funk (1912) isolated the anti-berberi substance from rice polishing.
 Jansen and Donath (1927) isolated thiamine in its pure form.
 Williams (1936) elucidated the chemical structure of Thiamin:
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A substituted pyrimidine and a thiazole coupled by a methylene bridge.
It is very water-soluble.
Readily decomposes in neutral solution.
Has the characteristic "meaty" odor and flavor.
 The active form is thiamin pyrophosphate (TPP)
 Thiamin is rapidly converted to thiamin pyrophosphate (TPP) in small
intestine, brain and liver.
 TPP is formed from thiamin by the action of thiamine diphosphotransferase
(see the next slide).
 Monophosphate (Thiamin -monophosphate (TMP) and -triphosphate
(TTP) forms are also present.
 Absorption is increased in times of deficiency, but reduced by thyroid
hormone, diabetes, alcohol consumption.
 Thiamine is carried by portal blood to the liver.
 Free thiamine is present in plasma, but the coenzyme (TPP) is the
primary cellular component.
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Chemical structure
2-methyl-4-amino pyrimidine + 4-methyl-5-β-hydroxyethylthiazole
Thiamine
MgATP2Thiamine
diphosphotransferase
MgAMP-
TPP
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Functions
1. Transketolase reactions of the
Pentose phosphate pathway
(hexose monophosphate shunt).
TTP (thiamine triphosphate)
is required for nerve function
(unrelated to coenzyme
activity).
1. Oxidative decarboxylation
of pyruvic acid.
2. Oxidative decarboxylation
of –ketoglutaric acid.
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Deficiency symptoms
1.
Classic deficiency disease syndromes is beriberi in humans:
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GI symptoms:
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Muscular weakness (through accumulation of lactic acid).
Neurological manifestations:
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Inappetence, poor growth, nausea, vomiting, fever, diminished gastric motility.
Progressive nervous dysfunction, Wernicke’s encephalopathy.
Cardiovascular manifestations:
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Palpitation, cardiac hypertrophy and dilation, congestive cardiac failure.
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1.
2.
3.
Causes:
It can happen if raw fish containing microbial thiaminases are ingested.
Tea may contain antithiamine factors.
Chronic alcoholism often leads to thiamine deficiency.
In alcoholics there is:
Reduced intake
Impaired absorption
Impaired use
Reduced storage
Alcohol is high in calorie but low in vitamin B1.
All this can lead to Wernike-Korsakoff syndrome.
4.
All diuretics including, Furosemide has been shown to cause thiamine (B-1) deficiency.
This can lead to "wet beriberi" which causes sodium retention, dilation of blood vessels
and heart failure.
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Thiamine Deficiency (B1) Beriberi
Wet beriberi –
dilated cardiomyopathy
Due to peripheral dilation of arterioles
Dry beriberi –
peripheral neuropathy, atrophy
Alcohol &
Wernicke-Korsakoff syndrome
Ataxia (inability to coordinate muscular
movements due to nervous disorders)
and confusion
Alcohol dilated
cardiomyopathy
Memory loss/confabulation
(to fill in gaps in memory by
fabrication)
Opthalmoplegia
– can’t follow light source
Nystagmus
-involuntary jerking of the eye
Sources
• Widely distributed.
• Brewers' yeast is very rich source.
• Cereal grains are rich sources, especially in
germ and seed coat.
• Fresh green, leafy plants
• Animal products (especially egg yolk, liver,
kidney) are good sources.
• Synthetic vitamin is usually available as
thiamin hydrochloride.
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Vitamin B2 or G = Riboflavin
• Yellow, crystalline compound with yellow-green
fluorescence in aqueous solution.
• Only sparingly soluble in water.
• Stable in acid or neutral, but not alkaline solutions.
• Unstable in light.
• Riboflavin is phosphorylated in the intestine to generate
FMN (riboflavin 5’-phosphate) by the action of Flavokinase.
Riboflavin + ATP Flavokinase
FMN + ppi
• FMN then reacts with ATP, yielding FAD:
FMN + ATP
FAD synthetase
FAD + ppi
ppi = inorganic pyrophosphate.
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Chemical structure
• Isoalloxazine ring system = dimethylbenzene + pteryn
• Ribitol (Reduced ribose) attached to N10
Riboflavin
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FMN
FAD
5
1
5
1
riboflavin 5’-phosphate
Flavokinase
(riboflavin kinase)
FAD
FMN + ATP
FAD + ppi
synthetase
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Chemical structure and atom numbering of
the flavin mononucleotide
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Riboflavin functions
• Essential constituent of the
– Flavoproteins
– Flavin mononucleotide (FMN)
– Flavin adenine dinucleotide (FAD)
• These play key roles in hydrogen transfer
reactions associated with
– Glycolysis
– TCA cycle
– Oxidative phosphorylation.
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Deficiency symptoms
1.
Inappetence, poor growth,
vomiting, skin eruptions and
eye abnormalities in pigs.
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Cheilosis/Angular stomatitis
(fissure at the angle of the
mouth)
Localized seborrheic dermatitis
of the face
Vascular changes in the cornea
Purple smooth tongue due to
loss of tongue papillae
(Glossitis).
Cheilosis/Angular stomatitis
2. Poor growth and "curled toe
paralysis" in chicks.
•
The toes frequently curl inward
and they may be unable to
stand.
Glossitis
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Dietary Sources
• Dairy products
• organ meats (liver and heart) but not
muscle meat.
• Green leafy plants (especially alfalfa)
• Yeast and animal products
• Cereals are poor sources so poultry fed
cereal-based rations should receive
supplemental riboflavin.
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Niacin = Vitamin B3
• Beta pyridine carboxylic acid
• Two forms: Nicotinic acid and Nicotinamide.
Nicotinamide is the amide derivative of nicotinic acid.
• In most animal species (including humans) niacin can be
synthesized from the essential amino acid, tryptophan.
• Both forms contain a pyridine ring.
Nicotinic acid
Nicotinamide
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NAD+
NADP+
Functions:
Active coenzymes:
nicotinamide-adenine
dinucleotide (NAD+)
nicotinamide-adenine
dinucleotide
phosphate (NADP+).
Both are extremely
important in
hydrogen transfer
reactions catalyzed
by dehydrogenase
enzymes.
ATP synthesis, from
oxidation of primary
fuels (glucose, fatty
acids and to a lesser
extent, amino acids)
(NAD+)
Also important in
reductive
biosynthesis
(NADP+)
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Deficiency symptoms
1. Pellagra in farm animals and humans (fiery inflammation of tongue, mouth and upper
esophagus).
2. Poor growth, enteritis and dermatitis.
3. Occurs in people who subsist mainly on corn which is low in both niacin and
tryptophan
4. The signs of pellagra include dermatitis, diarrhea, dementia (the three Ds) and loss of
tongue papillae.
Sources of B3
Most non-corn-based diets contain adequate amounts of nicotinamide or its
precursor, tryptophan.
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Vitamin B4- Adenine
• Adenine is no longer considered a vitamin !
• purine (pyrimidine + imidazole)
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FAD
NAD
NADP
CoA
S-AdoMet
PAPS (Phosphoadenosine
phosphosulfate)
• ATP
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Energy charge (EC) within cells
The energy charge can have a value ranging from 0 (all AMP) to 1(all ATP).
Most cells maintain EC at a constant value with very little variation: The energy
charge of most cells range from 0.8 to 0.95. As EC drops catabolic, energy
producing pathways, such as Glycolysis increase in rate, while anabolic, energy
consuming pathways decrease in rate. The opposite occurs as EC increases,
resulting in a tight control around an optimal value, as seen in the figure. It is evident
that control of these pathways has evolved to maintain the energy charge within
rather narrow limits. In other words, the energy charge like the pH of a cell is
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buffered.
Vitamin B5 / pantothenic acid
• Chemical nature
• Dipeptide derivative of the amino acid
β-alanine and a butyric acid derivative.
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Coenzyme A and Acetyl coenzyme A
• Essential constituent of coenzyme A, Pantothenic acid combines with
ATP and cysteine in the liver to generate CoA-SH.
• CoA-SH transfers activated acyl groups, R-(C=O)-, such as acetyl
group by binding them as a thioester. Acyl transfer is important in the
TCA cycle and de novo fatty acid synthesis.
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Vitamin B5 deficiency
• Deficiency symptoms
• 1. Poor growth, diarrhea, loss of hair, characteristic "goosestepping" in pigs.
• 2. Poor growth and feather development, dermatitis in chickens.
• Sources
• Widely distributed in plants (especially legumes and cereal) and
animal products.
• Deficiency has been observed in pigs fed a low protein (14%)
corn-soybean ration fortified with minerals and vitamins except
pantothenic acid.
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Lipoic Acid &
DihydroLipoic Acid (DHLA)
lipoic acid = Internal disulfur of 6,8-dithiooctanoic acid.
Lipoic Acid (LA) is part of a redox pair.
oxidized form
reduced form
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Structure
PDH = Pyruvate
dehydrogenase
complex
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Lipoic acid
• Alpha Lipoic acid is a natural substance
found in certain foods and also produced
in the human body.
• Alpha Lipoic acid is a disulfide
compound found naturally in
mitochondria as the coenzyme for
pyruvate dehydrogenase and ketoglutarate dehydrogenase.
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The coenzyme function for Pyruvate dehydrogenase
and α-ketoglutarate dehydrogenase
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• Clinical Uses for R Alpha Lipoic Acid
– Perhaps the best use of R-alpha lipoic acid is as a life extension
nutrient. It acts as:
•
•
•
•
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an anti-oxidant
anti-glycation agent
blood sugar normalizer
mitochondria activator
glutathione enhancer.
• Dosage of R Alpha Lipoic Acid
– As a nutritional supplement, doses of 50 to 100 mg per day are
generally recommended.
– As a Therapeutic agent, higher doses may be used.
– In Germany, dosages of 600 mg per day are prescribed for
preventing the damaging effects of hyperglycemia in diabetes.
– Larger doses, 1200 mg given intravenously, have been used to treat
aminita mushroom poisoning.
• R Alpha Lipoic Acid Side Effects and Precautions
– Clinical research has shown no evidence of carcinogenic effects
with administration of alpha lipoic acid. Serious side effects have not
been observed, even at high doses. Minor side effects include skin
reactions and gastrointestinal effects, such as nausea and vomiting.
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Pyruvate dehydrogenase complex (PDH)
The reaction is:
PDH
Pyruvate + NAD+ +CoASH
Acetyl CoA + NADH + H+ + CO2
5 non-protein molecules
(coenzymes) required for this
enzyme catalyzed reaction are:
NAD+ and CoASH (coenzyme
A); (these are present in the
equilibrated reaction formula,
as can be seen above)
E1 = Pyruvate dehydrogenase
TPP (thiamine pyrophosphate),
Lipoic acid and FAD (flavin
adenine dinucleotide)
participate in the reaction but
do not show up in the
equilibrated reaction formula.
E2 = Dihydrolipoamide acyltransferase
E3 = Dihydrolipoamide dehydrogenase
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Mechanism of the reaction catalyzed
by PDH complex
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E1 uses TPP to release CO2 and produce
HydroxyethylTPP (HETPP)
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E2 uses lipoic acid to transfer the
hydroxyethyl group from TPP to CoASH
in order to produce AcetylCoA
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6. PYRIDOXINE (vitamin B6)
Pyridoxal (PL)
Pyridoxamine (PM)
Pyridoxine or
Pyridoxol (PN)
Each of these forms can be phosphorylated at position 5 to form:
PLP, PMP, and PNP.
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Active (coenzyme) form
Pyridoxal phosphate
(PLP)
• Active functional form is pyridoxal
phosphate (PLP) and pyridoxamine
phosphate (PMP).
• For absorption, the “phosphorylated”
form must be hydrolyzed to
“dephosphorylated” form by the enzyme
alkaline phosphatase in the intestine.
• In the portal vein Vit B6 is present as PL,
PM, PN.
• In the liver they are converted back to
phosphorylated forms. This conversion is
catalyzed by the ATP requiring enzyme,
pyridoxal kinase.
• PLP and PL account for 90% of the
total B6 in the blood.
• In the blood B6 is transported both
in the plasma and the RBCs.
• In the blood PLP is hydrolyzed to
PL because only free PL gets inside
the cells.
• In muscle and other tissues, PL is
converted back to PLP by a reversible
reaction with the help of alkaline
phosphatase and pyridoxal kinase.
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Functions
FUNCTIONS: B6 is involved in:
Amino acid metabolism
Transamination reactions required for the synthesis and catabolism of
the amino acids.
Decarboxylation reactions.
Breakdown of glycogen Glycogenolysis (cofactor for glycogen phosphorylase).
80-90% of body vit B6 is present in the muscles, most of it in PLP
(coenzyme) form bound to glycogen phosphorylase. Only 1 mol or
less is present in the blood,
Synthesis of epinephrine (adrenaline) and norepinephrine (noradrenaline)
Synthesis of niacin (vitamin B3) from the amino acid tryptophan.
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Covalent bonds of -amino acids made labile by
their binding to PLP-containing enzyme
In the reactions of amino acid metabolism, the formyl (CHO) group of PLP
condenses with -NH2 group of an amino acid and forms a Schiffs base. This
linkage weakens or labilizes all the bounds around the -carbon of the amino acid.
The specific bond of an amino acid that is broken depends on the particular
enzyme to which PLP is attached.
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Mechanism of catalyzed reaction
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Deficiency
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•
•
•
Food sources:
– In animal foods major forms are PL and and PM along with their phosphorylated forms.
– In plants PN.
– Bananas, beans, lentils, walnuts, salmon, chicken, beef, whole grain breads and
cereals, soybeans, liver, eggs, dairy products are excellent sources.
Requirements:
– The requirement for vitamin B6 in the diet is proportional to the level of protein
consumption ranging from 1.4 - 2.0 mg/day for a normal adult.
– During pregnancy and lactation the requirement for vitamin B6 increases approximately
0.6 mg/day.
TOXICITIES:
– Megadoses of B6 (daily doses of >500mg) are used to treat pms symptoms. They can
cause neurotoxicity and photosensitivity in some individuals.
Deficiencies: are rare and usually are related to an overall deficiency of all the B-complex
vitamins.
Certain drugs form complexes with PL and PLP
– Penicillamine (used to treat rheumatoid arthritis and cystinurias).
– Isoniazid (the hydrazide derivative of isonicotinic acid) is the primary drug for
chemotherapy of tuberculosis.
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7. BIOTIN
It is
sometimes
called vitamin
H and also
coenzyme R.
• Biotin is relatively small, bicyclic (two-ring)
compound formed from a tetrahydrothiophene
(thiophene) ring
,
• and a second ring, which contains a ureido group.
• The thiophene ring also has a valeric acid side chain.
• Although eight different stereoisomers of biotin exist,
only one stereoisomer is found naturally and to have
biological activity as a coenzyme. It is called d-(+)biotin, D-biotin or simply biotin.
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In humans, the four holocarboxylases are : acetyl-CoA carboxylase,
propionyl-CoA carboxylase, pyruvate carboxylase and betamethylcrotonyl-CoA carboxylase. Biotin is chemically bonded in each of these
enzymes via an amide linkage between the carboxyl group of the valeric acid
side-chain in biotin and the epsilon-amino group of the lysine residue in the
apocarboxylase.
The enzyme that catalyzes the formation of this covalent bond is called
holocarboxylase synthetase.
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Biotin Cycle
Biotin cycle: the chain of chemical reactions involved in the use and reuse of the vitamin biotin.
One important role of biotinidase is:
1. To separate or free biotin from proteins to which it is bound in foods. Biotin in its free form
can then be used by the body.
2. Biotinidase lets the body recycle or reuse the biotin over and over again so that we do not
need to consume large amounts of this vitamin in our diets.
•Within cells, the carboxylases
(pyruvate carboxylase, acetyl-CoA
carboxylase, methycrotonyl-CoA
carboxylase, propionyl-CoA
carboxylase) are biotinylated via
holocarboxylase synthetase. Biotin
and apocarboxylases are the
substrates. ATP and magnesium also
participate in the reaction.
Biotinidase deficiency is a treatable,
inherited metabolic disorder in which the
body cannot process the vitamin biotin in a
normal manner.
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Biotin (functions)
• Coenzyme for several reactions involving CO2 fixation into various
compounds e.g.
Acetyl CoA to malonyl CoA
(acetyl CoA carboxylase)
- initial step in de novo fatty
acid synthesis.
Pyruvate to oxaloacetate
(pyruvate carboxylase)
Propionyl CoA to methylmalonyl CoA
(propionyl CoA carboxylase)
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Deficiency symptoms
•
•
•
Rare because of widespread distribution in plant and
animal food and significant lower gut synthesis.
– Sources
• Yeast, rice, soybeans, peanuts, fish (herring
and mackerel), mushrooms and bananas,
safflower meal, liver and milk are rich sources.
Can be induced by eating raw egg white
– The fact is that nature created the egg in such a way
that its yolk is very rich in biotin. One of the highest
concentration in nature. Eat the egg whole together
with the egg white and you will be fine.
– Egg whites contain a glycoprotein called "avidin"
which binds biotin - one of the B vitamins - very
effectively. The cooking process deactivates the
avidin in the egg, much the same way it deactivates
every other protein in the egg white.
Biotin deficiency is chief cause of fatty liver and kidney
syndrome.
This baby developed severe
biotin deficiency during
intravenous feeding without
biotin.
Aajonus Vonderplanitz,
in his book “We Want to
live” is a strong proponent
of raw eggs.
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1- Biotin carrier protein
2- Biotin carboxylase
3- Transcarboxylase
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Definition of terms
• MDR = Minimal Daily Requirement
– The minimal oral intake necessary to prevent the
symptoms and signs of vitamin deficiency from
appearing.
• RDA = Recommended Daily Allowance
– An estimate of the adequate vitamin intake in each
age group.
• Vitamin levels in foods or supplements are
sometimes stated in Retinol Equivalents (REs)
or in International Units (IUs).
– for Retinol: 3 IU = 1 RE = 1µg (= 6µg carotene)
– 10µg calciferol = 400 IU vit.D
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