Transcript Vitamin

TUMS
Azin Nowrouzi, PhD
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.
Active 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.
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.
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.
Mechanism of catalyzed reaction
Deficiency
• 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.
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.
Holocarboxylase
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.
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.
Functions
• Coenzyme involving CO2 transfer
– acetyl CoA to malonyl CoA
– Propionyl CoA to methylmalonyl CoA
– Pyruvate to oxaloacetate
• Deficiency
– Fatty liver and kidney syndrome, a fatal
metabolic disorder in chicks and turkey poults
• Raw egg white (avidin) can block
absorption
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)
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.
How Biotin Works
1- Biotin carrier protein
2- Biotin carboxylase
3- Transcarboxylase
9. FOLIC ACID (folacin)
• Folacin includes several derivatives of folic acid
(monopteroylglutamic acid).
• Folic acid is obtained primarily from yeasts and leafy vegetables as
well as animal liver. Animals cannot synthesize PABA nor attach
glutamate residues to pteroic acid, thus, requiring folate intake in the
diet.
“Microorganisms
Only can
synthesize Folacin”
Sulphonamides
and antibiotics
block PABA
incorporation
by competitive
inhibition
Structure
Folic acid exists in a polyglutamate form. Intestinal mucosal cells
remove some of the glutamate residues through the action of the
lysosomal enzyme, conjugase.
Active functional form is:
Tetrahydrafolic acid
(THF).
Humans and microorganisms:
Folic acid is reduced within cells
(principally in the liver where it is
stored) to tetrahydrofolate (THF or
H4folate) through the action of
folate reductase [or
dihydrofolate reductase (DHFR) ]
which is an NADPH-requiring
enzyme.
Active center (N5 and N10)
• Active center of tetrahydrofolate (THF). The N5 position is the site of
attachment of methyl and formimino groups, the N10 the site for
attachment of formyl group and that both N5 and N10 bridge the
methylene and methenyl groups.
Folate conversions
Carrier of one-carbon (e.g. methyl) groups
The one-carbon units are added to, or removed from, metabolites such as:
•
histidine
•
serine
•
methionine
•
purines.
Functions
•
Role of N5,N10-methylene-THF in dTMP
synthesis is the most metabolically
significant function for this vitamin.
•
Vitamin B12 and N5-methyl-THF in the
conversion of homocysteine to
methionine is important in helping cells to
regenerate needed THF.
Participation of H4folate in dTMP synthesis
______Deoxyuridine______________
________Deoxythymidine
____Monophosphate (dUMP)_______________Monophosphate (dTMP)_______
Deficiency symptoms
Deficiency is rare due to the adequate presence of folate in food.
Deficiency can occur when there is:
1. Poor dietary habits as those of chronic alcoholics.
2. Impaired absorption or metabolism
• Certain drugs such as anticonvulsants and oral contraceptives and
methotrxate can impair the absorption of folate.
3. An increased demand for the vitamin.
• Pregnancy
• Folate will nearly double by the third trimester of pregnancy.
• Identical to those for vitamin B12 deficiency:
• Effect of folate deficiency on cellular processes
is upon DNA synthesis.
– Impairment in dTMP synthesis and purine synthesis
– Cell cycle arrest in S-phase of rapidly proliferating cells, especially
hematopoietic cells.
• The result is megaloblastic leukemia as for vitamin B12 deficiency.
– The inability to synthesize DNA during erythrocyte maturation leads to
abnormally large erythrocytes termed macrocytic anemia.
• Deficiency during pregnancy can cause neural tube defects such as
spina bifidia.
VITAMIN B12 (cobalamin)
•
Vitamin B12, is also called cobalamin,
cyanocobalamin and hydroxycobalamin.
•
It is built from :
1. A nucleotide and
2. A complex tetrapyrrol ring structure
(corrin ring)
3. A cobalt ion in the center.
4. A R- group
•
•
•
When R is cyanide (CN), vitamin B12
takes the form of cyanocobalamin.
In hydroxycobalamin, R equals the
hydroxyl group (-OH).
In the coenzyme forms of vitamin B12,
–
–
•
R equals an adenosyl group in
adenosylcobalamin.
R equals a methyl (-CH3) group in
methylcobalamin.
Vitamin B12 is synthesized exclusively by
microorganisms (bacteria, fungi and algae)
and not by animals and is found in the liver
of animals bound to protein as
methycobalamin or 5'deoxyadenosylcobalamin.
• Known as the "red" vitamin because it
exists as a dark red crystalline compound,
Vitamin B12 is unique in that it is the only
vitamin to contain cobalt (Co3+) metal ion,
which, gives it the red color.
• The vitamin must be hydrolyzed from
protein in order to be active.
• Intrinsic factor, a protein secreted by
parietal cells of the stomach, carries it to the
ileum where it is absorbed.
• It is transported to the liver and other
tissues in the blood bound to
transcobalamin II.
• It is stored in the liver attached to
transcobalamin I.
– It is released into the cell as
Hydroxocobalamin (see the next slide)
• In the cytosol it is converted to
methylcobalamin.
• Or it can enter mitochondria and be
converted to 5’-deoxyadenosyl
cobalamin.
Dorothy Crowfoot Hodgkin
(1910-1994)
Dr. Stadtman in her lab
In the cytosol
In mitochondria
Functions
•
Only two reactions in the body require vitamin B12 as a
cofactor:
1. During the catabolism of fatty acids with an odd number of
carbon atoms and the amino acids valine, isoleucine and
threonine the resultant propionyl-CoA is converted to
succinyl-CoA for oxidation in the TCA cycle.
– methylmalonyl-CoA mutase, requires vitamin B12 as a cofactor in
the conversion of methylmalonyl-CoA to succinyl-CoA.
– 5'-deoxyadenosine derivative of cobalamin is required for this
reaction
2. The second reaction catalyzed by methionine synthase
converts homocysteine to methionine
– This reaction results in the transfer of the methyl group from N5methyltetrahydrofolate to hydroxycobalamin generating
tetrahydrofolate and methylcobalamin during the process of the
conversion.
Methionine and Folate cycles are interrelated
Methionine cycle
Folate cycle
Methionine
THF
CH2-THF
SAM
MS
Methyl
acceptor
methyl
transferases
B12
CH3-THF
Methyl
CH3- acceptor
Homocysteine
SAH
CBS
B6
cystathionine
B6
cysteine
Transulfuration
pathway
Deficiency symptoms
• Pernicious anemia in humans (inability to absorb B12
because of lack of gastric intrinsic factor).
• Neurological disorders due to progressive demyelination
of nerve cells.
– This results from increase in methylmalonyl-CoA.
– Methylmalonyl-CoA is a competitive inhibitor of malonyl-CoA in
fatty acid biosynthesis.
– Can substitute malonyl-CoA in any fatty acid biosynthesis and
create branched-chain fatty acid altering the architecture of
normal membrane structure of nerve cells.
• Sources
– Synthesized only by microorganisms, so traces only are present
in plants; liver is a rich source.
– B12 is found in organ and muscle meats, fish, shellfish, dairy
products, eggs and in fortified foods like breakfast cereals.
Vitamin C (Chemical nature)
• It is derived from glucose via uronic acid pathway. Enzyme
L-gluconolactone oxidase is responsible for conversion of
gluconolactone to ascorbic acid.
• This enzyme is absent in primates, including humans, some bats….
• The active form is ascorbic acid itself.
VITAMIN C
• Vitamin C is L-ascorbic acid, which is a colorless,
crystalline acid with strong reducing properties.
• Functions
• Vitamin C has antioxidant properties similar to those of
vitamin E,
– Protects cells from free radicals.
– Protects iron from oxidative damage, thus enhancing iron (Fe2+)
absorption in the gut.
• The main function is as a reducing agent.
– It has the potential to reduce cytochrome a and c of the
respiratory chain and molecular oxygen and nitrates.
• It is required for various hydroxylation reactions e.g.
proline to hydroxypoline for collagen synthesis (see next
slide).
Hydroxylation of proline and lysine residues in
collagen
• Vitamin C is required for the maintenance
of normal connective tissue as well as for
wound healing because synthesis of
connective tissue is the first event in
wound tissue remodeling.
Other activities
• Several other metabolic reactions require
vitamin C as a cofactor:
– The catabolism of tyrosine and the synthesis
of epinephrine from tyrosine and the synthesis
of the bile acids.
– It is also believed that vitamin C is involved in
the process of steroidogenesis.
• The adrenal cortex contains high levels of
vitamin C which are depleted upon
adrenocorticotropic hormone (ACTH)
stimulation of the gland.
Roles in the body
Sources
• Citrus fruits and green leafy vegetables
• Vitamin C is readily absorbed and so the primary cause of vitamin C
deficiency is poor diet and/or an increased requirement.
Deficiency symptoms
1. Scurvy
–
–
–
–
–
–
Bleeding gums
Small red spots on skin
Rough skin
Wounds fail to heal
Weak bones and teeth
Anemia and infections
2. Stress (e.g., infections, smoking)
– Mechanism unknown, but vitamin C requirements increase during stress
3. Common cold?
4. Disease prevention?
– Cancer, heart disease
Periodontal disease
Vitamin B-complex
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
(or choline)
Cyanocobalamin
8. Inositol (Vitamin Bh)
• Inositol is part of the vitamin B-complex.
• Since it is not essential in the human diet, it cannot be
considered a vitamin.
• Inositol is naturally present in foods high in fiber (wheat,
legumes, bran, etc).
• It is required for:
– For proper formation of cell membranes.
– For formation of lecithin
– It is not a vitamin per se, but it works synergistically with
many vitamins and nutrients.
• functions closely with a B complex vitamins, Choline, folacin,
Vitamins B-6 and B-12.
– Inositol is necessary for proper function of nerves, brain, and
muscles in the body.
– This nutrient is also often used to counter depression;
indeed, serotonin needs inositol for proper functioning.
– Exists in all human cells, where it plays an important role in
cell proliferation and differentiation.
• Low levels of this nutrient may result in depression and
some research has shown that increased levels of Inositol
appear to be a promising treatment for depression.
10. P-amino benzoic acid (Bx)
• A substance required for the synthesis of folic acid by
many organisms.
• PABA is an essential nutrient for some bacteria and is
sometimes called Vitamin BX.
• Para-aminobenzoic acid is included in the B-vitamin
complex, although it is not an essential nutrient for
humans and it varies in its activity from other B vitamins.
• Although humans lack the ability to synthesize folate
from PABA, it is sometimes marketed as an essential
nutrient under the premise that it can stimulate intestinal
bacteria.
• It also absorbs ultraviolet light and is used as
aminobenzoic acid, as a topical sunscreen. Abbreviated
PAB or PABA.
• The potassium salt is used as drug against fibrotic skin
disorders.
Structure
Folic acid
PABA (vitamin Bx)
11. L-CARNITINE (B11)
• L-carnitine
– Is made in the body from the amino acids
lysine and methionine,
– Is needed to release energy from fat.
– It transports fatty acids into mitochondria, the
powerhouses of cells.
– In infancy, and in situations of high energy
needs, such as pregnancy and breastfeeding, the need for L-carnitine can exceed
production by the body.
• Therefore, L-carnitine is considered a
"conditionally essential" nutrient.
L-carnitine
• L-carnitine’s actions appear to be particularly
important in the heart.
• As an example, patients with diabetes and high
blood pressure were given 4 grams of Lcarnitine per day in a preliminary study.
• After 45 weeks, irregular heartbeat and
abnormal heart functioning decreased
significantly compared with nonsupplemented
patients.
Sources of L-carnitine
• Dairy and red meat contain the greatest
amounts of carnitine. Therefore, people who
have a limited intake of meat and dairy products
tend to have lower L-carnitine intakes.
• Carnitine deficiencies are rare, even in strict
vegetarians, because the body produces
carnitine relatively easily.
• Rare genetic diseases can cause a carnitine
deficiency.
• Also, deficiencies are occasionally associated
with other diseases, such as diabetes and
cirrhosis.
• Most people do not need carnitine supplements.
For therapeutic use, typical amounts are 1–3
grams per day.