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Dr. Azin Nowrouzi, PhD

Tehran University of Medical Sciences

TUMS

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9. FOLIC ACID (folacin)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

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StructureStructure

Folic acid exists in a polyglutamate form. Intestinal mucosal cells remove some of the glutamate residues through the action of the lysosomal enzyme, conjugase.

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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 functional form is: Tetrahydrafolic acid (THF).

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Active center (N5 and N10)Active center (N5 and N10)

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• 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.

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Folate conversionsFolate 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.

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FunctionsFunctions

1. Role of N5,N10-methylene-THF in dTMP synthesis is the most metabolically significant function for this vitamin.

2. Vitamin B12 and N5-methyl-THF in the conversion of homocysteine to methionine is important in helping cells to regenerate needed THF.

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Participation of H4folate in dTMP synthesisParticipation of H4folate in dTMP synthesis______Deoxyuridine______________          ________Deoxythymidine

____Monophosphate (dUMP)_______________Monophosphate (dTMP)_______         

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Deficiency symptomsDeficiency symptoms

• 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.

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.

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VITAMIN B12 (cobalamin)VITAMIN B12 (cobalamin)• Vitamin B12, is also called cobalamin,

cyanocobalamin and hydroxycobalamin.

• It is built from : – A nucleotide and – A complex tetrapyrrol ring structure

(corrin ring)– A cobalt ion in the center.– 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.

1. 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.

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• 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

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In the cytosol

In mitochondria

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FunctionsFunctions• 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 1. This reaction results in the transfer of the methyl group from N5-

methyltetrahydrofolate to hydroxycobalamin generating tetrahydrofolate and methylcobalamin during the process of the conversion.

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CH3-THF

Methionine SAM

SAH

methyltransferases

CH3-

Methylacceptor

Homocysteine

MSTHF

B12CH2-THF

CBS

cystathionine

cysteine

B6

B6

Folate cycleFolate cycle

TransulfurationTransulfurationpathwaypathway

Methionine cycleMethionine cycle

Methylacceptor

Methionine and Folate cycles are interrelated

Methionine and Folate cycles are interrelated

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Deficiency symptomsDeficiency 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.

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• 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 (Chemical nature)Vitamin C (Chemical nature)

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VITAMIN CVITAMIN 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).

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Hydroxylation of proline and lysine residues in collagen

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.

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Other activitiesOther 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.

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Roles in the bodyRoles in the bodySources• 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 symptoms1. 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

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Periodontal diseasePeriodontal disease

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Vitamin Chemical name B1

B2

B3

BB44

B5

B6

B7

B8

B9

BB1010

BB1111

B12

Thiamine

Riboflavin

Nicotinamide (niacin)

Adenine (no longer considered a vitamin)Adenine (no longer considered a vitamin)

Pantothenic acid

Pyridoxine

Biotin

InositolInositol

Folacin (folic acid)

pp-aminobenzoic acid (PABA) / H1-aminobenzoic acid (PABA) / H1 L-carnitine / b-hydroxy-g-trimethylammonium butyrateL-carnitine / b-hydroxy-g-trimethylammonium butyrate

(or choline)(or choline)

Cyanocobalamin

Vitamin B-complexVitamin B-complex

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8. Inositol (Vitamin Bh) 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.

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10. P-amino benzoic acid (Bx)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.

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StructureStructure

Folic acid

PABA (vitamin Bx)

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11. L-CARNITINE (B11)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 breast-feeding, the need for L-carnitine can exceed production by the body.

• Therefore, L-carnitine is considered a "conditionally essential" nutrient.

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L-carnitineL-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 L-carnitine per day in a preliminary study.

• After 45 weeks, irregular heartbeat and abnormal heart functioning decreased significantly compared with nonsupplemented patients.

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Sources of L-carnitineSources 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.

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Vitamin classificationName(Letter) RDI

Retinol (A) 5000 IU

Calciferol (D) 400 IU

Tocopherol (E) 30 IU

Phylloquinone (K) 70 g

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Fat-soluble Vitamins• Absorbed 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)

• They are not easily excreted through urine.• Substantial amounts are stored in liver and fat

tissue.• Therefore, toxicity is possible.

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Vitamin ACompounds with 20-carbon structure.

Contain a methyl substituted cyclohexenyl ring (-ionone ring),

and an isoprenoid side chain with either a hydroxyl group, and aldehyde group, a carboxylic acid group, or an ester group (retinyl ester) at the terminal C15.

All-trans-retinal 11-cis-retinal

Retinol Retinoic AcidCan’t be reduced to retinol or retinal in the body.

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Vitamin A1. Active vitamin A- Preformed vitamin A can be obtained

either directly from foods that are substantial in vitamin A (beef liver, fish liver oils, egg yolks and butter)

• The active form of vitamin is retinol, an alcohol which can be converted to other forms (e.g. vitamin A esters) for storage in liver and tissues.

• much the body's vitamin A is stored in the liver as retinyl palmitate

2. Provitamin A- provitamins, substances that are transformed into vitamins in the body

1. Beta-carotene is the most abundant and widespread provitamin A.2. Beta-carotene comes from a group of compounds called the

"carotenoids (C40 polyisoprenoids).3. One need to eat approximately six times as much beta-carotene

to get the same amount of vitamin A as in retinol. 4. Dark-green leafy vegetables (spinach) and yellow-orange

fruits (apricots and mango) and vegetables (carrots, yellow squash and sweet potatoes) are high in beta-carotene and other carotenoids (-carotene, -cryptoxathin, etc.)

5. Carotenoids are not toxic even at high doses for long times.

Vitamin A: Absorption and transport

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- Micelle formation- Inside mucosal cell -carotene is cleaved

in the lumen of the intestine by -carotene dioxygenase to yield retinal.

- Retinal is reduced to retinol by retinal reductase, an NADPH requiring enzyme within the intestines.

- Retinol is esterified to palmitic acid and delivered to the liver with chylomicrons via lymphatic system.- Carotenoids which escape intestinal

conversion to retinol can be stored in adipose tissue.

- Species in which this occurs include humans, horses and cattle, which have yellow-pigmented body fat when carotenoid intake is high.

- Vitamin A absorption efficiency 70-90%; carotenoids 9-22%.

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Vitamin A: Biological functions

• Role in vision. Vitamin A (retinal) is an essential precursor for formation of the visual pigment, rhodopsin, in the retina of the eye. Retinal plays an important role in vision, especially night vision. Lowers cataract incidence.

• Role in growth. Helps regulate cell development, cell differentiation and cell division.

• Role in Bone and teeth formation. Promotes the proper growth of bones and teeth. Bone cells (osteoblasts and osteoclasts) depend on vitamin A for their normal functioning.– Is important in the formation and maintenance of healthy hair, skin and

mucous membranes. • Role in reproduction. Vitamin A holds an important place in sexual

reproduction. Adequate levels of vitamin A are needed for normal sperm production. The female reproductive cycle requires sufficient amounts of vitamin A.

• Boosts the body's immune system helping to increase body resistance to infectious diseases.

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Role of Vitamin A in Vision(Wald’s visual cycle)

1. When the rhodopsin is exposed to light it is bleached releasing the 11-cis-retinal from opsin. 2. Isomerization of the cis-isomer of retinal to all-trans-retinal, causes conformational changes in rhodopsin, hyperpolarization of the retinal rod cell, and extremely rapid transmission of electrical activity to the brain via the optic nerve3. Trans-retinal is isomerized to cis-retinal in the dark, which associates with opsin to regenerate rhodopsin.

Visual Pigment

All trans retinol = main circulating

form of Vit A

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Vitamin A: Biological functions (Cell growth and differentiation)

• Regulation of gene expression by retinoic acid, the acid form of vitamin A

• Retinoic acid is formed within the target cell from retinol transported in the bloodstream.

• Retinoic acid, combined with protein receptor, acts as transcription regulator by binding to specific sequences of DNA in the nucleus

• Affected cells include epithelium of numerous tissues, including skin and gut, and bone, ovary and testis.

• Retinoic acid is an especially important regulator of embryonic cell differentiation.

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Vitamin A: Deficiency symptoms 1. Night blindness" - lessened ability to see in dim light.2. Increased susceptibility to infection and cancer and anemia

equivalent to iron deficient.3. Prolonged lack of vitamin A

(keratinization of the cornea, a condition known as xerophthalmia). 4. Abnormal bone development in fetal and neonatal life.5. Various congenital defects.

Retinol and its precursors are used as dietary supplements to prevent the above symptoms.

Retinoic acid is used in dermatology to cure acne and psoriasis:1. Mild acne (Darier’s disease) and aging

Topical application of tretinoin (all-trans retinoic acid), along with benzoyl peroxide and antibiotics.

2. severe recalcitrant cystic acne Oral consumption of isotretinoin (13-cis retinoic acid). This drug is teratogenic. Should not be prescribed during pregnancy. It may lead to hyperlipidemia and increased LDL/HDL ratio (increased chance of heart disease) in long term.

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Vitamin A: Toxicity

• Hypervitaminosis A in humans– Symptoms include dry, pruritic skin with excessive itching and increase in

intracranial pressure. – is becoming an increasing problem in Western countries because of self-

medication and overprescription.

– has occurred through eating polar bear or seal liver by polar explorers.• Eat polar bear liver sparingly, 30 grams contain 450,000 IU of retinol!

Continued ingestion causes peeling of the skin from head to foot.

• It is possible that some early Arctic explorers died from eating their sled dogs in an attempt to survive.

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• Vitamin D is a family of fat-soluble sterol compounds:

• Vitamin D1 (lamisterol)

• Vitamin D2 (ergocalciferol)

• Vitamin D3 (cholecalciferol)

• Vitamin D4 (dihydroergocalciferol)

• Vitamin D5 (7-dehydrositosterol)

Vitamin D

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Vitamin D: Types and Sources• For humans, the two most important forms of

vitamin D are: – vitamin D2– vitamin D3.

• Vitamin D2 (ergocalciferol) is derived from plants and irradiated yeast and fungi.

• Vitamin D3 is synthesized in the body when skin is exposed to sunlight– Cholesterol + sunshine = Vitamin D3– “sunshine vitamin” – UV-B rays (5-10 minutes arms

and legs, mid-day sun). • Vitamin D3 can be obtained from foods like

milk, fortified cereals, tuna, salmon and fish oils.

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Diet

Sunlight

Ergosterol(in plants)

Vitamin D2(Ergocalciferol)

7-Dehydrocholesterol

Vitamin D3Cholecalciferol)

Sunlight

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Activation of Vitamin D• Vitamin D2 and vitamin D3 are

biologically inactive but can have equal biological activity:

• Both can be converted first to calcifediol in the liver and then to calcitriol, also known as 1,25-dihydroxycholecalciferol, in the kidneys.

• Calcitriol, which is the most active form of vitamin D3, is then transported via a carrier protein to the various sites in the body where it is needed.

Calcitriol is also called 1,25-dihydroxy vitamin D3, or (1,25-(OH)2D3.

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1,25-dihydroxyvitamin D3

25-hydroxyvitamin D3In the liver cholecalciferol is hydroxylated at the 25 position by a specific D3-25-hydroxylase generating 25-hydroxy-D3 [25-(OH)D3] which is the major

circulating form of vitamin D.

Conversion of 25-(OH)D3 to its biologically active form, calcitriol, occurs through the activity of a specific D3-1-hydroxylase present in the proximal convoluted tubules of the kidneys, and in bone and

placenta. Cytochrome P450, O2 and NADPH are needed.

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Functions of vitamin D

• Vitamin D regulates the calcium and phosphorus levels in the blood by promoting their absorption from food in the intestines, and by promoting re-absorption of calcium in the kidneys.

• It promotes bone formation and mineralization and is essential in the development of an intact and strong skeleton.

• It inhibits parathyroid hormone secretion from the parathyroid gland.

• Vitamin D affects the immune system by promoting immunosupression, phagocytosis, and anti-tumor activity.

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Vitamin D: Hormone for Calcium and Phosphate

regulation• Nerves and muscles must function properly; calcium is

vital for nerve cell transmissions and muscle fiber contractions.

• Calcitriol functions in concert with parathyroid hormone (PTH) and calcitonin to regulate serum calcium and phosphorous levels by:

1. Increasing dietary calcium absorption from the small intestine.2. Decreasing the urinary calcium excretion (increasing renal

reabsorption).3. Stimulating resorption of calcium from bone

• Instrumental in the growth, hardening and repair of bones. • Too much vitamin D, however, can increase calcium losses from bone

• Vitamin D is essential for normal insulin secretion by the pancreas and therefore control of blood sugar levels.

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When vitamin D goes abnormal• Too little (northern latitudes) leads to Vit D

deficiency: – Rickets (bone deformities in children)– Osteoporosis– Osteomalacia (weak bones)– Demineralization of bones

• Too much (5 times the RDA, chronically): It is most toxic of the vitamins.– Nausea, thirst, loss of appetite, stupor– Hypercalcemia: calcium gets deposited in soft

tissues, arteries and kidneys.

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Diseases caused by deficiency• Vitamin D malnutrition may also be linked to an increased

susceptibility to several chronic diseases such as – High blood pressure – tuberculosis – cancer – periodontal disease – multiple sclerosis – chronic pain – depression – schizophrenia– several autoimmune diseases

• The American Pediatric Associations advises vitamin D supplementation of 200 IU/day (5μg/d) from birth onwards.

• Liquid "drops" of vitamin D for infants.

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Vitamin E

-Tocopherolis the most potent of the tocopherols.

A family of eight different molecules. Four of the eight vitamin E molecules are called tocopherols (alpha, beta, gamma and delta) [also known as “Natural Tocopherols”] while the remaining four are called tocotrienols (alpha, beta, gamma and delta). D-alpha-tocopherol is the most biologically active in humans.

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Functions• Vitamin E in the form of d-alpha-tocopherol is an important fat-soluble

antioxidant, scavenging oxygen free radicals, lipid peroxy radicals and singlet oxygen molecules before these radicals can do further harm to cells. [Free radicals are very reactive atoms or molecules that typically possess a single unpaired electron.]

• New studies have revealed that the tocotrienol forms of vitamin E are even more potent antioxidants than the tocopherol isomers.

• Vitamin E helps maintain the structural integrity of cell membranes throughout the body.

• d-alpha-tocopherol has been shown to inhibit the "clumping" of blood platelets (thus helping to avoid blood clots) and enhancing vasodilation (the opening of blood vessels).

• d-alpha-tocopherol protects the fat component in low-density lipoproteins (LDLs) from oxidation and has shown moderate cholesterol-lowering capabilities. Studies have shown that gamma- and delta-tocotrienols may be better suited than the tocopherols at inhibiting the manufacture of cholesterol in the liver and hence in contributing to a greater cholesterol lowering effect.

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• Deficiency: rare in adults usually due to impaired fat absorption or transport; seen usually in children (anemia, edema in infants)– Muscular dystrophy– Hemolytic anemia– Dietary hepatic necrosis

• Excess: very safe below 800 IU/day

• Source: – Vitamin E is present in animal fats, meat, green vegetables, nuts/seeds. – Alpha-tocopherol is found in a number of vegetable oils, including safflower

and sunflower. It is also found in wheat germ. Soybean and corn oils contain mainly gamma-tocopherol.

• The major site of vitamin E storage is in adipose tissue.• Estimated requirements: 5mg/day = 0.6mg/day of unsaturated fat. • Uses:

– Hemolytic anemia in premature infants, unresponsive to B12, Fe and folic acids.

– Macrocytic megaloblastic anemia seen in children with severe protein-calorie malnutrition.

Vitamin E (deficiency)

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The symptoms of Vitamin E deficiency

• Muscle weakness  • lethargy                       • apathy               • a lack of vitality

                     • indigestion                  • muscle cramps               • inability to concentrate• irritability            • disinterest in physical

activity                            • red blood cell breakage • anemia • neurological problems

• An increasing body of evidence is emerging to implicate free radical activity in the pathogenesis of periodontal breakdown.

• Inadequate antioxidant availability could either predispose the host to the disease, or modify the progression of a pre-existing disease.

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Free radical = unpaired electron very reactive

Oxygen radicals: Hydroxy (HO•) / Peroxy (HOO•)

OH

OH

OH

OH

.

.

Free Radicals - the Metabolic Oxidizers

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An antioxidant is a chemical so easilyoxidized itself that it protects others from oxidation.

Double Bondeg. Vitamin A

Phenoleg. Vitamin E or C

OH

and / or

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Antioxidant

The antioxidant neutralizes a free radical by donating an electron.

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Vitamin K• The "K" in vitamin K comes from the German

word "koagulation," which refers to blood clotting (coagulation).

• Vitamin K is essential for the functioning of several proteins involved in normal blood clotting.

• There are several forms K1-K7

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__                                                                                               

Vitamin K1 (Phylloquinone)• Naturally occurring vitamin K is absorbed from the

intestines only in the presence of bile salts and other lipids through interaction with chylomicrons. Therefore, fat malabsorptive diseases can result in vitamin K deficiency.

• Present in green leafy vegetables like lettuce, parsley, spinach and various greens (beet and mustard). Broccoli and certain vegetable oils (soybean, cottonseed, and olive).are also a good source of vitamin K1.

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Vitamin K2 (Menaquinone)• Vitamin K2 is a group of compounds called the "menaquinones." • Synthesized by intestinal bacteria "n" can be 6, 7 or 9 isoprenoid

groups. – The number of isoprene residues in the side chain of the vitamin

K2 molecule designate the individual menaquinone compounds, e.g., menaquinone-4 (MK-4) has four isoprene units in the side chain of vitamin K2; menaquinone-7 (MK-7) has seven isoprene units in the side chain.

• Vitamin K2, which is the most biologically active form of vitamin K, is found in egg yolks, butter, liver, cheddar cheese and yogurt.

• It has been suggested that products like yogurt, may help to increase the functioning of these useful bacteria.

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Vitamin K3 (Menadione)

• The synthetic (man-made) vitamin K3 is water solubleand absorbed irrespective of the presence of intestinal lipids and bile.

Uses : essential cofactor in blood clotting.

Excess: Dangerous if taking anti-coagulants.Hemolytic anemia, jaundice in infants.

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Functions1. Blood coagulation

• Post-translational carboxylation of some glutamate residues in blood factors.

• Vitamin K is needed for the body to make four of the blood's coagulation factors, including prothrombin (also known as factor II), proconvertin (factor VII), Christmas factor (factor IX) and the Stuart-Power factor (factor X).

– It occurs in the liver– Vitamin K has to change to Hydroquinoine to function

as coenzyme for carboxylase.

2. Calcium binding proteins– Carboxylation of specific glutamate residues in

calcium binding proteins.3. Role in oxidative phosphorylation

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Prothrombin -Carboxylation

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Vitamin K role in -Carboxylation

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Deficiency1. Prolonged use of antibiotics

2. Malabsorption and biliary tract obstruction

3. Spoilt sweet-clover hay– Contains dicumarol (vit K antagonist)

4. Short circuiting of the bowel

5. In immediate post-natal infants• (bruising/bleeding in infants).– Sterile bowels (no intestinal microflora)– Low Vit K in mothers milk– Hemorrhagic disease of the newborn.

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Too Much Broccoli !

Two women with diseases characterized by abnormal blood clotting did not improve when they were given Warfarin.

When questioned about their diets, one woman reported that she ate at least a pound of broccoli every day, and the other ate broccoli soup and a broccoli salad every day.

When broccoli was removed from their diets, warfarin became effective in preventing the abnormal clotting of their blood.

Because broccoli is high in vitamin K, these patients had been getting enough dietary vitamin K to compete with the

drug, thereby making the drug ineffective.

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• Metabolically they have diverse functions as:

• Coenzymes (B vitamins, vitamin K)

• Hormones (retinoic acid, vitamin D)

• Modulators or regulators of growth and development (retinoic acid, folic acid)

• (apparently non-specific) antioxidants (Vitamins C and E)

What do vitamins do?

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• Vitamin C: • Bleeding gums• Loose teeth• Poor healing

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Cofactors and coenzymes

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Other coenzymes

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2H+

+2e

Coenzyme QCoenzyme Q

Coenzyme Q = Ubiquinone• A lipid in inner membrane of mitochondria.• Moves freely within membrane.• Carries electrons.• Coenzyme Q10 (CoQ 10) or ubiquinone is essentially a vitamin or

vitamin-like substance. – Found in small amounts in a wide variety of foods. – It is synthesized in all tissues. – The biosynthesis of CoQ10 from the amino acid tyrosine requires at least

eight vitamins and several trace elements.• Coenzyme Q10 is the coenzyme for at least three mitochondrial

enzymes (complexes I, II and III) as well as enzymes in other parts of the cell.

• CoQ10 has been studied in its reduced form as a potent antioxidant.

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Coenzyme Q - 'promoted' to a Vitamin?

A vital 'transport agent' in the use of oxygen to generate energy, especially in the heart muscle.

Supplements do aid in many forms of heart disease, gum disease, BUT >> slows Parkinsons/Alzheimers/ aging, relieves allergies, boosts athletic performance

and immunity, aids weight loss ?!

O

O

CH3CH3O

CH3O CH2 C

HCH2

CH3

10

H

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Causes of Deficiency• Significantly decreased levels of CoQ10 have

been noted in a wide variety of diseases in both animal and human studies.

• CoQ10 deficiency may be caused by1. Insufficient dietary CoQ10.2. Impairment in CoQ10 biosynthesis.3. Excessive utilization of CoQ10 by the body

• Increased body consumption of CoQ10 is the presumed cause of low blood CoQ10 levels seen in excessive exertion, hypermetabolism, and acute shock states.

4. or any combination of the three. 5. Drugs can cause CoQ deficiency

• HMG-CoA reductase inhibitors used to treat elevated blood cholesterol levels by blocking cholesterol biosynthesis also block CoQ10 biosynthesis.

• The resulting lowering of blood CoQ10 level is due to the partially shared biosynthetic pathway of CoQ10 and cholesterol.

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Non-nutrient compound Found in plant-derived foods and have biological activity in the body.

Some categories:

Antioxidants (anti-aging/cancer/heart disease?) - catechins (berries, green/black tea), lycopene (tomatoes,watermelon), bioflavanoids (citrus fruit, grapes), coenzyme Q (nuts,oils).

Estrogen mimics (cancer inhibitors?) - indoles (broccoli, cauliflower), isoflavones (legumes), lignans & omega-3- fatty acids

(canola, flaxseed), genistein (soy).

Phytochemicals

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Lycopene = red pigment in tomatoes, red grapefruit, watermelon

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Plant Pigments = Potent Antioxidants

Almost 2000 known plant pigments. >800 flavonoids, ~450 carotenoids and ~150 anthocyanins.

Red (lycopene) – tomatoes, pink/red grapefruit, watermelon, guava, red peppers.

Red/Blue/Purple (anthocyanins) – red/blue grapes, blue-/straw-/raspberries, beets, cherries,

egg plant, plums, red cabbage.

Orange (carotene) – squash, pumpkin, yams, carrots, mango, cantaloupe.

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Orange/Yellow (cryptoxanthin) – peach, orange, nectarine, papaya.

Yellow/Green (lutein), zeaxanthin = especially good for health of eyes) – corn, cucumber skins, yellow/green peppers, green beans/peas, spinach, honeydew melon, kiwi, romaine lettuce,

Plant Pigments = Phytochemicals

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Vitamin O - the next miracle supplement!

Recipe: Take 8oz water, add a pinch of salt, bubble

in oxygen/(air?) for 15 seconds then sell for $20(US) + shipping/handling.

Or maybe you would like to visit an 'oxygen bar'? Get fined for US$400,000 (for 'fraudulent claims'), change the wording and keep on selling. To-date an

estimated 1 million bottles have been sold!

Check out the ‘Net’ under ‘vitamin O’ eg. ~first 10 entries on ‘Yahoo’ or ‘Google’