Vitamins & Coenzymes

1. TUMS Vitamins & Coenzymes Part three Fat Soluble Vitamins Azin Nowrouzi, PhD

2. Vitamin classification

3. 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.

4. Vitamin A Compounds 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 Acid Can’t be reduced to retinol or retinal in the body.

5. Vitamin A • 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 • Provitamin A-provitamins, substances that are transformed into vitamins in the body • Beta-carotene is the most abundant and widespread provitamin A. • Beta-carotene comes from a group of compounds called the "carotenoids (C40 polyisoprenoids). • One need to eat approximately six times as much beta-carotene to get the same amount of vitamin A as in retinol. • 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.) • Carotenoids are not toxic even at high doses for long times.

6. Vitamin A: Absorption and transport • 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%.

7. 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.

8. 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 nerve • 3. Trans-retinal is isomerized to cis-retinal in the dark, which associates with opsin to regenerate rhodopsin. All trans retinol = main circulating form of Vit A Visual Pigment

9. 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.

10. Problems associated with Vitamin A Vit A excess • 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. Vit. A deficiency: 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. Skeletal malformations spontaneous fractures internal hemorrhages loss of appetite slow growth or weight loss 5. Various congenital defects.

11. Vitamin A: Uses Retinol and its precursors are used as dietary supplements to prevent deficiency 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.

13. Vitamin D • 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)

14. 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.

15. Sunlight Vitamin D2 (Ergocalciferol) Ergosterol (in plants) Diet Sunlight Vitamin D3 Cholecalciferol) 7-Dehydrocholesterol

16. 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 as1,25-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.

17. 1,25-dihydroxyvitamin D3 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. 25-hydroxyvitamin D3 In 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.

18. 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.

19. Vitamin D: Hormone for Calcium and Phosphate regulation • 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: • Increasing dietary calcium absorption from the small intestine. • Decreasing the urinary calcium excretion (increasing renal reabsorption). • 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.

20. Effects of PTH and Vit D3 Effects of PTH and Vit D3

21. 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.

22. 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.

23. Vitamin E 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. a-Tocopherol is the most potent of the tocopherols.

24. 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.

25. Vitamin E (deficiency) • 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. • Storage of vitamin E is limited. Vitamin E is stored in high amounts in the pituitary gland and theadrenals.The liverbriefly stores vitamin E but only in small quantities. 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.

26. 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.

27. Free Radicals - the Metabolic Oxidizers Free radical = unpaired electron very reactive . OH OH . OH OH Oxygen radicals: Hydroxy (HO•) / Peroxy (HOO•)

28. An antioxidant is a chemical so easily oxidized itself that it protects others from oxidation. and / or Double Bond eg. Vitamin A Phenol eg. Vitamin E or C

29. Antioxidant The antioxidant neutralizes a free radical by donating an electron.

30. 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

31. 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. • Source: 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. __

32. 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. • Source: 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.

33. Vitamin K3 (Menadione) • The synthetic (man-made) vitamin K3 is water soluble and 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.

34. Functions • 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. • Calcium binding proteins • Carboxylation of specific glutamate residues in calcium binding proteins. • Role in oxidative phosphorylation

35. Prothrombin -Carboxylation

36. Vitamin K role in -Carboxylation

37. Causes of Deficiency • Prolonged use of antibiotics • Malabsorption and biliary tract obstruction • Spoilt sweet-clover hay • Contains dicumarol (vit K antagonist) • Short circuiting of the bowel • 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.

38. 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.

39. What do vitamins do? • 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)

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

41. Cofactors and coenzymes

42. Other coenzymes

43. Coenzyme Q = Ubiquinone 2H++2e Coenzyme Q Coenzyme Q • 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. • (1) fish; (2) organ meats, including liver, kidney and heart; and (3) the germs of whole grains • 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.

44. 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 ?!

45. 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 by • Insufficient dietary CoQ10. • Impairment in CoQ10 biosynthesis. • Excessive utilization of CoQ10 by the body • excessive exertion • hypermetabolism • acute shock states • or any combination of the three. • 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.

46. Phytochemicals 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).

47. Lycopene = red pigment in tomatoes, red grapefruit, watermelon

48. 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.

49. Plant Pigments = Phytochemicals 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,

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