BIOCHEM L8 - Micronutrients, Vitamins.pdf

[BIOCHEMISTRY] LECTURE 8: MICRONUTRIENTS - VITAMINS MICRONUTRIENTS: VITAMINS Toxicity can result from excessive intake of LIPID-SOLUBLE VITAMINS Vitamins are org...

[BIOCHEMISTRY] LECTURE 8: MICRONUTRIENTS - VITAMINS MICRONUTRIENTS: VITAMINS Toxicity can result from excessive intake of LIPID-SOLUBLE VITAMINS Vitamins are organic compounds, required in Vitamins A, D and K the diet in small amounts for maintenance of Vitamin A normal metabolic integrity. The water-soluble vitamins B, C, Niacin, Vitamin D However, vitamin D, formed in the skin from 7- Folic Acid, Biotin, Pantothenic Acid and B Vitamin E dehydrocholes-terol on exposure to sunlight complex, functions mainly as enzyme Vitamin K and niacin, can be formed from essential cofactors. amino acid tryptophan that does not strictly Specific syndromes are characteristic of deficiencies of individual vitamins, such as: Vitamin A [Retinol] comply with this definition. VITAMIN DEFICIENCIES Retinoids BIOMEDICAL IMPORTANCE VITAMIN DISEASE Lipid soluble vitamins are hydrophobic DEFICIENT preformed vitamin A, found only in foods of Thiamine (Vit B1) Beriberi animal origin compounds that can be absorbed efficiently only when there is normal fat absorption. Cheilosis o Retinol Glossitis o Retinaldehyde Riboflavin (Vit B2) Angular stomatitis Transported in the blood in lipoproteins or Nasolabeal Seborrhea o Retinoic Acid attached to specific binding proteins. Seborrheic dermatitis Carotenoids Niacin (Vit B3) Pellagra They have diverse functions, examples, Vit. A, found in plants, precursors of vitamin A, can vision and cell differentiation; Vit. D, calcium Folic Acid (Vit B9) Megaloblastic anemia be cleaved to yield retinaldehyde, then retinol and phosphate metabolism; Vit. E, antioxidant; and retinoic acid. and Vit K, blood clotting. Megaloblastic anemia Methylmalonic o Alpha carotene Vitamin B12 aciduria Dietary inadequacy conditions affecting o Beta carotene Pernicious anemia digestion and absorption of these vitamins, o Gamma carotene such as very low-fat diet, steatorrhea, and Ascorbic Acid (Vit o Cryptoxanthin Scurvy disorders of the biliary system, can all lead to C) Carotenes, in intestinal mucosa are cleaved deficiency syndromes, including: Night blindness by carotene dioxygenase yielding Xerophthalmia o Night blindness and xerophthalmia [Vit A] Retinoid (Vit A) retinaldehyde, is reduced to retinol esterified Bitot’s spot o Rickets in the young and Osteomalacia in Keratomalacia and secreted in chylomicrons together with adults [Vit D] esters formed with dietary retinol. Rickets – young Vitamin D ▪ “malacia” - softening Osteomalacia - old Hemolytic anemia in Intestinal activity of carotene dioxygenase is o Neurological disorders Vitamin E low, and a large proportion of ingested the newborn o Hemolytic anemia in the NB [Vit E] Hemorrhagic disease carotene appear in circulation unchanged. Vitamin K o Hemorrhagic disease of the NB [Vit K]. of the newborn V. ANGELS NMD - 1 1  LECTURE 8: MICRONUTRIENTS - VITAMINS Two isoenzymes of carotene dioxygenase Vitamin A Deficiency o Retinoid X Receptors (RXR) bind 9-cis- o (a) One catalyzes the cleavage of central Most important preventable cause of retinoic acid bond on beta carotene blindness. RXRs also form dimers with vitamin D, Earliest sign of deficiency, loss of sensitivity o (b) Other catalyzes asymmetric thyroid, and other nuclear acting hormone to green light followed by impairment to adapt cleavage forming 8', 10' and 12; apo- receptors. to dim light, then nyctalopia (night blindness carotenals, which are oxidized to or inability to see in the dark). retinoic acid Deficiency of vitamin A impairs vitamin D A. Functions of Vitamin A and thyroid hormone function because of More prolonged deficiency leads to: lack of 9-cis retinoic acid to form active receptor dimers. o Bitot's spot (small gray plaques of the A. Chemistry of Vision: cornea) Unoccupied RXRs form dimers with occupied o Xerophthalmia (keratinization of the In retina, retinaldehyde functions as cornea) prosthetic group of the light-sensitive opsin vitamin D and thyroid receptors, but do not activate gene expression, so that vitamin A o Keratomalacia (corneal ulceration and protein, forming rhodopsin (in rods) and necrosis, iodopsin (in cones) deficiency has a more severe effect of on vitamin D and thyroid hormone function than o Blindness Any one cone cell contains only one type of simply failure to activate gene expression opsin and is sensitive to only one color. B. Regulation of Gene Expression and Tissue Vitamin A Toxicity Differentiation In pigment epithelium of the retina, all There is limited capacity to metabolize vitamin trans-retinol are isomerized to 11-cis-retinol All trans-retinoic acid and 9-cis-retinoic A and excessive intake leads to accumulation and oxidized to 11-cis-retinaldehyde. acid regulate growth development and beyond the capacity of intracellular binding tissue differentiation, they have different protein, unbound vitamin A causes 11-cis-retinaldehyde reacts with lysine actions in different tissues. membrane lysis and tissue damage. residue in opsin, forming the holoprotein Like the thyroid and steroid hormones and rhodopsin. vitamin D, retinoic acid binds to nuclear Symptoms of toxicity affect the: receptors that bind to response elements of o CNS (headache, nausea, ataxia, Absorption of light by rhodopsin causes DNA and regulate the transcription of anorexia, all due to increased intracranial isomerization of 11-cis retinaldehyde to all- specific genes pressure), trans, and a conformational change in o Liver (hepatomegaly with histological C. Differentiation of Immune System Cells opsin. changes and hyperlipidemia); Vitamin A is also important in differentiation o Altered calcium homeostasis This results in release of retinaldehyde from of the immune system cells, and even mild (thickening of long bones, and soft tissue the protein, and the initiation of a nerve deficiency leads to increased susceptibility to calcification impulse. Formation of an initial excited form infectious diseases. o Skin (excessive dryness, desquamation of rhodopsin, bathorhodopsin, occurs within Synthesis of retinol-binding protein, required to and alopecia). picoseconds of illumination. transport the vitamin in the bloodstream is Functions of Retinoid Acid reduced in response to infection (a negative acute phase protein) decreasing the There are two families of nuclear retinoic concentration of the vitamin, further impairing receptors immune response. o Retinoic Acid Receptors (RAR) bind all- trans retinoic acid and 9-cis-retinoic acid V. ANGELS NMD - 1 2  LECTURE 8: MICRONUTRIENTS - VITAMINS Vitamin D dihydroxycholecalferol, the most potent D. Intake higher than required to maintain form, or 24-hydroxylation to yield an calcium homeostasis reduce the risk of Not strictly a vitamin, can be synthesized in inactive metabolite 24,25- insulin resistance, obesity and metabolic skin and under most conditions, the major dihydroxyvitamin D (24-hydroxycalcidiol) syndrome & various cancers. source of vitamin A. Only when sunlight exposure is inadequate Functions of Vitamin D E. Calcitriol reduces its own synthesis by is dietary source required. inducing the 24-hydroxylase and A. Main function is regulation of calcium Deficiency of Vitamin D repressing 1-hydroxylase in the kidney absorption and homeostasis, most of its Deficiency leads to rickets in children actions are mediated by way of nuclear receptors that regulate gene expression. Vitamin D Toxicity (improper mineralization of bones) and osteomalacia in adults (demineralization of Calcitriol achieved this in three ways: Some infants are sensitive to intake of previously formed bones), continues to be a o It increases intestinal absorption of vitamin D as low as 50ug/day, resulting in an problem in regions where sunlight exposure is calcium mobilizes calcium transporters in elevated serum calcium. This can lead to inadequate. the intestinal mucosa contraction of blood vessels, high blood o Reduces calcium excretion (by pressure and calcinosis (calcification of soft Synthesis of Vitamin D stimulating absorption of calcium in tissues). Calcitriol is derived from ergosterol (in kidney tubules. plants) and 7-dehydrocholesterol o It mobilizes bone minerals Although excess dietary vitamin D is toxic, (intermediate in cholesterol synthesis that excessive exposure to sunlight does not lead Calcitriol functions in concert with to vitamin D poisoning, because there is accumulates in the skin) parathormone (PTH) and calcitonin in the limited capacity to form the precursor 7- o [Ergosterol upon ultraviolet irradiation is regulation of calcium and phosphorus levels. dehydrocholesterol and prolonged exposure of converted to ergocalciferol. provitamin D to sunlight leads to formation of PTH is released in response to low serum inactive compounds. o Ergocalciferol undergoes hydroxylation calcium, and induces the production of in the liver to yield calcitriol. calcitriol. When serum calcium is low, calcitriol Index of vitamin D nutritional status: The and PTH inhibit bone resorption and stimulate release of osteocalcin and nephrocalcin into o In the skin: 7-dehydrocholesterol, the distal kidney tubules calcium reabsorption. the circulation. undergoes nonenzymatic reaction upon ultraviolet light exposure yielding The role of calcitonin in calcium homeostasis is provitamin D, undergoes further reaction to decrease elevated calcium levels by Vitamin E [Tocopherol] over a period of hours to form inhibiting bone resorption. cholecalciferol, which is absorbed and Vitamin E is the generic description of two transported to the liver. B. Role in regulating cell proliferation and families of compounds: differentiation: o Tocopherols - the most active o In liver: cholecalciferol undergoes Inhibits production of interleukin by activated o Tocotrienols hydroxylation forming 25- T- lymphocytes and immunoglobulin by hydrocholecalfierol (calcidiol), the activated B-lymphocytes Functions of Vitamin E main storage form of the vitamin. This is Differentiation of monocyte precursor cells and released into the circulation bound to a modulation of cell proliferation. It acts as a lipid soluble antioxidant in cell vitamin D-binding globulin. membranes, and is important in maintaining C. Calcitriol is involved in insulin secretion, fluidity of cell membranes o In kidney: 25-hydroxycholecalciferol synthesis and secretion of PTH & thyroid It also has a role in cell signaling (calcidiol) undergo further 1- Main function of vitamin E is as a chain- hormones. hydroxylation to 1,25- breaking free radical-trapping antioxidant in V. ANGELS NMD - 1 3  LECTURE 8: MICRONUTRIENTS - VITAMINS cell membranes and plasma lipoproteins, by Functions of Vitamin K carboxylation of glutamate to gamma- reacting with the lipid peroxide radicals formed carboxyglutamate includes: by peroxidation of polyunsaturated fatty acids. Cofactor for the carboxylation of glutamate residues in the post synthetic modification o Osteocalcin and the matrix Gla protein The tocopherol radical is relatively unreactive of proteins to form the amino acid gamma- of bone and ultimately forms radical compounds. o Nephrocalcin in kidney Commonly, the tocopheryl radical is reduced carboxyglutamate. o Product of growth arrest specific Gas6, back to tocopherol by reaction with plasma involved in both regulation of vitamin C. The resultant, stable, Initially, vitamin K hydroquinone is oxidized differentiation and development in the monodehydroascorbate radical then to epoxide which activates a glutamate nervous system, and control of undergoes enzymatic or Nonenzymatic residue in the protein substrate to form a apoptosis in other tissues. reaction yield ascorbate and carbanion, which reacts nonenzymatically dehydroascorbate, neither of which is radical. with carbon dioxide to form gamma- Vitamin K Deficiency carboxyglutamate. Vitamin E Deficiency In vitamin K deficiency, or in the presence of Vitamin K epoxide is reduced to quinine by a warfarin, an abnormal precursor of In animals, vitamin E deficiency results in prothrombin (preprothrombin) containing warfarin-sensitive reductase and quinine is resorption of fetuses and testicular atrophy low or no gamma-carboxyglutamate, and reduced to active hydroquinone by either the Dietary deficiency of vitamin E in human same warfarin-sensitive reductase or a incapable of chelating calcium, is released into beings is unknown, although patients with warfarin-insensitive quinone reductase. the circulation, thus causes bleeding by severe fat metabolism, cystic fibrosis, & preventing blood clotting some form of chronic liver disease suffer With warfarin, vitamin K epoxide cannot be deficiency because they are unable to absorb reduced, but accumulates and is excreted. WATER-SOLUBLE VITAMINS and transport the vitamin, leading to muscle and nerve damage. If enough vitamin K is provided in the diet, it Vitamin B1 (Thiamin) Premature infants are born with inadequate Vitamin B2 (Riboflavin) can be reduced to active hydroquinone by reserves of the vitamin. Erythrocyte Vitamin B3 (Niacin) warfarin-insensitive reductase, and membranes are abnormally fragile as a Vitamin B6 carboxylation continues the utilization of result of lipid peroxidation, leading to vitamin K and excretion of the epoxide. Vitamin B12 (Cobalamin) hemolytic anemia. A high dose of vitamin K is the antidote of warfarin overdose. Vitamin B1 [Thiamine] Vitamin K Prothrombin (factor Il) and several other Functions of Thiamine Three compounds have biologic activity of proteins of the blood clotting system: vitamin K: Thiamine diphosphate is the coenzyme for o Factors VII three multienzyme complexes that catalyze o Phylloquinone - the normal dietary o Factor IX oxidative decarboxylation reactions: source from green vegetable o Factor X o Menaquinone - synthesized by o pyruvate dehydrogenase, in carbohydrate o Protein C and S, intestinal bacteria, with differing length metabolism of side chain Each contains 4 to 6 gamma- o alpha ketoglutarate dehydrogenase in o Menadione and Menadiol acetate - carboxyglutamate residues. Gamma- citric acid cycle. synthetic compounds that can be carboxyglutamate chelates calcium ions, and o branch-chain keto-acid dehydrogenase metabolized to phylloquinone so permits the binding of the blood clotting involved in metabolism of leucine, valine, proteins to membranes. and isoleucine Synthesis of a number of other proteins Thiamine diphosphate is the coenzyme for undergo the same vitamin K-dependent transketolase, in the Pentose PO4 Pathway V. ANGELS NMD - 1 4  LECTURE 8: MICRONUTRIENTS - VITAMINS Thiamine Deficiency Functions of Riboflavin NAD, source of ADP-ribose for ADP- ribosylation of proteins and poly ADP Can result in three distinct syndromes: Coenzymes as Electron Carriers in redox ribosylation of nucleoproteins involved in DNA reactions: repair mechanism. o Beriberi, chronic peripheral neuritis, with or without associated heart failure and o Mitochondrial respiratory chain Cyclic AMP-ribose and nicotinic acid edema. o Key enzymes in fatty acid and amino adenine dinucleotide formed from NAD act to o Acute pernicious (fulminating) beriberi acid oxidation, and the citric acid cycle increase intracellular calcium in response to (shoshin beriberi), heart failure and neurotransmitters and hormones metabolic abnormalities predominate Reoxidation of reduced flavin in oxygenases and mixed-function oxidases Deficiency of Niacin without peripheral neuritis, and o Wernicke Encephalopathy with proceeds by way of formation of flavin radical and flavin hyperoxide, with Pellagra caused by deficiency of tryptophan Korsakoff psychosis, associated with and niacin. alcohol and narcotic abuse. intermediate generation of superoxide and perhyhydroxyl radicals and hydrogen peroxide. Characterized by photosensitive dermatitis, The role of thiamine diphosphate in pyruvate Thus, flavin oxidases make a significant dementia & diarrhea. dehydrogenase means that in deficiency there contribution to total oxidant stress to the body. Untreated pellagra is fatal. is impaired conversion of pyruvate to acetyl- Nutritional etiology of pellagra is well CoA. Riboflavin Deficiency established, but additional factors include In subjects with a relatively high carbohydrate deficiency of riboflavin or pyridoxine, both are Riboflavin is centrally involved in fatty acid and required for synthesis of nicotinamide from diet, this results in increased plasma carbohydrate metabolism, deficiency is not tryptophan, may be important. concentration of lactate and pyruvate, which fatal, because of efficient conservation of Most outbreaks of pellagra, twice as many may cause life-threatening lactic acidosis. tissue riboflavin. women as men are affected, probably due to Index of thiamin nutritional status: is assessed Riboflavin released by catabolism of enzymes inhibition of tryptophan metabolism by by the activation of apo-transketolase in are rapidly incorporated into newly synthesized estrogen metabolites. erythrocyte lysate by thiamin diphosphate enzymes. Genetic diseases due to defects in tryptophan added in vitro. Deficiency is characterized by: metabolism are associated with development Vitamin B2 [Riboflavin] o Cheilosis- red denuded epithelium at the of pellagra despite adequate intake of both line of closure of the lips tryptophan and niacin, Riboflavin provides the reactive moieties of o Glossitis - tongue desquamation and o Hartnup's Disease, genetic condition the coenzymes flavin mononucleotide inflammation due to defect in membrane transport (FMN), and flavin adenine dinucleotide o Angular stomatitis - yellowish moist mechanism for tryptophan, resulting in (FAD). ridges at the corner of the mouth large losses due to intestinal o FMN is formed by ATP-dependent o Nasolabial seborrhea - enlarged sebum malabsorption and failure in renal phosphorylation of riboflavin; filled follicles on the sides of the nose reabsorption. o FAD is synthesized by further reaction o Seborrheic dermatitis- greasy and o In Carcinoid syndrome, there is with ATP in which the AMP moiety is scaliness of the skin metastasis of the primary liver tumor of transferred to FMN. enterochromaffin cells, which synthesizes Vitamin B3 [Niacin] 5- hydroxytryptamine. Overproduction of Main dietary sources are: milk and dairy 5-hydroxytryptamine may account for products. Include Nicotinic acid and nicotinamide 60% of the body's tryptophan Index of riboflavin nutritional status: is Can be synthesized from tryptophan. metabolism, causing pellagra because of assessed by measurement of the activation diversion away from NAD synthesis. Functions of Niacin of erythrocyte glutathione reductase by FAD added in vitro Serves as a nicotinamide ring of coenzymes NAD and NADP in redox reactions. V. ANGELS NMD - 1 5  LECTURE 8: MICRONUTRIENTS - VITAMINS Toxicity of Niacin Deficiency of Vitamin B6 preparations of vitamin B12 made by bacterial fermentation are available. Nicotinic acid has been used to treat Deficiency is rare, but a significant proportion Vitamin B12 is absorbed bound to an hyperlipidemia, when 1 to 6 gm/day is of the population have marginal vitamin B6 intrinsic factor, a small glycoprotein secreted required, causing dilatation of blood vessels status. by gastric parietal cells. and flushing, along with skin irritation. Moderate deficiency results in abnormalities Gastric acid and pepsin release the vitamin Intake of both nicotinic acid & nicotinamide in of tryptophan and methionine metabolism from protein binding in food and make it excess of 500 mg/day also cause liver Increased sensitivity to steroid hormone available to bind to cobalophilin, a salivary damage. action (estrogens, androgens, cortisol and binding protein. Vitamin B6 vitamin D) is important in the development of In duodenum, cobalophilin is hydrolyzed, hormone-dependent cancers of breasts, the free vitamin binds with the intrinsic uterus, & prostate. factor. Includes: Vitamin B6 status may affect the prognosis. Pancreatic insufficiency, therefore, is a o Pyridoxine Vitamin B6 Toxicity factor for development of vitamin B12 o Pyridoxal deficiency, resulting from excretion of o Pyridoxamine The development of sensory neuropathy has cobalophilin-bound vitamin B12 o Pyridoxine 5-phosphate been reported in patients taking 2 to 7 grams Intrinsic factor binds only to active vitamin o Pyridoxal 5-phosphate of pyridoxine per day (effective in post B12 vitamers and not other corrinoids. o Pyridoxamine 5-phosphate menstrual syndrome). Vitamin B12 is absorbed from the distal third Pyridoxal 5-phosphate, the active coenzyme. Index of vitamin B6 nutritional status is of the ileum via receptors that bind the assessed by the activation of erythrocyte intrinsic factor-vitamin B12 complex, but 80% of the body's total vitamin B6 is pyridoxal not free intrinsic factor or free vitamin B12. phosphate in muscle, mostly associated with transaminase by pyridoxal phosphate added There is considerable enterohepatic glycogen phosphorylase in vitro. circulation of vitamin B12, with excretion of Muscle pyridoxal is not available for Vitamin B12 [Cobalamin] the bile, then reabsorption after binding with deficiency, but released in starvation, when the intrinsic factor in the ileum. glycogen reserve become depleted, and is then available, especially to liver & kidney, to The term "vitamin B12" is used in the generic Functions of Vitamin B12 meet increased requirements for description for cobalamins, those corrinoids gluconeogenesis from amino acids (cobalt-containing compounds possessing Cofactors of Methymalonyl-CoA mutase and corrin rings) having the biologic activity of a methionine synthase enzymes. Functions of Vitamin B6 vitamin. Methylmalony-CoA is formed as intermediate Pyridoxal phosphate is a coenzyme for Some corrinoids are growth factors for in valine catabolism and decarboxylation of microorganisms that not only have no vitamin proprionyl-CoA arising from the catabolism of many enzymes involved in amino acid activity, but may also be antimetabolite to the isoleucine, cholesterol and fatty acid with an metabolism, especially transamination, and vitamin. odd number of carbon atoms. decarboxylation. Synthesized exclusively by microorganisms, Propionyl-CoA undergoes a vit. B12- Cofactor of glycogen phosphorylase, where but vitamin B12 is found in foods of animal dependent isomerization to succinyl-CoA the phosphate group is catalytically important. origin, there being no plant sources of the catalyzed by methylmalonyl-CoA mutase. Important in steroid hormone action. Pyridoxal vitamin Methylmalonyl-CoA mutase activity is greatly phosphate removes the hormone-receptor complex from DNA binding, terminating the Thus, strict vegetarians are at risk of reduced in vitamin B12 deficiency, leading to developing B12 deficiency. an accumulation of methylmalony-CoA and actions of the hormones. Small amount of vitamin B12 formed by the urinary excretion of methylmalonic acid, which bacteria on the surface of fruits, may be provides a means of assessing vitamin B12 adequate to meet the requirement, but nutritional status V. ANGELS NMD - 1 6  LECTURE 8: MICRONUTRIENTS - VITAMINS Vitamin B 12 Deficiency Pernicious anemia arises when vitamin B12 deficiency impairs folic acid metabolism, leading to functional folate deficiency that disturbs erythropoiesis, causing release of immature RBC into the circulation, (megaloblastic anemia). Most common cause of pernicious anemia is failure of Vit. B12 absorption rather than dietary deficiency. This can be due to failure of intrinsic factor secretion caused by autoimmune disease affecting parietal cells or from the production of anti-intrinsic factor antibodies V. ANGELS NMD - 1 7 LECTURE 8: MICRONUTRIENTS - VITAMINS V. ANGELS NMD - 1 8