Micronutrients

Vitamins

Vitamins Vitamins are chemically unrelated organic compounds that cannot be synthesized by humans, and therefore must be supplied by the diet. Vitamins are required to perform specific cellular functions. Many of the water-soluble vitamins are precursors of coenzymes for the enzymes of intermediary metabolism. Only vitamin K of the fat-soluble vitamins has a coenzyme function. Fat soluble vitamins are released, absorbed & transported with the fat of the diet. They are not readily excreted in urine. Significant amounts are stored in the liver & adipose tissue.

Vitamins cont. Vitamins are classified into   Water soluble vitamins: 1- Folic 2- Cobalamin 3- Pyridoxine 4- Thiamine 5- Niacin 6- Riboflavin 7- Biotin 8- Pantothenic Acid 9- Ascorbic Acid Fat soluble vitamins; 1- Vitamin A 2- Vitamin D 3- Vitamin K 4- Vitamin E

Water Soluble Vitamins Some water Soluble vitamins are studied in the current lecture (micronutrients): Thiamine (Vitamin B1) Riboflavin Niacin Pyridixine (Vitamin B6) Other water soluble vitamins: are studied in lectures of the Heme-Immune (HMIM) Block Folic acid Cobalamine (Vitamin B12) Ascorbic acid (vitamin C)

Thiamine (Vitamin B1) Sources: Active form of thiamine:   Sources: Plants: yeast, bran, vegetables and fruits Animals: liver, kidney, milk & fish. Active form of thiamine: Thiamine pyrophosphate (TPP) is the biologically active form of the vitamin B1. It is formed by the transfer of pyrophosphate group from ATP to thiamine.

Thiamine (Vitamin B1) cont. Functions of TPP: I- TPP is a coenzyme of oxidative decarboxylation of a- keto acids. (Mitochondrial Enzymes)   1- The oxidative decarboxylation of pyruvate to acetyl CoA (Pyruvate dehydrogenase complex) 2- The oxidative decarboxylation of a ketoglutarate to succinyl CoA in TCA cycle (a ketoglutarate dehydrogenase complex)   1 & 2 are roles of thiamine in carbohydrate metabolism 3- The oxidative decarboxylation of a -keto acids derived from leucine, valine & isoleucine (branched chain amino acids catalyzed by a single enzyme complex , branched-chain a -keto acids dehydrogenase complex

Thiamine (Vitamin B1) cont. II- Functions of TPP: TPP acts as a coenzyme of tranketolase enzyme(cytosolic) in the nonoxidative reactions of pentose phosphate pathway N.B. Thiamine deficiency is diagnosed by an increase in erythrocyte transketolase activity observed on addition of thiamine pyrophosphate (TPP).

Thiamine (Vitamin B1) cont. Clinical indications for thiamine: The oxidative decarboxylation of pyruvate & a ketoglutarate plays a key role in energy metabolism (especially for carbohydrates) in most cells particularly nervous system tissues (that require continuous supply of sufficient energy). In thiamine deficiency, the activity of these two dehydrogenase reactions is decreased, resulting in a decreased production of ATP and, thus, impaired cellular functions.

Thiamine (Vitamin B1) cont. Thiamine deficiency diseases:   1-Beriberi: occurs in areas where the main diet is polished rice. Signs of infantile beriberi: Tachycardia, vomiting & convulsions Signs of adult beriberi: Dry skin, irritability & progressive paralysis (peripheral neuritis). 2-Wernicke-Korskoff syndrome: Develops in alcoholics due to decreased absorption of the vitamin B1. Signs: Neuropsychiatric (mainly) Apathy, loss of memory & rhythmical to- and fro- movements of eyeballs

NIACIN Sources: 1- Dietary sources niacin (main source):   1- Dietary sources niacin (main source): is found in grains & cereals, milk, meat & liver. 2- Tryptophan metabolism: Limited quantities can be obtained from metabolism of amino acid tryptophan 1 mg of niacin is formed from 60 mg of tryptophan. This occurs after needs for protein synthesis and energy production.

NIACIN cont. Forms of niacin in the body: 1-Niacin (nicotinic acid)   1-Niacin (nicotinic acid) Available in diet The active coenzyme forms are nicotinamide adenine dinucleotide (NAD+) & nicotinamide adenine dinucleotide phosphate (NADP+). 2-Nicotinamide Available in diet. A derivative of nicotinic acid that contains an amide instead of carboxyl group. Nicotinamide is readily deaminated in the body & therefore, is nutritionally equivalent to nicotinic acid. 3-NAD+ & NADP+ (coenzymes) Serve as coenzymes in oxidation-reduction reactions in which the coenzyme undergoes reduction into NADH & NADPH.

NIACIN cont. Clinical indications for niacin: 1-Deficiency of niacin: causes pellagra, involving the skin, GIT and CNS Manifestations: THREE Ds : Dermatitis, Diarrhea, Dementia (Death, if untreated)   2-Treatment of hyperlipidemia: Niacin (at a dose of 1.5 g/day or ~ 100 times the RDA) strongly inhibits lipolysis in adipose tissue, the primary producer of circulating free fatty acid. The liver normally uses these circulating fatty acids as a major precursor for triacylglycerol synthesis. Thus, niacin causes a decrease in triacylglycerol synthesis, required for synthesis of production of VLDL. LDL is derived from VLDL in the plasma. Thus, VLDL & LDL are lowered. Therefore, niacin is particularly useful in the treatment of type IIb hyperlipoproteinemia, in which VLDL & LDL are elevated.

Riboflavin (Vitamin B2) Sources:   Plants: yeast and vegetables Animals: liver, eggs & milk Active forms of riboflavin: 1-Flavin mononucleotide (FMN) 2-Flavin adenine dinucleotide (FAD)

Riboflavin (Vitamin B2) cont. Functions:  FMN & FAD are coenzymes for many enzymes used for different metabolic pathways. FMN & FAD are each capable of reversibly accepting two hydrogen atoms, forming FMNH2 or FADH2 Riboflavin deficiency: Riboflavin deficiency is not associated with major human disease. Symptoms: include: dermatitis, cheliosis (fissuring at the corners of mouth) and glossitis (smooth and purplish tongue)

Pyrodoxine (VITAMIN B6)   Vitamin B6 is a collective term of pyridoxine, pyridoxal & pyridoxamine, all derivatives of pyridine & differs only in the nature of the functional group attached to the ring. Sources: Pyrodoxine occurs primarily in plants Pyridoxal & pyridoxamine are found in foods obtained from animals. The active form: All three compounds can serve as precursors of the biologically active coenzyme pyridoxal phosphate (PLP).

Pyrodoxine (VITAMIN B6) cont. Functions of pyridoxal phosphate (PLP):   PLP acts as a coenzyme for a large number of enzymes, especially those involved in amino acid metabolism. 1-Transamination: Aspartate Tansaminase (AST) Oxalactetate + Glutamate Aspartate + a ketoglutarate   PLP Alanine Tansaminase (ALT) Pyruvate + Glutamate Alanine + a ketoglutarate PLP Transamination is an essential component of disposal of amino group in amino acid metabolism

Pyrodoxine (VITAMIN B6) cont. 2-Deamination : Serine Pyruvate + NH3    3-Decarboxylation of amino acids: Histidine Histamine + CO2   (histamine is required in allergic reactions) Glutamic acid GABA + CO2   (GABA is a neurotransmitter in CNS) 4-Condensation: Glycine + Succinyl CoA d aminolevulinic acid First step in heme synthesis in erythrocyte producing cells in bone marrow  

Pyrodoxine (VITAMIN B6) cont. 5- for disposal of homocysteine: Homocysteine is produced from metabolism of amino acid methionine Then, it is metabolized into amino acid cysteine by: Cystathionine Synthase PLP (B6) Homocysteine + Serine Cystathionine Cystathionase Cystathionine cysteine + a-ketobutyrate + NH3 N.B: The other pathway for homocysteine is conversion to methionine by homocysteine methyltransferase (coenzyme: methylcobalamin, B12) Defect in homocysteine metabolism leads to accumulation of homocysteine that predisposes in atherosclerosis

Pyrodoxine (VITAMIN B6) cont. Clinical indications for pyridoxine:   Isoniazid (izonicotinic acid hydrazide) An anti-tuberculous drug that can bind with PLP forming an inactive derivative, leading to vitamin B6 deficiency Accordingly, B6 should be supplied with isoniazid treatment. Dietary deficiency of pyridoxine are rare but seen in: New born infants fed formulas low in B6. Women taking oral contraceptives Alcoholics Toxicity of pyridoxine is manifested by neurological symptoms at intakes more than 2 g/day.

Fat Soluble Vitamins Vitamin A: is studied in the CNS Block Vitamin D: is studied in Endocrine , Urinary & Musculoskeletal Blocks Vitamin K : is studied in the Heme-Immune Block Vitamin E: is studied in the current lecture (GIT Block)

Vitamin E E vitamins consist of 8 naturally occurring tocopherols, of which - tocopherol is the most active. The primary function of vitamin E is an antioxidant in prevention of the nonenzymic oxidation of cell components as polyunsaturated fatty acids by molecular O2 & free radicals.

Vitamin E Distribution & requirements of vitamin E: Vegetable oils are rich sources (plant sources) Liver & eggs contain moderate amounts (animal sources) RDA for a-tocopherol is 10 mg for men 8 mg for women Requirement is increased with increased intake of polyunsaturated fatty acids.

Vitamin E cont. Deficiency of vitamin E Deficiency of vitamin E is almost entirely restricted to premature infants. In adults, it is usually associated with defective lipid absorption or transport. Signs of vitamin E deficiency include sensitivity of RBCs to peroxide & appearance of abnormal cellular membrane.

Vitamin E cont. Clinical indications Vitamin E is not recommended for the prevention of chronic disease, such as coronary heart disease or cancer. Subjects in the Alpha-Tocopherol, Beta Carotene Cancer Prevention Study trial who received high doses of vitamin E, not only lack cardiovascular benefit but also had an increased incidence of stroke. Toxicity of vitamin E: no toxicity at 300mg / day dose

Minerals & Trace Elements Macrominerals (needed in quantities more than 100 mg/day) calcium, phosphorous, sodium , potassium, chloride, magnesium Calcium & phosphorous: in ENDO Block Sodium, potassium & chloride: in Urinary Block Microminerals (needed in quantities less than 100 mg/day) 1- Trace elements (needed in amounts of mgs) iron, iodine, copper, zinc, cobalt Iron: in HMIM Block Iodine: ENDO Block 2- Ultraelement (needed in amounts less than mg) as manganese, selenium , fluoride, chromium

Magnesium It is the second most abundant intracellular cation. It is essential for the activity of many enzymes. Bone contains about 50 % of the body’s magnesium. Dietary intake of magnesium is normally about 250 mg/ day When dietary intake is restricted, renal conservation mechanism are normally so efficient that depletion, if develops at all, comes on very slowly.

Magnesium cont. Magnesium deficiency Rarely occurs isolated but usually accompanies deficiency of potassium, calcium and phosphates Manifested by muscle weakness, sometimes accompanied by tetany, cardiac arrythmias and CNS abnormalities (convulsions) Hypermagnesemia Most often due to acute renal failure or the advanced stage of chronic renal failure

Copper It is a major component of enzymes involved in redox reactions , like superoxide dismutase, cytochrome C oxidase In plasma copper is bound mainly to ceruloplasmin (mainly in addition to small fraction bound to albumin) Deficiency is uncommon and usually occurs with malunutrition and malabsorption Manifested by: microcytic hypochromic anemia low concentrations of ceruoloplasmin

Copper cont. Menkes’ syndrome: a recessive X-linked genetic defect in copper transport and storage, where there is defect in transport of copper from mucosal cell, leading to mental deterioration, failure to thrive, diminished activities of copper containing enzymes. Wilson’s disease (hepatolenticular degeneration): is associated with copper accumulation in liver (cirrhosis) & brain Copper may deposit in cornea (Kayser- Fleischer rings) There is plasma low level of ceruloplasmin & copper and increased urinary copper excretion

Zinc It is the most abundant trace element next to iron Rich sources of zinc include meat , fish, and dairy products. Typical diet supply 10-15 mg of zinc/day The body does not store zinc, the main route for excretion is through the gut Along with magensium , zinc is the most frequently encountered metal cofactor for enzyme activity, where it mainly serves as integral part of the active site PBG synthase and carbonic anhydrase alkaline phosphatase are among the enzymes which need Zn

Zinc (cont.) Zinc enzymes are essential for growth, wound healing , integrity of C.T., reproductive function , the immune system DNA and RNA polymerases require zinc to maintain the structure conformation of DNA Symptoms of zinc deficiency include growth retardation, skin lesions, slow wound healing, impotence, dwarfism , loss of body hair Causes of zinc deficiency: - Insufficient dietary zinc (major cause) - Pregnancy ,lactation , old age - Administration of metal chelating agents, diuretics , anti –cancer drugs - Gastrointestinal malabsorption syndromes - patients receiving total parenteral nutrition

Selenium Selenium is a component of glutathione peroxidase , which has anti-oxidant function . It is also part of iodothyronine deiodinase enzyme essential for formation of T3 Selenium deficiency has been associated with cardiomayopathy and selected muscle weakness, osteoarthritis and increase incidence of cancer