Nutrients II Handout PDF

Folic Acid “folium” {latin} = leaf Best sources: Green leafy vegetables; Uncooked fruits In intestinal mucosa: Tetrahydrofolate 2 NADPH2 2 NADP...

Folic Acid “folium” {latin} = leaf Best sources: Green leafy vegetables; Uncooked fruits In intestinal mucosa: Tetrahydrofolate 2 NADPH2 2 NADP (THF) Folate reductase Dihydrofolate reductase (-) Anticancer drug Methotrexate  Function of THF Carrier of “C1- bodies” (One-carbon units) One-carbon units transferred to acceptor molecule in biosynthetic reactions Synthesis of purine and thymidine nucleotides (DNA building blocks) require several C1- body transfers No THF→ No DNA reduplication → No mitosis Methotrexate prevents THF formation!  THF deficiency Impairment of DNA synthesis Clinical expression: Megaloblastic changes (large cytoplasm) Reason: DNA synthesis↓ Impaired nuclear maturation DNA replication inhibited seen as open, immature Nuclear maturation ↓ chromatin (cut-salami pattern) Cytoplasmic maturation unaffected www.med-ed.virginia.edu Hematological changes: Megaloblastic anemia (Macrocytic anemia) Normal RBC Large, but not enough erythrocytes Megaloblastic RBC Required amount of Folic Acid increases significantly during pregnancy Pregnancy can precipitate megaloblastic anemia THF deficiency possibly results in birth defects  Vitamin B12 (Cobalamin) Source: Synthesized only by microorganism Corrin ring system No cobalamin in plants!! with Cobalt ion in center Animal products are the only dietary source Strict vegetarians at risk for deficiency Liver stores up to 10 mg Only max. 0.0002 mg per day needed Sudden switch of diet → Stored amount would last 136 years Provided there are no problems with intestinal absorption Clinical symptoms within 2 years when intestinal absorption is impaired  Dietary B12 Esophagus B12 alone cannot be absorbed Liver Daily up to 10 μg B12 via bile from liver Biliary B12 into duodenum into ileum followed by Stomach excretion Common bile duct Dietary B12 via stomach towards excretion Parietal cells secrete 50kDa Gallbladder Parietal glycoprotein “Intrinsic Factor, IF” cells Duodenum IF forms tight complex with B12, which is absorbed in ileum IF in blood replaced by other transport protein (transcobalamin), which prevents renal excetion and which mediates uptake of B12 into tissue Excretion Terminal Ileum Blood Tissue cells  Vitamin B12 Deficiency Megaloblastic anemia, which is indistinguishable from that of THF deficiency MOA: “Methyl folate trap” Homocysteine See 5. “Coenzymes” (#16): SAM for methylation The only use for Methyl-THF CH3-THF B12 dependent THF Methionine Regeneration with another methyl group donor No regeneration of No methionine from Methyl-THF B12 homocysteine not used up Methyl-THF No free THF THF accumulates available anymore deficiency  Vitamin C (Ascorbic acid) Structure of Vitamin C identified in 1932, following its isolation from lemon juice MOA Vitamin C Oxidation of Vit C Cred (Ascorbate) Cox (Dehydroascorbate) - 2H+ - 2e-  Physiological Degradation and Excretion of Vitamin C 1) Hydrolysis of inner ester (lactone) 1 cm © New York University School of Medicine Large doses of Vitamin C plus large amounts of calcium in daily diet may lead to kidney stones 2) Final degradation to oxalate  The two major physiological functions of Vitamin C A) Hydroxylations One oxygen “inserted’ between C and H to form hydroxy group The second oxygen reacts with 2H from Vitamin C to form water Several physiological hydroxylation reactions affected by C deficiency Deficiency symptoms Physiological Vitamin C dependent Hydroxylation Reactions 1) Hydroxylation of prolyl and lysyl residues in procollagen No collagen Damaged connective tissue Essential for collagen synthesis Scurvy 2) Synthesis of carnitine Carrier for transport of fatty acids into mitochondrial matrix In matrix, fatty acids oxidized for ATP synthesis Carnitine deficiency Decrease of ATP (energy!) level Fatigue and lassitude  3) Synthesis of norepinephrine from dopamine Norepinephrine (noradrenaline) = Precursor for Epinephrine (adrenaline) “Stress Hormones”: Mobilize additional energy by degradation of glycogen Fight or Flight Response 4) Synthesis of bile salts 7-alpha-Hydroxylase Involved in conversion of cholesterol into bile salts Without bile salts no fat digestion Bile salts emulsify fat droplets (decrease size)  B) Antioxidans Mitochondria forms during ATP production “Reactive Oxygen Species” (ROS) C radical removes first H O2. (-) HO. HOO. R-CH2. removes second H Another C radical Radicals are highly reactive, “try to get” 2nd electron from anywhere: ROS oxidize DNA, lipids, proteins Cred (Ascorbate) - 2H+ - 2e- Resulting RH and oxidized C Cox (Dehydroascorbate) harmless, i.e. not reactive Vit C acts as a “radical scavenger” Result: Vit.C has inactivated reactive radicals = Antioxidans  Fat-soluble Vitamins 20 - 50 nm Individual Bile salt molecules Hydrophobic inner space encapsulates water- insoluble molecules (fat, fat-soluble vitamins) Micelle Fatty meal triggers increased excretion of bile salts into duodenum Fat-soluble vitamins as supplement best taken with fatty meal Fat-soluble vitamins cannot be excreted by kidney Accumulates in lipid-rich tissues  Source #1 Vitamin A β-Carotene = Orange pigment in carrots and other vegetables β - Carotene dioxygenase in intestinal mucosa cells oxidizes carotene yielding 2 molecules retinal Retinal is prosthetic group in rhodopsins (visual pigments of rods and cones) Deficiency leads to night blindness  Other forms of vitamin A Retinol (alcoholic group) forms esters with fatty acid = Storage form in animal tissues and source #2 (milk, butter, egg yolk, liver) Retinal (aldehyde group) in rhodopsin Retinoic acid (carboxylic acid group) involved in regulation of gene expression Retinolphosphate (ester of retinol and phosphoric acid) crucially involved in transfer reactions of carbohydrate onto proteins Important for synthesis of glycoproteins!  Vitamin A Deficiencies 1) Vit. A: Maintenance of epithelial tissues via synthesis of glycoproteins Deficiency: Mucus producing cells slow down & Glycoprotein content of tears ↓ “Dry eyes” (Xerophthalmia) Bacterial infections Perforation of cornea Blindness  2) Vit. A: Function of osteoblasts and osteoclasts Optimal supply of Vit.A essential for balance between osteoclasts and osteoblasts Retinoic acid activates osteoclasts, Osteoclasts Osteoblasts enhancing bone resorption. degradate bones synthesize bones  Vitamin D Minimal exposure to sun: Sufficient endogenous synthesis (Vitamin ?) MOA Vit. D: “Vitamin D” Induces synthesis of Ca-binding proteins … Cholesterol Activation in … via interacting liver and kidney with DNA Hydroxylations (Regulation of Acetyl-CoA transcription) 3 major functions: Active form of Vitamin D Release of Ca Prevents renal from bone Intestinal Ca Ca excretion absorption  Long-term Vitamin D deficiency Ca in blood remains constant at the expense of bone tissue Bones gradually depleted from Calcium Bone tissue becomes poorly mineralized, softens leading to deformations “Osteomalacia” (in adults) “Rickets” (in children) Hypervitaminoses D Chronically elevated Ca level in blood leads to cardiovascular and renal damage  Vitamin E (Tocopherol) More than 8 different derivatives in plants - differ in ring substitutions and side chain α-Tocopherol most abundant Deficiencies are almost unknown; Mild hemolytic anemia in premature infants due to poor intestinal absorption Non-toxic @ 50x RDA Epidemiological studies indicate an inverse relationship between Vit. E supplement intakes and Coronary Heart Diseases … …which is similar to other antioxidants  Vitamin K K … Koagulation Phylloquinone (in vegetables) Menaquinone (synthesized by n = 7 - 13 bacteria including intestinal bacteria Menadione = Synthetic previtamine Must be alkylated in human body Absorption easy w/o bile salts K is not significantly stored; 1st fat-soluble vitamin to be deficient during fat malabsorption Vit. K deficiencies result in bleeding disorders Hemorrhagic diseases of the newborn caused by: In some U.S. Low tissue stores at birth states Vitamin K Not enough Vit. K in breast milk prophylaxis mandatory Immature intestinal flora does not produce enough  Vitamin K is the essential co-enzyme for the carboxylation of glutamate residues in prothrombin Reduced K Precursor of prothrombin with “normal” glutamate www.chemsoc.org/ Carboxylase uses Vit. K as coenzyme Prothrombin with Oxidized K γ-carboxyglutamate Micronutrients: Minerals  Minerals 4-5% body weight (2.8 - 3.5 kg per adult) 50% = Ca 99% of Ca and 70% of P 25% = P in bones and teeth Remaining 25% Mg, Na, K, Cl, S Fe, Zn, I, Se, Mn, F, Mo, Cu, Cr, Co, B Essential Macrominerals Essential Microminerals > 100 mg intake / day < 15 mg intake / day Ultratrace Elements: As, Al, Sn, Ni, V, Si (microgram range of intake per day)  “Problem Minerals” in the U.S. Diet Consumed in less than optimal amounts by large percentage of people Calcium (Ca) Iron (Fe) Zinc (Zn) Magnesium (Mg) Fortification of food (ready-to-eat cereals) : ↑Fe and Zn, but not Ca  Calcium (& Phosphate) Three major pools of Ca in human body Bone: 99% of total body Ca Blood (and extracellular fluids): 2.5 mM TIGHTLY REGULATED Intracellular: 100... 1000 nM (release from ER and mitochondria) 2.5 mM : 1000 nM = 2500 : 1 !Ca-transporters! Majority of physiologic processes depending on Calcium Hypocalcemia: Low blood Ca level Muscle spasm, tetany, cardiac dysfunction OSTEOMALACIA Hypercalcemia: Elevated blood Ca level Diffuse precipitation of (Ca)3(PO4)2 Magnesium The Magnesium - ATP Complex >300 metabolic enzymes Mg dependent! No formation of cAMP w/o Mg Iron Oxygen transport Electron transport (OXPHOS) ATP Iron deficiency = Precursor of iron deficiency anemia Most common of all nutritional deficiency diseases Mostly affected are children and women of childbearing age @ Greatest risk: Infants < 2 years, adolescent girls, pregnant women, older adults @ Very greatest risk: Pregnant teenagers (poor eating habits, continuing growth) Iron requirements (mg/day) Final stage of iron deficiency: Hypochromic microcytic anemia Decreased hemoglobin Decreased hematocrit Bone marrow depleted of stainable iron Low serum ferritin Cells from patient with Normal red iron deficiency blood cells anemia www.academic.marist.edu  Zinc Primarily an intracellular ion Part of > 300 different enzymes from almost all pathways Symptoms of deficiency: Growth retardation Delayed sexual maturation Hypogonadism and hypospermia Delayed wound healing Skin lesions Immune deficiencies Behavioral disturbances Eye lesions Impaired appetite Impaired taste Skin lesions appearing in rats fed a Zn-deficient diet for 50 days H. Yanagisawa et al., Zinc deficiency further increases the enhanced expression of endothelin-1 in glomeruli of the obstructed kidney. Kidney International 2000, 58, 575-586