Water-Soluble Vitamins PDF

Water-soluble Vitamins Marks’ Basic Medical Biochemistry , 6th Ed pages: 13-16 Biochemistry, Cell and Molecular Biology, and Genetics Part VI Chapter 46 (386-391) Zeynep Gromley, Ph.D. MANS 429 [email protected]...

Water-soluble Vitamins Marks’ Basic Medical Biochemistry , 6th Ed pages: 13-16 Biochemistry, Cell and Molecular Biology, and Genetics Part VI Chapter 46 (386-391) Zeynep Gromley, Ph.D. MANS 429 [email protected] 1  Learning Objectives Explain the cellular and physiological functions of water-soluble vitamins in the metabolism Determine what types of disorders are associated with deficiency of water- soluble vitamins (Thiamine, Riboflavin, Niacin, Pyridoxine, Biotin, Folate, Cyanocobalamin, Ascorbate) Distinguish differences in deficiencies of water-soluble vitamins (Thiamine, Riboflavin, Niacin, Pyridoxine, Biotin, Folate, Cyanocobalamin, Ascorbate) 2  Vitamin Enzyme Pathway Human deficiency Coenzyme Disease Thiamine (B1) Pyruvate dehydrogenase PDH Beriberi Thiamin pyrophosphate (TPP) α-ketoglutarate dehydrogenase TCA cycle Wernicke-Korsakoff transketolase HMP shunt Riboflavin (B2) Dehydrogenases Oxidation- Corneal neovascularization FAD(H2) reduction Cheilosis or stomatitis Magenta-colored tongue Niacin (B3) Dehydrogenases Oxidation- Pellagra (4D disease) NAD(H) and NADP(H) reduction Pantothenic acid (B5) Fatty acid synthase Fatty acid N/A Coenzyme A Pyruvate dehydrogenase metabolism α-ketoglutarate dehydrogenase PDH Pyridoxine (B6) Aminotransferases Protein catabolism Cheilosis or stomatitis PLP ALA synthase Heme synthesis Sideroblastic anemia Biotin (B7) Pyruvate carboxylase Carboxylation Alopecia (hair loss) Acetyl CoA carboxylase Inflammation Propionyl-CoA carboxylase Muscle pain Folic acid (B9) Thymidylate synthase One carbon group Megaloblastic anemia THF Purine synthesis enzymes transfer Neural tube defects Cyanocobalamin (B12) Homocysteine methyltransferase One carbon group Pernicious anemia Methyl-malonyl-CoA mutase transfer Megaloblastic anemia Peripheral neuropathy Ascorbate Prolyl and lysyl hydroxylase Collagen synthesis Scurvy Vit C Dopamine b-hydroxylase Catecholamine synthesis 3  Thiamine (B1) Thiamine PyroPhosphate (TPP) - Pyruvate dehydrogenase (PDH) - α-ketoglutarate dehydrogenase (TCA cycle) - Branched chain ketoacid dehydrogenase (metabolism of valine, leucine, and isoleucine) maple syrup urine disease - Transketolase (HMP shunt) 4  deficiency of thiamine causes weakness and amnesia (forgetfulness) The activity of PDH and alpha-KG dehydrogenase is important in energy metabolism particularly nervous system and muscle (skeletal and cardiac muscle) Lactate and pyruvate builds up in tissues of the body, especially in aerobic tissues such as cardiac muscle and the brain. The insufficient generation of ATP in these tissues causes neuropathy, ataxia, and dilated cardiomyopathy. 5  Deficiency of Thiamine Deficiency can be due to diet that lacks thiamine, or it can be due to chronic consumption of alcohol, which prevents absorption of thiamine from the jejunum. Beriberi: dry beriberi (peripheral neuropathy, muscle wasting, partial paralysis) wet beriberi (high-output cardiac failure, fluid retention) The combination of thiamine deficiency and alcohol toxicity causes Wernicke-Karsokoff syndrome which is characterized by – mental derangement, loss of memory, delirium, ataxia and paralysis of the eye muscles. – symptoms of confusion, hallucinations, disorientation, and frenzy Treatment with thiamine injections. 6  Riboflavin (B2) is a precursor for FAD and FMN - Coenzyme for several dehydrogenases - Involved in oxidation/reduction reactions Deficiency due to poor diet or infant receiving phototherapy to treat jaundice. Deficiency can cause corneal neovascularization, cheilosis, glossitis, stomatitis, (cracking or scaling of lip borders and corners of the mouth) magenta-colored tongue 7  Niacin (B3) is a precursor for NAD and NADP Dietary coenzymes are hydrolyzed in GI and free nicotinic acid and nicotinamide are absorbed in the small intestine. Found in whole grains, milk, meat. Niacin deficiency known as Pellagra (rough skin). Due to malnutrition (historically poverty and maize-based diet). 8  The signs of severe niacin deficiency (4D disease) Pellagra – Dermatitis (especially in the sun-exposed areas), month sores/glossitis, skin inflammation – Diarrhea, – Dementia, mental confusion – If not treated Death 9 Pharmacological doses of niacin for treating hypercholesterolemia – 5-25% reduction in LDL Increases HDL, decreases LDL – Proposed mechanism Inhibits lipolysis in adipose tissue and esterification of TG in liver. Reduces VLDL synthesis in liver so the LDL levels decreases. Increases LPL activity – Side effects: flushing, itching, GI distress, hyperglycemia, hyperuricemia, hepatotoxicity 10  Pantothenic acid (B5) is a building block of CoA Functions in the transfer of acyl groups. CoA contains a thiol group that carries acyl compounds as activated thiol esters. – Succinyl CoA – Fatty acyl CoA – Acetyl CoA – Component of the acyl carrier protein of fatty acid synthase. Deficiency is rarely observed in humans. 11  Pyridoxine (vitB6) plays key role in amino acid metabolism Many enzymes of amino acid metabolism contain PLP as a tightly bound prosthetic group. – Transamination (ALT, AST) – Decarboxylation (Dopa decarboxylase) – Condensation (ALAS) Serious deficiency is rare. Vit B6 deficiency is most common in alcoholics. Isoniazid (TB) treatment can interfere absorption 12  Pyridoxine (vitB6) Clinical manifestations: – characterized by peripheral neuropathy, stomatitis, glossitis (swollen tongue), irritability, psychiatric symptoms, epileptic seizures. (because glutamate decarboxylase, in GABA synthesis, is PLP-dependent enzyme. – Sideroblastic anemia (microcytic, hypochromic anemia) due to decreased activity of ALA synthase 13  Biotin (B7) is a coenzyme in carboxylation reactions Biotin is prosthetic group of 14  Biotin (B7) Deficiency Egg white contains the protein avidin, binds biotin tightly preventing its absorption. Symptoms of biotin deficiency: – dermatitis, alopecia, glossitis, loss of appetite, nausea. Biotinidase cleaves biotin-lysine conjugate biocytin Biotinidase deficiency causes nondietary biotin deficiency. – biotinidase deficiency is often included in newborn screening. 15  Folic Acid (B9) Tetrahydrofolate (coenzyme for one-carbon transfer) - Thymidylate synthase (pyrimidine metabolism) - Enzymes in purine synthesis Deficiency - Folate pool quickly depleted in alcoholics and during pregnancy - Deficiency during pregnancy may cause neural tube defect Clinical Manifestations: - Megaloblastic anemia, thrombocytopenia, hyper segmented neutrophils - Hyperhomocysteinemia with risk of deep vein thrombosis and atherosclerosis 16 Folic acid deficiency causes megaloblastic anemia 17  Folate metabolism is target for chemotherapeutic drugs and antibacterial drugs Folate analog methotrexate inhibits DHFR thus, depletes functional (active) folate (FH4) pool Trimethoprim is an inhibitor of bacterial but not human dihydrofolate reductase. Sulfonamides inhibits the synthesis of pteroic acid in bacteria, inhibits FH4 formation in bacteria. Therefore, inhibits the bacterial growth. 18  Vitamin B12 requires intrinsic factor for its absorption Most cases of vit B12 deficiency is not caused by dietary deficiencies but by malabsorption. Pernicious anemia shows two types of abnormalities: – Megaloblastic anemia (methyl folate trap hypothesis) – Neurological dysfunction with demyelination (because SAM is required for choline (phosphatidyl choline) biosynthesis, B12 deficiency causes neurologic symptoms) B12 deficiency can cause hyperhomocysteinemia 19 An elderly female was hospitalized due to a recent, severe weight loss. Her tongue was red and fissured, and she was slightly jaundiced. She complained of chronic fatigue and shortness of breath upon exertion. Physician noted that some neurological symptoms such as decreased sensation in fingers and toes. Blood test results revealed: folate, 10.1 ng/mL (normal); bilirubin, 2.5 mg/dL (high); AST, 35 U/mL (normal); ALT, 30 U/mL (normal). Image shows her blood smear. What is a likely cause of this patient’s symptoms? A. Deficiency of vitamin B6 B. Deficiency of vitamin B12 C. Cholestasis (blockage of the bile duct) D. Overproduction of intrinsic factor E. Homocystinuria 20 An elderly female was hospitalized due to a recent, severe weight loss. Her tongue was red and fissured, and she was slightly jaundiced. She complained of chronic fatigue and shortness of breath upon exertion. Physician noted that some neurological symptoms such as decreased sensation in fingers and toes. Blood test results revealed: folate, 10.1 ng/mL (normal); bilirubin, 2.5 mg/dL (high); AST, 35 U/mL (normal);ALT, 30 U/mL (normal). Image shows her blood smear. What is a likely cause of this patient’s symptoms? A. Deficiency of vitamin B6 (microcytic anemia) B. Deficiency of vitamin B12 C. Cholestasis (blockage of the bile duct) D. Overproduction of intrinsic factor vitamin B12 deficiency leads to E. Homocystinuria progressive peripheral neuropathy, methylmalonic aciduria pernicious anemia and neurologic deterioration Hyperhomocysteinemia/homocystinuria 21 Glossitis (inflammation of tongue): appearance of tongue such as color and texture changes. Thiamine (B1) deficiency can cause glossitis Riboflavin (B2) deficiency leads to poor growth, corneal neovascularization, cheilosis (inflammation and cracking of the corners of the mouth), glossitis of the tongue, sore throat, skin inflammation, photophobia, and anemia. Magenta-colored tongue. Niacin (B3) deficiency can cause glossitis. Pellagra – dermatitis Pyridoxine (B6) deficiency can cause glossitis. Microcytic anemia Folate (B9) deficiency can cause glossitis. Megaloblastic anemia, thrombocytopenia, hyper- segmented neutrophils 22  Vitamin C is water soluble antioxidant Ascorbic acid is a reducing agent and a scavenger of free radicals. Vit C is required for maintenance of normal connective tissue, as well as for wound healing. Vit C also facilitates absorption of iron from the intestine. Many iron and copper-containing enzymes require vit C to keep their metal in the reduced state. – Hydroxylation of prolyl and lysyl residues in procollagen – Carnitine synthesis requires two Fe+2 containing vit C dependent oxygenases. – Dopamine synthesis requires vit C dependent copper enzyme dopamine β-hydroxylase. – Bile acid synthesis is regulated by vit C-dependent enzyme 7 α-hydroxylase. 23  Deficiency of Vitamin C Deficiency causes scurvy, develops ~ 2-3 months after vitC-free diet. – Dry mouth and eyes, decaying peeling gums, loose teeth, delayed wound healing, ecchymosis, petechia, weakness and lethargy. – Many symptoms due to deficiency in the hydroxylation of collagen, resulting defective connective tissue. Consumption of diets rich in antioxidants (vitC, vitE, and vitA) is associated with decreased incidence of some chronic diseases such as coronary heart diseases and certain cancers. 24 A 14-month-old girl is brought to her physician because she seems to be in pain when she tries to move. Physical examination shows the infant exhibits a reluctance to move her arms and legs. She has bowing of her legs, a depression of the sternum with outward projection of the ends of the ribs, numerous bruises on her legs, and gingival hemorrhages. Which of the following vitamin deficiencies is most likely in this patient? A. Ascorbate B. Riboflavin C. Thiamine D. Vitamin A E. Vitamin B12 F. Vitamin D G. Vitamin K 25 A 14-month-old girl is brought to her physician because she seems to be in pain when she tries to move. Physical examination shows the infant exhibits a reluctance to move her arms and legs. She has bowing of her legs, a depression of the sternum with outward projection of the ends of the ribs, numerous bruises on her legs, and gingival hemorrhages. Which of the following vitamin deficiencies is most likely in this patient? A. Ascorbate B. Riboflavin C. Thiamine D. Vitamin A E. Vitamin B12 Deficiencies of vitamin C and D can produce similar F. Vitamin D skeletal abnormalities. However, vitamin C G. Vitamin K deficiency is accompanied by hemorrhages, which leads to hemarthrosis (bleeding into joints) that makes movement very painful. 26