Vitamins : are –chemically unrelated organic compounds –cannot be synthesized by humans –must be supplied by the diet. water-soluble Vitamins; –folic acid - cobalamin (B12) –ascorbic acid (C) - pyridoxine (B6) –Thiamine (B1) - niacin (B3) –Riboflavin (B2) - biotin –pantothenic acid Many of the water-soluble vitamins are precursors of coenzymes for the enzymes of intermediary metabolism.
FOLIC ACID (Folate) Plays a key role in one-carbon metabolism. Essential for the biosynthesis of AA, purines, thymine...etc. Folic acid deficiency is the most common vitamin deficiency in the United States, particularly among pregnant women and alcoholics. Serine, glycine, and histidine one-carbon fragments to Tetrahydrofolate transfers them to intermediates in the synthesis of amino acids, purines, and thymine - a pyrimidine found in DNA. Function of Folic acid
Nutritional anemias Low blood [Hb] O 2 transport Anemia a)Microcytic anemia (MCV<80 m 3 ): caused by lack of iron the most common form of nutritional anemia. b) Macrocytic anemias (MCV>100 m 3 ): due to folic acid or vit B12 def. called megaloblastic because folic acid or vit B12 def. accumulation of large, immature red cell precursors (megaloblasts) in the bone marrow. Nutritional anemias : classified according to RBC size or MCV.
Folate and anemia: –The causes of the megaloblastic anemia should be evaluated prior to instituting therapy because vitamin B 12 deficiency indirectly causes this disorder. Causes of serum folate levels folate levels increased demand: Pregnancy Pregnancy Lactation Lactation poor absorption: pathology of gut pathology of gut Alcoholism Alcoholism ttt with : Methotrexate ttt with : Methotrexate (DHF reductase inhibitor) (DHF reductase inhibitor) folate-free diet Results of folic acid deficiency megaloblastic anemia due to synthesis of purines and thymidine DNA synthesis and cell division.
Folate and neural tube defects in the fetus: Spina bifida and anencephaly, the most common neural tube defects. affect ~ 4000 pregnancies in USA / year. Folic acid supplementation before conception and during the first trimester ( 0.4 mg/day) the risk of neural tube defects in the fetus. The U.S. FDA has authorized the addition of folic acid to enriched grain products, ( about 0.1 mg day). This supplementation will allow ~ 50% of all reproductive- aged women to receive 0.4 mg of folate from all sources. Folic acid intake should not exceed ~ 1 mg/day to avoid misdiagnosis of vit B 12 deficiency.
COBALAMIN (VITAMIN B12) COBALAMIN (VITAMIN B12) Required in humans for 2 essential enzymatic reactions: Required in humans for 2 essential enzymatic reactions: A) Methionine synthesis B) isomerization of methylmalonyl CoA (produced during the degradation of some AA, and fatty acids with odd numbers of carbon atoms) Deficiency of B12 accumulation of abnormal fatty acids incorporated into cell membranes, including nervous system neurologic manifestations.
A. Structure of cobalamin and its coenzyme forms cyanide is replaced by CH3 group cyanide is replaced with 5-deoxyadenosine Cobalt is held in the center of the corrin ring by four coordination bonds from the nitrogens of the pyrrole groups differs from the porphyrins in that two of the pyrrole rings are linked directly rather than through a CH3 bridge Coordination bonds bonds
Distribution of vit B12 : Vitamin B12 is synthesized only by microorganisms. It is not present in plants. Animals obtain the vitamin preformed from: – their natural bacterial flora. – by eating foods derived from other animals. liver liver whole milk whole milk eggs eggs oysters oysters fresh shrimp fresh shrimp chicken chicken B12 is present in:
Folate trap hypothesis : need both N 5 -N 10 -methylene & N 10 - formyl forms of THF for nucleotides synthesis required for DNA replication. the erythropoietic tissue of bone marrow the erythropoietic tissue of bone marrow the mucosal cells of the intestine the mucosal cells of the intestine B12 deficiency affects: B 12 deficiency is hypothesized to deficiency of the THF forms needed in purine and thymine synthesis, megaloblastic anemia. B 12 deficiency is hypothesized to deficiency of the THF forms needed in purine and thymine synthesis, megaloblastic anemia. Methylated form of THF cannot be converted directly to other forms accumulation of he N 5 -methyl form & of other forms. Methylated form of THF cannot be converted directly to other forms accumulation of he N 5 -methyl form & of other forms. In B 12 deficiency, the N 3 -methyl form of tetrahydrofolate is not efficiently used.In B 12 deficiency, the N 3 -methyl form of tetrahydrofolate is not efficiently used.
Clinical indications for vitamin B12 Unlike other water-sol Vitamins, significant amounts of vitamin B12 (4 - 5 mg) are stored in the body. SO, SO, Development of clinical symptoms of B12 deficiency take several years in individuals with partial or total gastrectomy (intrinsic factor-deficient with loss of B12 absorption).
Pernicious anemia: Vitamin B12 deficiency is rarely due to dietary insufficiency. Vitamin B12 deficiency is rarely due to dietary insufficiency. Deficiencies are more common in patients with intestinal malabsorption of the vitamin pernicious anemia. Deficiencies are more common in patients with intestinal malabsorption of the vitamin pernicious anemia. Autoimmune destruction of the gastric parietal cells synthesis of the intrinsic factor (Glycoprotein). Autoimmune destruction of the gastric parietal cells synthesis of the intrinsic factor (Glycoprotein). Normally, dietary vitamin B12 binds to intrinsic factor in the intestine cobalamin - intrinsic factor complex travels through the gut binds to specific receptors on the surface of mucosal cells of the ileum transported into the mucosal cell general circulation carried by B12-binding proteins. Normally, dietary vitamin B12 binds to intrinsic factor in the intestine cobalamin - intrinsic factor complex travels through the gut binds to specific receptors on the surface of mucosal cells of the ileum transported into the mucosal cell general circulation carried by B12-binding proteins.
–Lack of intrinsic factor prevents vitamin B12 absorption pernicious anemia. –Neuropsychiatric symptoms develops later. –CNS symptoms may occur in the absence of anemia. –The CNS effects are irreversible. –by giving high-dose B12 orally, or cyanocobalamin IM. – Therapy must be continued throughout the lives of patients with pernicious anemia. Treatment Treatment Folic acid administration alone reverses the hematologic abnormality masks the B12 deficiency severe neurologic dysfunction and pathology; therefore, megaloblastic anemia should be treated with a combination of folate and vitamin B12
ASCORBIC ACID (VITAMIN C) The active form of vitamin C is ascorbic acid. The main function is as a reducing agent in several different reactions. Vitamin C has an essential role as a coenzyme in hydroxylation reactions, e.g, hydroxylation of prolyl- and lysyl-residues of collagen. Vitamin C is required for: –maintenance of normal connective tissue –wound healing –facilitates the absorption of dietary iron from the intestine.
Deficiency of ascorbic acid: Deficiency of ascorbic acid deficiency in the hydroxylation of collagen defective connective tissue scurvy. sore sore spongy gums spongy gums loose teeth loose teeth fragile blood vessels fragile blood vessels swollen joints swollen joints anemia anemia Scurvy
Prevention of chronic disease: Vitamin C, vitamin E and -carotene are known as antioxidants. Consumption of food or supplements rich in these compounds Coronary heart disease and certain cancers. Supplementation with the isolated antioxidants have low beneficial effects.
PYRIDOXINE (VITAMIN B6) They differ only in the nature of the functional group attached to the ring They differ only in the nature of the functional group attached to the ring primarily in plants in animal foods All three compounds can serve as precursors of the biologically active coenzyme, pyridoxal phosphate. Pyridoxine Pyridoxine pyridoxal pyridoxal pyridoxamine, pyridoxamine, Derivatives of pyridine. of pyridine. Pyridoxal phosphate functions as a coenzyme catalyze reactions involving amino acids
Example Reaction type Oxaloacetate + glutamate aspartate + α-ketoglutarate Transamination Serine pyruvate + NH3 Deamination Histidine histamine + CO2 Decarboxylation Glycine + succinyl CoA δ- aminolevulinic acid Condensation
Clinical indications for pyridoxine: Isoniazid (isonicotinic acid hydrazide), [a drug frequently used to treat TB] B6 deficiency by forming an inactive derivative with pyridoxal phosphate. Dietary supplementation with B6 is important with isoniazide treatment. Dietary deficiencies in pyridoxine are rare but observed in: –newborn infants fed formulas low in vitamin B6 –women taking oral contraceptives –alcoholics. Toxicity of pyridoxine: intakes of greater than 2 g/day intakes of greater than 2 g/day Neurologic symptoms Substantial improvement, but not complete recovery, occurs when the vitamin is discontinued
Thiamine pyrophosphate (TPP) is: the biologically active form of the vitamin, formed by the transfer of a pyrophosphate group from ATP to thiamine THIAMINE (VITAMIN B1) THIAMINE (VITAMIN B1) PP from ATP
Thiamine pyrophosphate (TPP) serves as a coenzyme in : the oxidative decarboxylation of pyruvate and α -keto acids of pyruvate and α -keto acids Important for CNS the formation or degradation of α-ketols by transketolase α-ketols by transketolase Clinical indications for thiamine: Thiamine deficiency: activity of dehydrogenase reactions ATP impaired cellular function. activity of dehydrogenase reactions ATP impaired cellular function. Thiamine deficiency is diagnosed by: erythrocyte transketolase activity observed on addition of TPP.
Beri beri: –Severe thiamine-deficiency syndrome. –Found in areas where polished rice is the major component of the diet. –Rapid onset in nursing infants whose mothers are deficient in thiamine. – tachycardia – vomiting – convulsions – death (if untreated) - dry skin - irritability - disorderly thinking - progressive paralysis Adult beriberi infantile beriberi
Wernicke-Korsakoff syndrome: Wernicke-Korsakoff syndrome: –In the United States, thiamine deficiency, which is seen primarily with chronic alcoholism, is due to: dietary insufficiency. dietary insufficiency. impaired intestinal absorption of the vitamin. impaired intestinal absorption of the vitamin. Some alcoholics Wernicke - Korsakoff syndrome - apathy, - loss of memory - rhythmical to-and-fro motion of the eyeballs
NIACIN Niacin, or nicotinic acid, is a substituted pyridine derivative The biologically active coenzyme forms are: 1. nicotinamide adenine dinucleotide (NAD) and its phosphorylated derivative, 2. nicotinamide adenine dinucleotide phosphate (NADP) Nicotinamide, a derivative of nicotinic acid that contains an amide instead of a carboxyl group, deaminated in the bodySo it is nutritionally equivalent to nicotinic acid. Nicotinamide, a derivative of nicotinic acid that contains an amide instead of a carboxyl group, deaminated in the body So it is nutritionally equivalent to nicotinic acid.
NAD + and NADP + serve as coenzymes in oxidation-reduction reactions in which the coenzyme undergoes reduction of the pyridine ring by accepting a hydride ion (hydrogen atom plus one electron) NAD + and NADP + serve as coenzymes in oxidation-reduction reactions in which the coenzyme undergoes reduction of the pyridine ring by accepting a hydride ion (hydrogen atom plus one electron) The reduced forms: NAD + NADH NAD + NADH NADP + NADPH
A. Distribution of niacin A. Distribution of niacin unrefined and enriched grains and cereals unrefined and enriched grains and cereals milk milk lean meats especially liver. lean meats especially liver. Sources Limited quantities of niacin can also be obtained from metabolism of tryptophan. 60 mg tryptophan 1 mg nicotinic acid tryptophan is metabolized to niacin only when there is a relative abundance of the amino acid
B. Clinical indications for niacin : B. Clinical indications for niacin : Deficiency of niacin Pellagra Dermatitis Diarrhea Dementia Death if untreated
Treatment of hyperlipidemia: Niacin is particularly useful in the treatment of type lIb hyperlipoproteinemia (in which VLDL & LDL ). inhibits lipolysis in adipose tissue inhibits lipolysis in adipose tissue ( the primary producer of circulating free fatty acids). Niacin (at doses of 1.5 g /day or 100 times the RDA) triacylglycerol synthesis in liver triacylglycerol synthesis in liver VLDL and LDL VLDL and LDL
RIBOFLAVIN (VITAMIN B2) RIBOFLAVIN (VITAMIN B2) FMN & FAD are: the 2 biologically active forms. formed by transfer of AMP from ATP FMN. capable of reversibly accepting 2 H atoms FMNH2 or FADH2 bound tightly - sometimes covalently - to flavoenzymes that catalyze the oxidation or reduction of a substrate. FMN & FAD are: the 2 biologically active forms. formed by transfer of AMP from ATP FMN. capable of reversibly accepting 2 H atoms FMNH2 or FADH2 bound tightly - sometimes covalently - to flavoenzymes that catalyze the oxidation or reduction of a substrate. (FMN) (FAD) dermatitis (fissuring at the corners of the mouth), cheilosis (fissuring at the corners of the mouth), (the tongue appearing smooth & purplish). glossitis (the tongue appearing smooth & purplish). Deficienc y
BIOTIN A coenzyme in carboxylation reactions, ( serves as a carrier of activated CO2 ). Covalently bound to the -amino groups of lysine residues of biotin- dependent enzymes. Required by all organisms. Can only be synthesized by: bacteria, yeasts, molds, algae, and some plant species.
Each Carboxylase catalyzes an essential metabolic reaction: Each Carboxylase catalyzes an essential metabolic reaction: Acetyl-CoA carboxylase: catalyzes the binding of HCO3 - to acetyl- CoA to form malonyl-CoA required for the synthesis of fatty acids. Pyruvate carboxylase: in gluconeogenesis formation of glucose from amino acids and fats. in gluconeogenesis formation of glucose from amino acids and fats. Methylorotonyl-CoA carboxylase: in the metabolism of leucine, an essential amino acid. in the metabolism of leucine, an essential amino acid. Propionyl-CoA carboxylase: in the metabolism of amino acids, cholesterol, and odd chain fatty acids (fatty acids with an odd number of carbon molecules)
very rare. does not occur naturally. the vitamin is widely distributed in food. in humans, big percentage is supplied by intestinal bacteria. Biotin deficiency Human requirement for dietary biotin in: for dietary biotin in: prolonged IV feeding without biotin supplementation.prolonged IV feeding without biotin supplementation. consumption of raw egg white for a prolonged period.consumption of raw egg white for a prolonged period.
Raw egg white contains a glycoprotein, avidin tightly binds biotin prevents its absorption from the intestine. Cooking egg white denatures avidin renders it digestable unable to prevent the absorption of dietary biotin. Addition of raw egg-white to the diet as a source of protein symptoms of biotin deficiency depression depression lethargy lethargy hallucination hallucination numbness numbness tingling of extremities. tingling of extremities. dermatitis dermatitis glossitis glossitis loss of appetite loss of appetite loss of hair loss of hair nausea nausea scaly red rash around the eyes, nose, mouth, and genital area. scaly red rash around the eyes, nose, mouth, and genital area. Neurologicsymptoms in adults in adults
With a normal diet, 20 raw eggs / day would be required to induce a deficiency syndrome. The Adequate Intake (AI): average intakes of biotin (35 mcg to 60 mcg/day) are meeting the dietary requirement. Biotin is incorporated into almost all nutritionally complete dietary supplements and infant formulas. In larger doses, biotin is used to treat inborn errors of metabolism such as biotinidase deficiency. Uses:
PANTOTHENIC ACID A component of coenzyme A, which functions in the transfer of acyl groups Coenzyme A contains a thiol group that carries acyl compounds as activated thiol esters. such structures are succinyl CoA, fatty acyl C0A, and acetyl CoA. Pantothenic acid is also a component of fatty acid synthase. Sources: Eggs Eggs Liver Liver Yeast Yeast Deficiency Is not well characterized Is not well characterized in humans, in humans, No RDA is established. No RDA is established.