7 vitamins and cofactors

1. Principle of Biochemistry 7-Vitamins and Cofactors Course code: HFB324 Credit hours: 3 hours Dr. Siham Gritly 1 Dr. Siham Gritly

2. Lecture content Vitamins: Definition, classification, requirements and chemical properties. Importance of vitamins to biological processes of the living body. vitamins deficiencies. Dr. Siham Gritly 2

3. Vitamin (water soluble vitamin, fat soluble vitamin): an organic substance needed in small amounts for normal body functions that the body cannot synthesize in adequate amounts enzyme: a protein that is a catalyst cofactor: a small, inorganic or organic substance that facilitates enzyme action; includes both organic coenzymes made from vitamins and inorganic substances such as minerals Coenzymes are non-protein organic molecules that are mostly derivatives of vitamins soluble in water by phosphorylation ; they bind apoenzyme to proteins to produce an active holoenzyme Dr. Siham Gritly 3

4. prosthetic group: a cofactor permanently associated with the protein, often covalently bound holoenzyme : catalytically active enzyme-cofactor complex. apoenzyme : an enzyme without its cofactor enzymatically inactive protein FADH 2 flavin adenine dinucleotide (reduced form); a molecule, central to metabolism, which carries a pair of electrons only slightly less energetic than those of NADH NADH nicotinamide adenine dinucleotide (reduced form); a molecule, central to metabolism, which carries a pair of high-energy electrons Dr. Siham Gritly 4

5. free radicals: unstable and highly reactive atoms or molecules that have one or more unpaired electrons in the outer orbital 1,25-dihydroxyvitamin D: vitamin D that is made from the hydroxylation of calcidiol in the kidneys ; the biologically active hormone; also called calcitriol or active vitamin D . 25-hydroxyvitamin D: vitamin D found in the blood that is made from the hydroxylation of cholecalciferol in the liver; also called calcidiol acetyl CoA ; a 2-carbon compound ( acetate, or acetic acid) to which a molecule of CoA is attached. Dr. Siham Gritly 5

6. antioxidant: a substance that signifi cantly decreases the adverse effects of free radicals on normal physiological functions Dr. Siham Gritly 6

7. Vitamins Vitamins are organic molecules needed for variety of biological function within the body. The most important function of the vitamins is to serve as cofactors (co-enzymes) for enzymatic reactions. protein + coenzyme (vitamin)= enzyme protein + cofactor (metal ion)= enzyme the vitamins cannot be synthesized by mammalian cells and, therefore, must be supplied in the diet in small quantities (microgram or milligram per day). Dr. Siham Gritly 7

8. Coenzyme and vitamins Most of the B vitamins are coenzymes and are essential in facilitating the transfer of atoms or groups of atoms between molecules in the formation of carbohydrates, fats, and proteins coenzymes: complex organic molecules that work with enzymes to facilitate the enzymes’ activity . Many coenzymes have B vitamins as part of their structures. coenzymes is to act as transporters of chemical groups from one reactant to another. Examples include; - nicotinamide adenine dinucleotide (NAD), which accepts hydrogen (and gives it up in another reaction), -ATP, which gives up phosphate groups while transferring chemical energy Dr. Siham Gritly 8

9. The vitamins are of two distinct types, water soluble and fat soluble . Water Soluble Vitamins Fat Soluble Vitamins Thiamin (B 1 ) Riboflavin (B 2 ) Niacin (B 3 ) Pantothenic Acid (B 5 ) Pyridoxal , Pyridoxamine , Pyridoxine (B 6 ) Biotin Cobalamin (B 12 ) Folic Acid Ascorbic Acid Vitamin A Vitamin D Vitamin E Vitamin K Dr. Siham Gritly 9

10. Water soluble vitamins - soluble in water, consist of carbon, hydrogen, oxygen nitrogen, sulfur, cobalt, -deficiency usually occur more than fat soluble vitamins -Water-soluble vitamins that body cannot store Dr. Siham Gritly 10

11. -enter in energy production and in essential enzyme system. They help with release of energy from carbohydrates, proteins, and fats -activate chemical reaction inside the body and act as coenzymes -excretion in urine through urination -the most important water soluble vitamins are B complex and vitamin C Dr. Siham Gritly 11

12. Thiamine or vitamin B 1 thiamine- sulfur containing water soluble vitamin of B complex, exist in tissues in the active form of Thiamine Pyrophosphate (TPP) - Thiamine Pyrophosphate (TPP) is essential co-enzyme involve in energy extraction and cellular process in catabolism of sugar and amino acid -human and other animal obtain it through diet Dr. Siham Gritly 12

13. The majority of thiamine in serum is bound to proteins, mainly albumin. Approximately 90% of total thiamine in blood is in erythrocytes (red blood cell). Dr. Siham Gritly 13

14. Thiamin chemical structure Thiamin is derived from a substituted amino pyrimidine ring and a thiazole ring with methyl and hydroxyethyl side chains linked by a methylene bridge . C 12 H 17 N 4 OS Dr. Siham Gritly 14

15. Thiamin pyrophosphate the active form of vitamin B 1 A thiazole ring is found naturally in thiamin Thiazole is a heterocyclic compound featuring both a nitrogen atom and sulfur atom as part of the aromatic five- membered ring. a thiazole ring stabilizes charge and electron transfer Dr. Siham Gritly 15

16. Thiamin is rapidly converted to its active form, thiamin pyrophosphate , TPP, in the brain and liver by a specific enzyme;- thiamin diphosphotransferase . TPP is necessary as a cofactor for the;- 1- pyruvate dehydrogenase ( PDH) and 2-α-ketoglutarate dehydrogenase catalyzed reactions associated with the TCA cycle 3-transketolase catalyzed reactions of the pentose phosphate pathway Dr. Siham Gritly 16

17. Thiamin functions -the main function of thiamine is its role in metabolic reaction acting as co-enzyme for energy and carbohydrate metabolism -its deficiency in tissues affect energy metabolism and thus affect nerve and cardiac functions Dr. Siham Gritly 17

18. TPP is necessary as a cofactor for the important enzyme pyruvate dehydrogenase (PDH), α- ketoglutarate dehydrogenase and transketolase 1-Pyruvate dehydrogenase is the key enzyme in CHO metabolism to complete oxidation (via the TCA cycle) TPP participate in catalyzing oxidative decarboxylation of pyruvate , to form acetyl- CoA in citric acid cycle, where a carboxyl group is removed from a compound and released as CO2. Dr. Siham Gritly 18

19. An example is the conversion of pyruvate to acetyl- CoA , which is irreversible, during CHO metabolism Oxidative decarboxylation reactions are oxidation reactions in which a carboxylic group is removed, forming CO 2 Dr. Siham Gritly 19

20. 2-α-ketoglutarate dehydrogenase -thiamine involved in decarboxylation of alph ketoglutrate to succinate in krebs cycle by the emzyme α- ketoglutarate dehydrogenase -deficiency of thiamine lead to accumulation of pyruvate in the blood thus affect peripheral nervous system and heart Dr. Siham Gritly 20

21. 3- transketolase; catalyzed reactions of the pentose phosphate pathway oxidative phase, NADPH is generated when glucose 6-phosphate is oxidized to ribose 5-phosphate. Dr. Siham Gritly 21

22. deficiency of thiamin -two different diseases may result as deficiency of thiamin 1-Beri Beri (wet and dry beri beri ) Usually beri beri diseases result due to long term deficiency and high intake of carbohydrates - Korsakoff syndrome (psychosis) Dr. Siham Gritly 22

23. Wernicke-Korsakoff syndrome ; This disease is most commonly found in chronic alcoholics due to their poor dietetic lifestyles. Wernicke-Korsakoff syndrome is characterized by acute encephalopathy ( brain dysfunction) followed by chronic impairment of short-term memory - Wet beriberi is associated with mental confusion, muscular atrophy, edema, tachycardia, caridomegaly and congestive heart failure in addition to peripheral neuropathy ( is damage to nerves of the peripheral nervous system - Dry beriberi is c haracterized principally by peripheral neuropathy. Muscle become waste and week, difficult walking, patient become bedridden and may die. Dr. Siham Gritly 23

24. Riboflavin, vitamin B 2 Active form of riboflavin is Riboflavin Phosphate It is the central component of the cofactor FAD and FMN, and therefore required for energy metabolism vitamin B 2 is required for a wide variety of cellular processes transferring oxygen from plasma to the tissues. It plays a key role in energy metabolism, and for the metabolism of fats, ketone bodies, carbohydrates and proteins. Dr. Siham Gritly 24

25. Vitamin B2, or riboflavin is an intermediary the transfer of electrons in the cellular oxidation-reduction reactions which generate energy from protein, carbohydrate and fat. The riboflavin coenzymes are also important for the transformation of vitamin B6 and folic acid into their respective active forms, and for the conversion of tryptophan into niacin. Dr. Siham Gritly 25

26. Riboflavin structure Dr. Siham Gritly 26

27. Structure of FAD Riboflavin is the precursor for the coenzymes, flavin mononucleotide (FMN) and flavin adenine dinucleotide (FAD), used to oxidized substrates. FAD contains riboflavin and adenine. Dr. Siham Gritly 27

28. The enzymes that require FMN or FAD as cofactors are termed flavoproteins . During the enzymatic reactions involving the flavoproteins the reduced forms of FMN and FAD are formed, FMNH 2 and FADH 2 , respectively. The hydrogens of FADH 2 are on nitrogen 1 and 5 Dr. Siham Gritly 28

29. Synthesis of these two cofactors occurs in a two step process. 1- FMN is synthesized from riboflavin via the ATP-dependent enzyme riboflavin kinase (RFK). RFK introduces a phosphate group onto the terminal hydroxyl of riboflavin. Dr. Siham Gritly 29

30. 2-FMN is then converted to FAD via the attachment of AMP (derived from ATP) though the action of FAD pyrophosphorylase Dr. Siham Gritly 30

31. Deficiency of riboflavin In humans, signs and symptoms of riboflavin deficiency -include cracked and red lips, inflammation of the lining of mouth and tongue, mouth ulcers, cracks at the corners of the mouth (Angular cheilitis ), and a sore throat. -A deficiency may also cause dry and scaling skin, fluid in the mucous membranes, and iron-deficiency anemia. The eyes may also become bloodshot, itchy, watery and sensitive to bright light. Dr. Siham Gritly 31

32. Riboflavin Deficiency Dr. Siham Gritly 32 Riboflavin Deficiency ( Glossitis Riboflavin Deficiency ( Cheilosis )

33. Niacin Vitamin B 3 nicotinic acid, nicotinamide , niacinamide Niacin (nicotinic acid and nicotinamide ) is also known as vitamin B 3 . Both nicotinic acid and nicotinamide can serve as the dietary source of vitamin B 3 . Niacin is required for the synthesis of the active forms of vitamin B 3 , nicotinamide adenine dinucleotide (NAD + ) and nicotinamide adenine dinucleotide phosphate (NADP + ). Dr. Siham Gritly 33

34. Nicotinic acid formula C 5 H 4 NCO 2 H Dr. Siham Gritly 34

35. Dr. Siham Gritly 35

36. NADH, NAD + , NADP + and NADPH which are coenzymes found in all living cells. NAD + and NADP + are oxidizing agents.(loss of electron) NADH and NADPH are reducing agents.(gain of electron) Dr. Siham Gritly 36

37. Important co-enzymes Niacin is the main components of important two Co- enzymes 1-nicotin-amide Dinucleotide (NAD) 2-nicotin-amide Adenin Dinucleotide Act as co-enzyme for reactions involved dehydrogenase enzymes Main function act as electron transport and hydrogen carrier involved in fats, carbohydrates and protein metabolism Dr. Siham Gritly 37

38. nicotinamide adenine dinucleotide (NAD + ) NAD+ is capable of carrying and transferring electrons and functions as oxidizing agent in redox reactions Dr. Siham Gritly 38

39. Oxidoreduction : Pyridine nucleotide coenzymes (NAD+/NADP+) (Vitamin B3, Niacin) NAD+/NADH; NADP+/NADPH Dr. Siham Gritly 39

40. Niacin functions Role of NAD + in oxidation-reduction reactions 1-reaction of transport hydrogen atom from one part to another, occur in mitochondria and cytoplasm of the cells –oxidative reactions of NAD------NADH * glycolysis ------- glyceraldehyde 3P to 1,3 diphosphglycerate *oxidative decarboxylation of pyruvate to lactate Dr. Siham Gritly 40

41. oxydation of acetyl Co A in TCA cycle - malate to oxaloacetate -glutamate to α ketoglutrate * β oxidation of fatty acid 2-NAD---- dehydrogenase for catabolism of vitamin B6 pyridoxal to its excretory product ( pyridoxin acid) Dr. Siham Gritly 41

42. 3-NADPH (reduced form) involved in; Fatty acid synthesis Cholesterol synthesis Deoxy-ribonucleotide molecules (DNA) 4-NADPH --- convert folate to dihydrofolate (DHF) and synthesis of 5 methyl- tetrahydrofolate the active form of folic acid Dr. Siham Gritly 42

43. niacin deficiency Severe deficiency of niacin in the diet causes the disease pellagra characterized by three Ds; Diarrhea, loss of fluids Dermatitis , hyperpigmentation , thickening of the skin, inflammation of the mouth and tongue, digestive disturbances, Dementia, (mental symptoms) such as irritability, poor concentration, anxiety, fatigue, restlessness, apathy, and depression Could lead to death Dr. Siham Gritly 43

44. pellagra Dr. Siham Gritly 44

45. Pyridoxine vitamin B6 Pyridoxal , pyridoxamine Pyridoxine are collectively known as vitamin B 6 . The three forms equal vital activities in their active forms Dr. Siham Gritly 45

46. All three compounds are efficiently converted to the biologically active form of vitamin B 6 , pyridoxal phosphate (PLP). - pyridoxal phosphate -pyridoxine phosphate - pyridoxamine phosphate This conversion is catalyzed by the ATP requiring enzyme, pyridoxal kinase . Pyridoxal kinase requires zinc for full activity thus making it a metaloenzyme . Dr. Siham Gritly 46

47. Pyridoxine structure It is based on a pyridine ring, with hydroxyl, methyl, and hydroxymethyl Dr. Siham Gritly 47

48. Pyridoxal Dr. Siham Gritly 48

49. Pyridoxamine Dr. Siham Gritly 49

50. Pyridoxal phosphate; the active form of B6 Vitamin B6 is precursor to coenzyme pyridoxal phosphate (PLP) which is required in certain transformation of amino acids including transamination , deamination , and decarboxylation . Dr. Siham Gritly 50

51. Pyridoxal phosphate functions as a cofactor in enzymes involved in transamination reactions required for the synthesis and catabolism of the amino acids Act as co-enzyme needed in amino acid metabolism such as conversion of essential amino acid tryptophan to vitamin niacin Dr. Siham Gritly 51

52. Also it function in glycogenolysis as a cofactor for glycogen phosphorylase Vitamin B6 is involved in over 100 metabolic reactions in the body, including the production of energy and hemoglobin, a protein in red blood cells. Intakes below the DRI can hurt performance. Deficiencies of vitamin B 6 are rare and usually are related to an overall deficiency of all the B-complex vitamins Dr. Siham Gritly 52

53. Pantothenic acid Pantothenic acid is used in the synthesis of co-enzyme A ( CoA ). This coenzyme is formed when the vitamin combines with a derivative of ADP and the amino acid cysteine . Coenzyme A may act as an acyl group carrier to form acetyl- CoA and other related compounds; this is a way to transport carbon atoms within the cell. Dr. Siham Gritly 53

54. CoA is also important in the biosynthesis of many important compounds such as fatty acids, cholesterol. CoA is important in energy metabolism for pyruvate to enter the Kerbs cycle or tricarboxylic acid cycle (TCA cycle) as acetyl- CoA , and for α- ketoglutarate to be transformed to succinyl-CoA in the cycle. Dr. Siham Gritly 54

55. Co A A coenzyme is a small, organic, non-protein molecules that carries chemical groups between enzymes Dr. Siham Gritly 55

56. Acetyle co A Acetyl –contain methyl group bonded to carbonyl The carbonyl center of an acyl radical has one nonbonded electron with which it forms a chemical bond to the remainder R of the molecule. Dr. Siham Gritly 56

57. Deficiency of Pantothenic Acid deficiency of pantothenic acid in rats leads to elevated serum concentrations of triglycerides and non- esterified fatty acids, reflecting impaired β - oxidation. with B-oxidation would have an effect on fat use. Co-A is also necessary in CHO metabolism, as it is a part of acetyl- CoA Dr. Siham Gritly 57

58. Folic acid The folates are a group of heterocyclic compounds consisting of a pteridine ring structure linked to para-aminobenzoic acid (PABA) that forms pteroic acid. Pteridine is a group of organic compounds having two fused six-member rings each containing two nitrogen atoms and four carbon atoms. One of the rings is a pyrimidine , the other a pyrazine . Dr. Siham Gritly 58

59. Pyrazine , a group of organic compounds having a six-member ring in which the first and fourth atoms are nitrogen and the rest are carbon Dr. Siham Gritly 59 pyrimidine , and pyrazine

60. The chemical structures of folic acid consist of three ringed structures plus one or more molecules of the amino acid glutamate (or glutamic acid). The number of glutamate molecules affects the absorption and metabolism of folate or folic acid in the body. Dr. Siham Gritly 60

61. active form of folic acid is tetrahydrofolate Chemical structure of THF. The N5 and N10-nitrogen atoms that can carry one-carbon functional groups Dr. Siham Gritly 61

62. Folic acid structure positions 7 and 8 carry hydrogens in dihydrofolate (DHF) positions 5–8 carry hydrogens in tetrahydrofolate (THF) Dr. Siham Gritly 62

63. Folic acid is reduced within cells (principally the liver where it is stored) to tetrahydrofolate (THF also H 4 folate) through the action of dihydrofolate reductase (DHFR), an NADPH-requiring enzyme. When stored in the liver or ingested folic acid exists in a polyglutamate form Polyglutamate is the storage form of folic acid in the liver Dr. Siham Gritly 63

64. Deficiency causes megaloblastic anemia as for vitamin B 12 deficiency. The inability to synthesize DNA during erythrocyte maturation leads to abnormally large erythrocytes termed macrocytic anemia Folic acid is important in preventing neuraltube defects (NTDs) in the developing human fetus. Dr. Siham Gritly 64

65. Vitamin B12 cyanocobalamin Vitamin B 12 is the name for a class of related compounds that have the vitamin activity. These compounds contain the rare element cobalt . Humans can not synthesis B 12 and must obtain it from diet. Enzymes that catalyze certain rearrangement reaction required B 12 or its derivatives. Vitamin B12 is synthesized exclusively by microorganisms and is found in the liver of animals bound to protein as methycobalamin or 5'-deoxyadenosylcobalamin . Dr. Siham Gritly 65

66. The vitamin must be hydrolyzed from protein in order to be active. Hydrolysis occurs in the stomach by gastric acids or the intestines by trypsin digestion following consumption of animal meat. The vitamin is then bound by intrinsic factor, a protein secreted by parietal cells of the stomach, and carried to the ileum where it is absorbed. Following absorption the vitamin is transported to the liver in the blood bound to transcobalamin II. Dr. Siham Gritly 66

67. There are only two clinically significant reactions in the body that require vitamin B 12 as a cofactor. 1- During the catabolism of fatty acids with an odd number of carbon atoms and the amino acids valine , isoleucine and threonine the resultant propionyl-CoA is converted to succinyl-CoA for oxidation in the TCA cycle. One of the enzymes in this pathway, methylmalonyl-CoA mutase , requires vitamin B 12 as a cofactor in the conversion of methylmalonyl-CoA to succinyl-CoA . The 5'-deoxyadenosine derivative of cobalamin is required for this reaction. Dr. Siham Gritly 67

68. 2-The second reaction requiring vitamin B 12 catalyzes the conversion of homocysteine to methionine and is catalyzed by methionine synthase . This reaction results in the transfer of the methyl group from N 5 -methyltetrahydrofolate to hydroxycobalamin generating tetrahydrofolate (THF) and methylcobalamin during the process of the conversion Dr. Siham Gritly 68

69. Pyrrole is a heterocyclic aromatic organic compound , a five- membered ring with the formula C 4 H 4 N H Dr. Siham Gritly 69

70. Vitamin B 12 is composed of a complex tetrapyrrol ring structure ( corrin ring) and a cobalt ion in the center. Tetrapyrroles are compounds containing four pyrrole rings Dr. Siham Gritly 70

71. Dr. Siham Gritly 71

72. Deficiencies of B12 The liver can store up to six years vitamin B 12 , therefore deficiencies in this vitamin are rare. Pernicious anemia is a megaloblastic anemia resulting from vitamin B 12 deficiency that develops as a result a lack of intrinsic factor in the stomach leading to malabsorption of the vitamin. The anemia results from impaired DNA synthesis due to a block in purines and thymidine biothynthesis . Dr. Siham Gritly 72

73. Pernicious anemia : a blood disorder that reflects a vitamin B12 deficiency caused by lack of intrinsic factor and characterized by abnormally large and immature red blood cells. Other symptoms include muscle weakness and irreversible neurological damage Dr. Siham Gritly 73

74. Biotin Biotin, one of the water soluble B-vitamins, occurs in 8 different forms but only one of these, D-biotin, is found in nature and has full vitamin activity It is water soluble and important in the metabolism of fatty acids and the amino acid Leucine Biotin in its coenzyme form participates in numerous reactions involved in the metabolism of fat and CHO involved in carboxylation reactions, e.g. acetyl- CoA carboxylase and pyruvate carboxylase . Dr. Siham Gritly 74

75. participates in the entry of certain carbon skeletons from amino acids into the energy-yielding pathways, as well as in DNA synthesis. Dr. Siham Gritly 75

76. Biotin structure Dr. Siham Gritly 76

77. Biotin is found in numerous foods and also is synthesized by intestinal bacteria and as such deficiencies of the vitamin are rare. Deficiencies are generally seen only after long antibiotic therapies which deplete the intestinal fauna or following excessive consumption of raw eggs. The latter is due to the affinity of the egg white protein, avidin , for biotin preventing intestinal absorption of the biotin. Dr. Siham Gritly 77

78. Deficiency is rare, but can result in:Anorexia Nausea Vomiting Dermatitis Symptoms that may appear if biotin is deficient are extreme exhaustion, drowsiness, muscle pain, loss of appetite, depression, and grayish skin color. Some of the richest sources of biotin are tomatoes, romaine lettuce, and carrots. Additional sources include onions, cabbage, cucumber, cauliflower, mushrooms, peanuts, almonds, walnuts, oat meal, bananas, raspberries, strawberries, soy, egg yolk, and cow and goat milk. Dr. Siham Gritly 78

79. Vitamin C Ascorbic Acid Vitamin C is found in most plants and animals it is an essential in many biosynthetic pathways such as synthesizing collagen. Deficiency leads to a disease called Scurvy . Vitamin C helps regulate the immune system and relieve pain caused by tired muscles. It also is needed in the manufacture of collagen and norepinephrine . Vitamin C is also an antioxidant which can enhance the immune system by stimulating white blood cells in the body. Vitamin C also helps to benefit the skin, teeth, and bones. Dr. Siham Gritly 79

80. Ascorbic Acid structure Dr. Siham Gritly 80

81. Examples of Coenzymes and Vitamins reference; Cooper GM; The Central Role of Enzymes as BiologicalCatalysts The Cell: A Molecular Approach. 2nd edition Coenzyme Related vitamin Chemical reaction NAD + , NADP + Niacin Oxidation-reduction FAD Riboflavin (B 2 ) Oxidation-reduction Thiamine pyrophosphate Thiamine (B 1 ) Aldehyde group transfer Coenzyme A Pantothenate Acyl group transfer Tetrahydrofolate Folate Transfer of one-carbon groups Biotin Biotin Carboxylation Pyridoxal phosphate Pyridoxal (B 6 ) Transamination Dr. Siham Gritly 81

82. Fat soluble vitamins Dr. Siham Gritly 82 Fat soluble vitamins dissolve within the body’s fat cells and are usually found in fats and fatty foods. If they are not needed immediately, the body will store fat soluble vitamins for later use in the liver and fatty tissues fat soluble vitamins do not need to be consumed as frequently as water soluble vitamins to ensure proper functioning of the body’s cells .

83. Vitamin A Vitamin A consists of three biologically active molecules, 1-retinol, (hydroxyl) involved in vision 2- retinal ( aldehyde ) involved in vision 3-retinoic acid. (carboxyl) for cellular differentiation (regulate gene expression) Each of these compounds are derived from the plant precursor molecule, β-carotene (a member of a family of molecules known as carotenoids ). Dr. Siham Gritly 83

84. Beta-carotene, which consists of two molecules of retinal linked at their aldehyde ends, is also referred to as the provitamin form of vitamin A . Vitamin A is found in dark green and yellow vegetables and yellow fruits, such as broccoli, spinach, turnip greens, carrots, squash, sweet potatoes, pumpkin, cantaloupe, and apricots, and in animal sources such as liver, milk, butter, cheese, and whole eggs. Dr. Siham Gritly 84

85. Structure of vitamin A consist of a single6-membered ring to which is attached an 11-carbon side chain Dr. Siham Gritly 85 Beta-carotene consist of two molecules of retinal linked at their aldehyde ends

86. Absorption, transport and storage Ingested β-carotene is cleaved in the lumen of the intestine by β-carotene dioxygenase to yield retinal. Retinal is reduced to retinol by retinaldehyde reductase , an NADPH requiring enzyme within the intestines. Retinol is esterified to palmitic acid and delivered to the blood via chylomicrons . The uptake of chylomicron by the liver results in delivery of retinol to this organ for storage as a lipid ester within lipocytes (adipose tissues). Dr. Siham Gritly 86

87. Transport of retinol from the liver to extrahepatic tissues occurs by binding of hydrolyzed retinol to aporetinol binding protein (RBP). the retinol-RBP complex is then transported to the cell surface within the Golgi and secreted. Within extrahepatic tissues retinol is bound to cellular retinol binding protein (CRBP ). Plasma transport of retinoic acid is accomplished by binding to albumin Dr. Siham Gritly 87

88. Vitamin A functioning as vitamin and hormone retinol and retinoic acid with in the cell bind to specific receptor present in the nucleolus of tissues This receptor-vitamin complex interact with several genes that involved in growth and cell differentiation thus affect expression of genes cell differentiation is the process by which immature cells develop specific functions different from those of the original that are characteristic of their mature cell type . Dr. Siham Gritly 88

89. Vision and Vitamin A the process of vitamin A in vision known as Rhodopsin cycle or Ward’s visual cycle the Photoreception in the eye is the function of two specialized cell types located in the retina ; Rods Cones Both rod and cone cells located in the retina contain a photoreceptor pigment in their membranes and vitamin A is a component of these pigments Dr. Siham Gritly 89

90. the rod;- The opsin of rod cells is called Rhodopsin (visual purple) consist of 11-cis retinal bound to protein opsin ( vision in dim light ) Rhodopsin absorbs light, 11-cis retinal is converted to all trans retinal The isomerization act on the conformation change in the protein opsin This process lead to generate nerve impulse that transmitted to brain through the optic nerve Dr. Siham Gritly 90

91. This is followed by dissociation of the trans retinal from opsin The trans retinal is immediately isomerised by the enzyme isomerase to 11-cis retinal 11-cis retinal combines with opsin to regenerate rhodopsin and complete the vision cycle Dr. Siham Gritly 91

92. cone cells , contain colour pigments, * porphyropsin (red) * Iodopsin (green) * Cyanopsin (blue) The pigments are converted to trans retinal and the protein opsin is released The reaction stimulate the nerve impulse thus the brain red the colour Dr. Siham Gritly 92

93. cis -retinal, the hydrogens (light gray in the molecular model on the left) are on the same side of the double bond (yellow in the molecular model ). In the trans-retinal, the hydrogens are on opposite sides of the double bond. In fact, all of the double bonds are in the trans-configuration in this isomer: the hydrogens , or hydrogen and -CH3, are always on opposite sides of the double bonds Dr. Siham Gritly 93

94. Dr. Siham Gritly 94

95. Vitamin A Deficiency Vitamin A is stored in the liver and deficiency of the vitamin occurs only after prolonged lack of dietary intake. The earliest symptoms of vitamin A deficiency are night blindness. Additional early symptoms include follicular hyperkeratinosis , increased susceptibility to infection and cancer and anemia equivalent to iron deficient anemia. Prolonged lack of vitamin A leads to deterioration of the eye tissue through progressive keratinization of the cornea, a condition known as xerophthalmia . Dr. Siham Gritly 95

96. The earliest symptoms of vitamin A deficiency ;- *impaired dark adaptation –night blindness ( nyctalopia ) *poor vision in dim light * xerophthalmia The first stage of xerophthalmia is conjunctival xerosis Later Bitot’s spots form ( keratinization of epithelial cells) A deficiency progresses degenerative changes of retina occurs ( keratomalcia ) Ulceration and necrosis developed in the cornea that lead to blindness Dr. Siham Gritly 96

97. Xerophthalmia Xerophthalmia is a severe drying of the eye surface caused by a malfunction of the tear glands . it occurs most commonly because of decreased intake or absorption of vitamin A. Symptoms include night blindness and eye irritation. Dr. Siham Gritly 97

98. Ulceration and necrosis developed in the cornea that lead to blindness Dr. Siham Gritly 98

99. Vitamin D cholecalciferol Vitamin D is known as the sunshine vitamin because exposure to sunlight prompt the body’s cells to start producing it. Vitamin D 2 functions as a steroid hormone and vitamin regulate calcium and phosphorous homeostasis Apart from sunlight, dairy products (such as eggs, milk and butter), fatty fish and fish oils are all good sources of vitamin D. Dr. Siham Gritly 99

100. Vitamin D comes in many forms, but the two most important in the diet are;- 1-plant sterol ergosterol which isolated from plant and by commercial irradiation l igh UV coverted to vitamin D2 or ergocalciferol 2-animal sources or naturally produced called vitamin D3 or cholecalciferol . Dr. Siham Gritly 100

101. Vitamin D 2 and Vitamin D 3 a group of steroid compound Dr. Siham Gritly 101 Vitamin D 2 ergocalciferol Vitamin D 3 cholecalciferol .

102. Formation of vitamin D3 in the skin The naturally found vitamin D3 cholecalciferol is the form obtained either from animal sources or made in the skin by the action of ultraviolet light from the sun on 7-dehydrocholesterol 7-dehydrocholesterol found in animal tissues synthesized in the sebaceous glands of the skin and secreted into the skin surface During exposure to sunlight 7-dehydrocholesterol forming pre- cholecalcefirol ( previtamin D3) Dr. Siham Gritly 102

103. 7-Dehydrocholesterol and Ergosterol structures Dr. Siham Gritly 103 7-Dehydrocholesterol; accumulates in the skin By sunlight converted to cholecalciferol Ergosterol previtamin D2 found in plant foods not found in human tissues

104. Active form of the hormone 1,25-dihydroxycholecalciferol The biologically active form of the hormone is 1,25-dihydroxy vitamin D 3 (1,25-(OH) 2 D 3 , also called 1,25-dihydroxycholecalciferol or calcitriol ). Dr. Siham Gritly 104

105. activation of vitamin D must be achieved through; 1-Liver 2-kidneys In the Liver;- cholecalciferol fuses into the blood carried by D-binding protein (DBP) known as transcalciferin to the liver By the action of liver enzyme 25-hydroxylase hydroxylate cholecaciferol at carbon 25 to form 25-OH cholecalciferol /D3 The activity of this enzyme related to the concentration of vitamin D 25-hydroxylase also found in lungs, intestine and kidneys Dr. Siham Gritly 105

106. 25-hydroxyvitamin D 3 in the liver enzyme 25-hydroxylase hydroxylate cholecaciferol at carbon 25 to form 25-OH cholecalciferol /D3 Dr. Siham Gritly 106

107. In the kidneys ;-a second hydroxylation of 25-OH D 3 (25-hydroxylcalcefirol) occur at position 1 by the action of enzyme 1-hydroxylase in the kidnyes , 25-cholecalsiferol hydrolyized to 1,25-(OH) 2 cholecalecalciferol or known as ( calcitriol ) the active form of vitamin D By the transporter DBP which is the majour protein in the blood transported the active form calcitriol (1,25-(OH) 2 cholecalciferol ) to the target tissues Dr. Siham Gritly 107

108. The activity of 1-hydroxylase is influenced by -parathyroid hormone -low plasma concentration -The concentration of 1,25 hydoxycholecaciferol - high concentration inhibit the enzyme activity,- low concentration stimulate it Low intake of phosphours Dr. Siham Gritly 108

109. 1,25-dihydroxyvitamin D3 by the action of enzyme 1-hydroxylase in the kidnyes , 25-cholecalsiferol hydrolyized to 1,25-(OH)2 cholecalecalciferol active form of vitamin D Dr. Siham Gritly 109

110. 25-(OH)D 3 can also be hydroxylated at the 24 position by a specific D 3 -24-hydroxylase in the kidneys, intestine, placenta and cartilage Dr. Siham Gritly 110

111. 1,25-dihydroxcholecaliciferol D3 formation Tissue cholesterol ↓ Sun ↓ 7-dehydrocholesterol Plasma Cholecaliciferol D3 ↓ liver 25-hydroxycholecaliciferol ↓ kidneys 1,25-dihydroxycholecaliciferol → target tissue Dr. Siham Gritly 111

112. deficiency results in harmful changes in bone, a condition known as rickets in children and osteomalacia in adults. Vitamin D–Deficiency Symptoms—Bowed Legs and Beaded Ribs of Rickets Dr. Siham Gritly 112

113. Osteoporosis Any failure to synthesize adequate vitamin D or obtain enough from foods sets the stage for a loss of calcium from the bones, which can result in fractures. Highlight 12 describes the many factors that lead to osteoporosis, a condition of reduced bone density. Dr. Siham Gritly 113

114. Vitamin E tocopherol Vitamin E is an antioxidant a substance that that stops chain reactions caused by free radicals that can damage cells and affect its normal physiological function . free radicals: is an unstable and highly reactive atoms or molecules that have one or more unpaired electrons in the outer orbital Vitamin E acts primarily in lipid-rich areas of the body, where free radicals can initiate a chain of reactions known as peroxidation . Dr. Siham Gritly 114

115. peroxidation is a type of reaction in which oxygen atoms are formed leading to the production of peroxides. It is stimulated in the body by certain toxins and infections Lipid peroxidation reactions break apart fatty acids and create free radicals called lipid peroxyl radicals (also called reactive oxygen species because they contain oxygen radicals). Dr. Siham Gritly 115

116. The most concern free radicals in biological systems are derived from oxygen, Example of free radicals;- Superoxide radical (O2.- ), Hydrogen peroxide (H2O2), Hydroxyl radical (.OH) and others such as Nitric oxide (.NO) and others Read more about free radicals Dr. Siham Gritly 116

117. In addition to vitamin E, the body has various other antioxidant compounds , such as glutathione peroxidase , catalase , superoxide dismutase, to protect against oxidative damage. Dr. Siham Gritly 117

118. Alpha- Tocopherol structure alcoholic hydroxyl group and a 12-carbon aliphatic side chain containing two methyl groups in the middle and two more methyl groups at the end the side chain is saturated Dr. Siham Gritly 118

119. Vitamin K phylloquinone The K vitamins exist naturally as;- K 1 ( phylloquinone ) in green vegetables K 2 ( menaquinone ) produced by intestinal bacteria K 3 is synthetic menadione . Vitamin K is needed for the process of clotting of blood and Ca 2 + binding. Vitamin K can be synthesized by bacteria in the intestines. Vitamin K is needed for catalyzing the carboxylation of the γ-carbon of the glutamate side chain in proteins. Dr. Siham Gritly 119

120. Vitamin K phylloquinone and menaquinone share a methylated ring structure Dr. Siham Gritly 120

121. Vitamin K’s main function is to help the blood clot but it also assists with calcium retention in the body. Vitamin K contributes to the body’s blood-clotting ability by facilitating the conversion of precursor proteins, such as prothrombin , to active clotting factors thrombin that promote blood coagulation. Dr. Siham Gritly 121

122. Green leafy vegetables (such as spinach, broccoli and cabbage) are rich in vitamin K but eggs and milk also contain lower levels of the vitamin.   Deficiency can be very serious and cause heavy, uncontrolled bleeding in multiple areas of the body. consuming too much vitamin K can damage both blood cells and liver . Dr. Siham Gritly 122

123. Dr. Siham Gritly 123

124. Vitamins that are Cofactor & coenzyme Precursors Cofactor Vitamin Additional component Chemical group(s) transferred Distribution Thiamine pyrophosphate [24] Thiamine (B 1 ) None 2-carbon groups, α cleavage Bacteria , archaea and eukaryotes NAD + and NADP + [25] Niacin (B 3 ) ADP Electrons Bacteria , archaea and eukaryotes Pyridoxal phosphate [26] Pyridoxine (B 6 ) None Amino and carboxyl groups Bacteria , archaea and eukaryotes Lipoamide [3] Lipoic acid None electrons , acyl groups Bacteria , archaea and eukaryotes Methylcobalamin [27] Vitamin B 12 Methyl group acyl groups Bacteria , archaea and eukaryotes Dr. Siham Gritly 124

125. Cobalamine [3] Cobalamine (B 12 ) None hydrogen , alkyl groups Bacteria , archaea and eukaryotes Biotin [28] Biotin (H) None CO 2 Bacteria , archaea and eukaryotes Coenzyme A [29] Pantothenic acid (B 5 ) ADP Acetyl group and other acyl groups Bacteria , archaea and eukaryotes Tetrahydrofolic acid [30] Folic acid (B 9 ) Glutamate residues Methyl , formyl , methylene and formimino groups Bacteria , archaea and eukaryotes Dr. Siham Gritly 125

126. Menaquinone [31] Vitamin K None Carbonyl group and electrons Bacteria , archaea and eukaryotes Ascorbic acid [32] Vitamin C None Electrons Bacteria , archaea and eukaryotes Flavin mononucleotide [33] Riboflavin (B 2 ) None Electrons Bacteria , archaea and eukaryotes Flavin adenine dinucleotide [33] Riboflavin (B 2 ) None Electrons Bacteria , archaea and eukaryotes Coenzyme F420 [34] Riboflavin (B 2 ) Amino acids Electrons Dr. Siham Gritly 126

127. Murry K. Robert, Granner K. daryl , Mayes A. peter, Rodwell W. Victor (1999). Harpers Biochemistry. Appleton and Lange , twent fifth edition Campbell, Neil A.; Brad Williamson; Robin J. Heyden (2006). Biology: Exploring Life . Boston, Massachusetts: Pearson Prentice Hall A. Burtis , Edward R. Ashwood , Norbert W. Tietz (2000), Tietz fundamentals of clinical chemistry Maton , Anthea ; Jean Hopkins, Charles William McLaughlin, Susan Johnson, Maryanna Quon Warner, David LaHart , Jill D. Wright (1993). Human Biology and Health. Englewood Cliffs, New Jersey, USA: Prentice Hall. pp. 52–59 Maitland, Jr Jones (1998). Organic Chemistry. W W Norton & Co Inc ( Np ). p. 139. ISBN 0-393-97378-6 . Nelson DL, Cox MM (2005). Lehninger's Principles of Biochemistry (4th ed.). New York, New York: W. H. Freeman and Company. Matthews, C. E.; K. E. Van Holde ; K. G. Ahern (1999) Biochemistry. 3rd edition. Benjamin Cummings. http://wiki.answers.com/Q/What_is_dehydration_synthesis#ixzz2BuiK645 Dr. Siham Gritly 127

128. D. Voet , J. G. Voet , Biochemistry, second edition ed., John Wiley & Sons, New York, 1995 Sareen Gropper, Jack Smith and James Groff, Advanced Nutrition and Human Metabolism, fifth ed. WADSWORTH Melvin H Williams 2010; Nutrition for Health, Fitness and Sport. 9 th ed , McGraw Hill Heymsfield , SB.; Baumgartner N.; Richard and Sheau -Fang P. 1999. Modern Nutrition in Health and Disease; Shils E Maurice, Olson A. James, Shike Moshe and Ross A. Catharine eds. 9th edition Guyton, C. Arthur. 1985. Textbook of Medical Physiology. 6th edition, W.B. Company Lehninger . Principles of bochemistry . by Nelson and Cox, 5th Edition; W.H. Freeman and Company Emsley , John (2011). Nature's Building Blocks: An A-Z Guide to the Elements (New ed.). New York, NY: Oxford University Press. ISBN 978-0-19-960563-7 . Koppenol , W. H. (2002). "Naming of New Elements (IUPAC Recommendations 2002)" (PDF). Pure and Applied Chemistry 74 (5): 787–791. doi : 10.1351/pac200274050787 . http://media.iupac.org/publications/pac/2002/pdf/7405x0787.pdf . http://www.differencebetween.com/difference-between-acyl-and-vs-acetyl/#ixzz2HmrSvksL Dr. Siham Gritly 128

129. acyl group is characterized by a carbon and oxygen atom, which is linked by a double bond. Identifying an acyl group is easy because of the C=O part. Acetyl group is a common example for an organic acyl group. This is also known as ethanoyl group. It has the chemical formula of CH 3 CO. Therefore, the R group in the acyl is replaced by a methyl group. Other bond in the carbon can be with a –OH, -NH 2 , -X,-R,-H etc. For example, CH 3 COOH is known as acetic acid. The introduction of an acetyl group into a molecule is called acetylation . Dr. Siham Gritly 129