number 38 Done by Omar Odeh Corrected by Doctor Nafeth 1
Micronutrients: Vitamins Chapter 28 lipp. In the end of this course, we will talk about fat soluble vitamins. We took water soluble vitamins last semester because they all act as coenzymes so we had to take them to understand the mechanism of action of the enzymes we took. But first, here s an overview about vitamins in general: Vitamins are organic compounds clinically unrelated to each other as each one has its own distinguishable structure. They are required in small amounts thus they are classified as micronutrients, and our bodies cannot synthesize them in adequate amounts so they should be acquired from exogenous sources. They are converted to an active form which acts in the body. Vitamins can be classified into water soluble vitamins and fat soluble vitamins. - Water soluble vitamins readily excreted in the urine They act as coenzymes for proteins that aren t stored in the body, thus they aren t stored in the body too Toxicity arising due to excess amounts of water soluble vitamins is rare. - Fat soluble vitamins They are released, absorbed, and transported with the fat of the diet They are not readily excreted in the urine They are stored in the liver and adipose tissue Note: water soluble vitamins are named after one compound ex: vitamin B 6 is pyridoxine, while fat soluble vitamins are named after compounds with a very similar structure ex: vitamin A includes retinol, retinal, and retinoic acid. Now we will start talking about fat soluble vitamins in details (vitamins A, D, E, and K) 2
Vitamin A Overview Vitamin A stands for a group of structurally related chemicals called retinoids; retinol, retinal, and retinoic acid. The retinoids are essential for vision, reproduction, growth, and maintenance of epithelial tissue. Retinoic acid, derived from oxidation of dietary retinol, mediates most of the actions of the retinoids, except for vision and spermatogenesis, which depends on retinal, the aldehyde derivative of retinol. We can t synthesize retinoids, thus they must be acquired through the diet; from animal sources like liver, kidney, cream, butter, and egg yolk which are good sources of preformed vitamin A, vitamin A can also be acquired from plants, where it is in the form of β-carotene, which can be cleaved in the intestines to give 2 molecules of vitamin A. Structure As mentioned, retinoids can be acquired from the diet in 4 forms; retinol which is an alcohol, retinal which is an aldehyde, retinoic acid which is a carboxylic acid, and β-carotene which is the parent molecule as it is broken down in the intestines to yield 2 retinal molecules. Retinol is the form of vitamin A acquired in the diet from animal tissue ingestion (we will talk about it in details later), it is a primary alcohol thus it can be oxidized to retinal, and retinal can also be oxidized to retinoic acid. Retinal can be reduced back to retinol, thus they can be interconverted, however, retinoic acid can t be reduced back to retinal, and this indicates that retinol and retinal have similar functions in the body that are different from the functions of retinoic acid. 3
Metabolism and functions of vitamin A In general, differentiation and proliferation of cells is related to retinoic acid, and vision and spermatogenesis is related to retinal and retinol. Vitamin A is acquired from the diet in 2 forms; from animal sources as retinyl esters with long chain fatty acids, and from certain plants (Yellow and dark green vegetables and fruit) as β carotene, which is also called provitamin A. Both forms (retinyl esters and β carotene) involve the eventual release of retinol, which is then esterified with long chain fatty acids to give retinyl esters, the fatty acid donor is a fatty acyl-coa molecule. - Retinyl esters from animal sources They are first broken down to give retinol This is as long chain fatty acids can t be absorbed by cells. The retinol then is absorbed by intestinal cells The retinol is esterified to form retinyl esters - β carotene from plant sources it is absorbed by the intestinal cells without modification in the intestinal cells, it is broken down to give 2 molecule of retinal the retinal molecules are reduced to form retinol the retinol molecules are then esterified to give retinyl esters Eventually the retinyl esters will be transported from the intestinal cells to the liver by chylomicrons through the lymphatic system and blood, where in the liver it can be stored as retinyl esters. When in need of vitamin A, the retinyl esters are hydrolyzed to give retinol which is then transported to extra hepatic tissue through a Retinol Binding Protein (RBP) complexed with transthyretin. This is as the retinyl esters are highly hydrophobic thus they can t be transported in the blood plasma. 4
Mechanism of action In tissues other than the eye, when the retinol-rbp reaches the tissue, it is broken down to give retinol which is absorbed by the cells. Retinol then is oxidized to retinoic acid, which binds with high affinity to specific receptor proteins present in the nucleus of the target tissue. This complex then binds to transcription factors that regulate gene expression, stimulating or inhibiting them. Inhibition occurs as transcription is still induced by the complex, but the activity of the cell is less than in the absence of retinoic acid, this is why vitamin A is given in pathologic conditions such as skin conditions. In the eye, retinol is oxidized to retinal, which binds to opsin, forming rhodopsin which is the visual pigment of the rod cells in the retina. When rhodopsin is exposed to light, retinal and opsin are released from rhodopsin and this activates a G-protein which then triggers a nerve impulse. The figure below summarizes the mechanism of action and metabolism of vitamin A 5
Clinical indications Vitamin A deficiencies aren t usually fatal, however, the absence of vitamin A from the body is what causes severe symptoms. Regarding vision, a deficiency in vitamin A prevents the eye cells from maturing and differentiating normally (keep in mind that eyes still contain epithelial tissues), and it prevents the formation of rhodopsin and this is how the symptoms arise. A mild deficiency causes night blindness (nyctalopia) as the visual threshold increases from the decrease in rhodopsin level. A moderate deficiency causes scarring of the eye which leads to irreversible loss of eye cells, and a severe deficiency leads to xerophthalmia, which is the ulceration and dryness of conjunctiva and cornea, followed by scarring and blindness. As mentioned, vitamin A is prescribed for dermatologic problems such as acne and psoriasis. Toxicity of retinoids As vitamins A,D,E,K as fat soluble, they can be stored in the body. And like any molecule than can be stored in the body if it is found in excessive amounts it might cause diseases in the body. Excessive intake of any fat soluble vitamin is termed hypervitaminosis X, where X is replaced by the letter of the vitamin ex: hypervitaminosis A is excessive vitamin A. Hypervitaminosis A leads to dry skin due to a decrease in keratin synthesis, enlargement of the liver and it can become cirrhotic, and it leads to a rise in intracranial pressure in the CNS where it might mimic a brain tumor. Pregnant women shouldn t ingest excessive amount of vitamin A as it is teratogenic (it might cause congenital malformations in the developing fetus). 6
Vitamin D The topic of vitamin D is one of the hottest topics in biochemistry nowadays as its correlation with the treatment of many diseases is still unknown, thus it is still open for research. Overview The D vitamins are a group of sterols that have a hormone-like function, this is as its active form (1, 25-dihydroxycholecalciferol) binds to intracellular receptor proteins, where it interacts with response proteins in a similar manner as vitamin A. The most prominent actions of 1,25-diOH-D3 are to regulate the plasma levels of calcium and phosphorus Sources of vitamin D Vitamin D 3 (cholecalciferol) which is an intermediate in the synthesis of the active form of vitamin D can be synthesised in the skin when exposed to sunlight, where then it is transported to the liver by vitamin D binding proteins. Vitamin D 2 and vitamin D 3 can also be acquired from plants and animals respectively, where the difference between them is that vitamin D 2 contains an additional double bond and a methyl group. 7
Metabolism The inactive forms of vitamin D (D 2 and D 3 ) are first hydroxylated at the 25 position catalyzed by a specific 25-hydroxylase present in the liver, 25-hydroxycalciferol is the predominant form of vitamin D in the serum and the major storage form, then it is further hydroxylated at the 1 position by a specific 25-hydroxycholicalciferol 1-hydroxylase present in the kidney. The 1-hydroxylation reaction is tightly regulated by the levels of phosphate and calcium ions present in the serum, where a low level of these ions stimulate the enzymes, and calcium is an indirect stimulator as it stimulated the production of parathyroid hormone (PTH), which upregulates the 1-hydroxylase. The reaction is also regulated by feedback inhibition, where the product inhibits the enzyme. Function The main function of vitamin D is to maintain adequate serum levels of calcium ions. This is achieved by: - increasing uptake of calcium by the intestine - minimizing the loss of calcium by the kidney and increasing reabsorption - stimulating demineralization of the bones when blood calcium is low Thus, vitamin D has the same functions as the PTH hence this is why it is given to people who can t produce PTH Clinical indications Deficiencies in vitamin D lead to the loss of calcium ions in the serum, which leads to the demineralization of bone. With time, bones will become bent due to incomplete mineralization and continuous formation of the collagen matrix of bone. This is called rickets in children and osteomalacia in adults. These diseases are called nutritional when it s due to inadequate intake of vitamin D, and renal when it is associated with chronic kidney disease (renal osteodytrophy) Hypoparathyroidism is the lack of PTH. 8
Toxicity of vitamin D High doses of vitamin D leads symptoms like loss of appetite, nausea, thirst, and stupor (which is a state of unconsciousness). It can also cause hypercalcemia, which leads to calcium deposition in the body, which leads to atherosclerosis inn the arteries and kidney stones. Vitamin K Vitamin K is a group of quinones since their structures contain a cyclic di-ene molecule. Vitamin K exists in several active forms; phylloquinone in plants, menaquinone in intestinal bacteria. Menadione is a synthetic form of vitamin K 2. The main function of vitamin K is that it takes place in the post-translational modification of clotting factors, where it activates clotting factors by acting as a coenzyme in the carboxylation of glutamic acid residues in the proteins, forming γ-carboxyglutamate. This allows the clotting factors to be able to bind to calcium ions, allowing them to bind to platelets, leading to platelet aggregation. - Excess vitamin K in the body leads to hemolytic anemia and jaundice as it starts to bind to red blood cells. - A deficiency leads to excessive bleeding due to the impairment of the clotting process. 9
Deficiency of vitamin K Vitamin K can be acquired in the diet by the ingestion of vegetables and fruits, and it is also synthesised by the intestinal bacteria. Thus, it is very rare to get a deficiency in vitamin K. However, in certain conditions a vitamin K deficiency might occur. These include: - The use of antibiotics which kill the intestinal bacteria - The case of newborns where they are sterile and they don t have normal flora Human milk provides 20% of the needed vitamin K newborns receive a single intramuscular dose of vitamin K as prophylaxis against hemorrhagic disease since the amount of vitamin K acquired from milk isn t enough Vitamin E Now for the last vitamin in our course, vitamin E. Vitamin E are a collection of tocopherols, where the most important one is α-tocopherol. The primary function of vitamin E is as an antioxidant, this is as is contains a ring that can accept electrons and still be stable due to resonance, thus it is used in the body to remove free radicals. A deficiency in vitamin E is rare as it is needed in very small amounts, thus a vitamin E deficiency is almost entirely restricted to premature infants. In adults, it is associated with defective lipid absorption or transport, but this leads to deficiencies in other fat soluble vitamins too. And good luck with your exams, and we wish you a bright future and an amazing life. Don t hesitate to contact me if you found any mistakes, and don t forget to go through the slides. Also this semester wouldn t be complete without something from TNT, because we re the bomb. Mic drop 10