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Azin Nowrouzi, PhD TUMS. 6. PYRIDOXINE (vitamin B6) Pyridoxal (PL)Pyridoxamine (PM) Pyridoxine or Pyridoxol (PN) Each of these forms can be phosphorylated.

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Presentation on theme: "Azin Nowrouzi, PhD TUMS. 6. PYRIDOXINE (vitamin B6) Pyridoxal (PL)Pyridoxamine (PM) Pyridoxine or Pyridoxol (PN) Each of these forms can be phosphorylated."— Presentation transcript:

1 Azin Nowrouzi, PhD TUMS

2 6. PYRIDOXINE (vitamin B6) Pyridoxal (PL)Pyridoxamine (PM) Pyridoxine or Pyridoxol (PN) Each of these forms can be phosphorylated at position 5 to form: PLP, PMP, and PNP.

3 Active form Pyridoxal phosphate (PLP) PLP and PL account for 90% of the total B6 in the blood. In the blood B6 is transported both in the plasma and the RBCs. In the blood PLP is hydrolyzed to PL because only free PL gets inside the cells. In muscle and other tissues, PL is converted back to PLP by a reversible reaction with the help of alkaline phosphatase and pyridoxal kinase. Active functional form is pyridoxal phosphate (PLP) and pyridoxamine phosphate (PMP). For absorption, the “phosphorylated” form must be hydrolyzed to “dephosphorylated” form by the enzyme alkaline phosphatase in the intestine. In the portal vein Vit B6 is present as PL, PM, PN. In the liver they are converted back to phosphorylated forms. This conversion is catalyzed by the ATP requiring enzyme, pyridoxal kinase.

4 Functions FUNCTIONS: B6 is involved in: Amino acid metabolism Transamination reactions required for the synthesis and catabolism of the amino acids. Decarboxylation reactions. Breakdown of glycogen Glycogenolysis (cofactor for glycogen phosphorylase) % of body vit B6 is present in the muscles, most of it in PLP (coenzyme) form bound to glycogen phosphorylase. Only 1  mol or less is present in the blood, Synthesis of epinephrine (adrenaline) and norepinephrine (noradrenaline) Synthesis of niacin (vitamin B3) from the amino acid tryptophan.

5 Covalent bonds of  -amino acids made labile by their binding to PLP-containing enzyme In the reactions of amino acid metabolism, the formyl (CHO) group of PLP condenses with  -NH2 group of an amino acid and forms a Schiffs base. This linkage weakens or labilizes all the bounds around the  -carbon of the amino acid. The specific bond of an amino acid that is broken depends on the particular enzyme to which PLP is attached.

6 Mechanism of catalyzed reaction

7 Deficiency Food sources: –In animal foods major forms are PL and and PM along with their phosphorylated forms. –In plants PN. –Bananas, beans, lentils, walnuts, salmon, chicken, beef, whole grain breads and cereals, soybeans, liver, eggs, dairy products are excellent sources. Requirements: –The requirement for vitamin B6 in the diet is proportional to the level of protein consumption ranging from mg/day for a normal adult. –During pregnancy and lactation the requirement for vitamin B6 increases approximately 0.6 mg/day. TOXICITIES: –Megadoses of B6 (daily doses of >500mg) are used to treat pms symptoms. They can cause neurotoxicity and photosensitivity in some individuals. Deficiencies: are rare and usually are related to an overall deficiency of all the B-complex vitamins. Certain drugs form complexes with PL and PLP –Penicillamine (used to treat rheumatoid arthritis and cystinurias). –Isoniazid (the hydrazide derivative of isonicotinic acid) is the primary drug for chemotherapy of tuberculosis.

8 7. BIOTIN Biotin is relatively small, bicyclic (two-ring) compound formed from a tetrahydrothiophene (thiophene) ring, and a second ring, which contains a ureido group. The thiophene ring also has a valeric acid side chain. Although eight different stereoisomers of biotin exist, only one stereoisomer is found naturally and to have biological activity as a coenzyme. It is called d-(+)- biotin, D-biotin or simply biotin. It is sometimes called vitamin H and also coenzyme R.

9 Holocarboxylase In humans, the four holocarboxylases are : acetyl-CoA carboxylase, propionyl-CoA carboxylase, pyruvate carboxylase and beta- methylcrotonyl-CoA carboxylase. Biotin is chemically bonded in each of these enzymes via an amide linkage between the carboxyl group of the valeric acid side-chain in biotin and the epsilon-amino group of the lysine residue in the apocarboxylase. The enzyme that catalyzes the formation of this covalent bond is called holocarboxylase synthetase.

10 Biotin Cycle Biotin cycle: the chain of chemical reactions involved in the use and reuse of the vitamin biotin. One important role of biotinidase is: 1. To separate or free biotin from proteins to which it is bound in foods. Biotin in its free form can then be used by the body. 2. Biotinidase lets the body recycle or reuse the biotin over and over again so that we do not need to consume large amounts of this vitamin in our diets. Within cells, the carboxylases (pyruvate carboxylase, acetyl-CoA carboxylase, methycrotonyl-CoA carboxylase, propionyl-CoA carboxylase) are biotinylated via holocarboxylase synthetase. Biotin and apocarboxylases are the substrates. ATP and magnesium also participate in the reaction. Biotinidase deficiency is a treatable, inherited metabolic disorder in which the body cannot process the vitamin biotin in a normal manner.

11 Functions Coenzyme involving CO 2 transfer –acetyl CoA to malonyl CoA –Propionyl CoA to methylmalonyl CoA –Pyruvate to oxaloacetate Deficiency –Fatty liver and kidney syndrome, a fatal metabolic disorder in chicks and turkey poults Raw egg white (avidin) can block absorption

12 Biotin (functions) Coenzyme for several reactions involving CO2 fixation into various compounds e.g. Pyruvate to oxaloacetate (pyruvate carboxylase) Propionyl CoA to methylmalonyl CoA (propionyl CoA carboxylase) Acetyl CoA to malonyl CoA (acetyl CoA carboxylase) - initial step in de novo fatty acid synthesis.

13 Deficiency symptoms Rare because of widespread distribution in plant and animal food and significant lower gut synthesis. –Sources Yeast, rice, soybeans, peanuts, fish (herring and mackerel), mushrooms and bananas, safflower meal, liver and milk are rich sources. Can be induced by eating raw egg white –The fact is that nature created the egg in such a way that its yolk is very rich in biotin. One of the highest concentration in nature. Eat the egg whole together with the egg white and you will be fine. –Egg whites contain a glycoprotein called "avidin" which binds biotin - one of the B vitamins - very effectively. The cooking process deactivates the avidin in the egg, much the same way it deactivates every other protein in the egg white. Biotin deficiency is chief cause of fatty liver and kidney syndrome. This baby developed severe biotin deficiency during intravenous feeding without biotin. Aajonus Vonderplanitz, in his book “We Want to live” is a strong proponent of raw eggs.

14 How Biotin Works 1- Biotin carrier protein 2- Biotin carboxylase 3- Transcarboxylase

15 9. FOLIC ACID (folacin) Folacin includes several derivatives of folic acid (monopteroylglutamic acid). Folic acid is obtained primarily from yeasts and leafy vegetables as well as animal liver. Animals cannot synthesize PABA nor attach glutamate residues to pteroic acid, thus, requiring folate intake in the diet. “Microorganisms Only can synthesize Folacin” Sulphonamides and antibiotics block PABA incorporation by competitive inhibition

16 Structure Folic acid exists in a polyglutamate form. Intestinal mucosal cells remove some of the glutamate residues through the action of the lysosomal enzyme, conjugase.

17 Humans and microorganisms: Folic acid is reduced within cells (principally in the liver where it is stored) to tetrahydrofolate (THF or H4folate) through the action of folate reductase [or dihydrofolate reductase (DHFR) ] which is an NADPH-requiring enzyme. Active functional form is: Tetrahydrafolic acid (THF).

18 Active center (N 5 and N 10 )

19 Active center of tetrahydrofolate (THF). The N5 position is the site of attachment of methyl and formimino groups, the N10 the site for attachment of formyl group and that both N5 and N10 bridge the methylene and methenyl groups.

20 Folate conversions Carrier of one-carbon (e.g. methyl) groups The one-carbon units are added to, or removed from, metabolites such as: histidine serine methionine purines.

21 Functions Role of N5,N10-methylene-THF in dTMP synthesis is the most metabolically significant function for this vitamin. Vitamin B12 and N5-methyl-THF in the conversion of homocysteine to methionine is important in helping cells to regenerate needed THF.

22 Participation of H4folate in dTMP synthesis ______Deoxyuridine ______________ ________Deoxythymidine ____Monophosphate (dUMP)_______________Monophosphate (dTMP) _______

23 Deficiency symptoms Identical to those for vitamin B12 deficiency: Effect of folate deficiency on cellular processes is upon DNA synthesis. –Impairment in dTMP synthesis and purine synthesis –Cell cycle arrest in S-phase of rapidly proliferating cells, especially hematopoietic cells. The result is megaloblastic leukemia as for vitamin B12 deficiency. –The inability to synthesize DNA during erythrocyte maturation leads to abnormally large erythrocytes termed macrocytic anemia. Deficiency during pregnancy can cause neural tube defects such as spina bifidia. Deficiency is rare due to the adequate presence of folate in food. Deficiency can occur when there is: 1.Poor dietary habits as those of chronic alcoholics. 2.Impaired absorption or metabolism Certain drugs such as anticonvulsants and oral contraceptives and methotrxate can impair the absorption of folate. 3.An increased demand for the vitamin. Pregnancy Folate will nearly double by the third trimester of pregnancy.

24 VITAMIN B12 (cobalamin) Vitamin B12, is also called cobalamin, cyanocobalamin and hydroxycobalamin. It is built from : 1.A nucleotide and 2.A complex tetrapyrrol ring structure (corrin ring) 3.A cobalt ion in the center. 4.A R- group When R is cyanide (CN), vitamin B12 takes the form of cyanocobalamin. In hydroxycobalamin, R equals the hydroxyl group (-OH). In the coenzyme forms of vitamin B12, –R equals an adenosyl group in adenosylcobalamin. –R equals a methyl (-CH3) group in methylcobalamin. Vitamin B12 is synthesized exclusively by microorganisms (bacteria, fungi and algae) and not by animals and is found in the liver of animals bound to protein as methycobalamin or 5'- deoxyadenosylcobalamin.

25 Known as the "red" vitamin because it exists as a dark red crystalline compound, Vitamin B12 is unique in that it is the only vitamin to contain cobalt (Co 3+ ) metal ion, which, gives it the red color. The vitamin must be hydrolyzed from protein in order to be active. Intrinsic factor, a protein secreted by parietal cells of the stomach, carries it to the ileum where it is absorbed. It is transported to the liver and other tissues in the blood bound to transcobalamin II. It is stored in the liver attached to transcobalamin I. –It is released into the cell as Hydroxocobalamin (see the next slide) In the cytosol it is converted to methylcobalamin. Or it can enter mitochondria and be converted to 5’-deoxyadenosyl cobalamin. Dorothy Crowfoot Hodgkin ( ) Dr. Stadtman in her lab

26 In the cytosol In mitochondria

27 Functions Only two reactions in the body require vitamin B12 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. –methylmalonyl-CoA mutase, requires vitamin B12 as a cofactor in the conversion of methylmalonyl-CoA to succinyl-CoA. –5'-deoxyadenosine derivative of cobalamin is required for this reaction 2.The second reaction catalyzed by methionine synthase converts homocysteine to methionine –This reaction results in the transfer of the methyl group from N5- methyltetrahydrofolate to hydroxycobalamin generating tetrahydrofolate and methylcobalamin during the process of the conversion.

28 CH3-THF Methionine SAM SAH methyl transferases CH3- Methyl acceptor Homocysteine MS THF B12 CH2-THF CBS cystathionine cysteine B6 Folate cycle Transulfurationpathway Methionine cycle Methyl acceptor Methionine and Folate cycles are interrelated

29 Deficiency symptoms Pernicious anemia in humans (inability to absorb B12 because of lack of gastric intrinsic factor). Neurological disorders due to progressive demyelination of nerve cells. –This results from increase in methylmalonyl-CoA. –Methylmalonyl-CoA is a competitive inhibitor of malonyl-CoA in fatty acid biosynthesis. –Can substitute malonyl-CoA in any fatty acid biosynthesis and create branched-chain fatty acid altering the architecture of normal membrane structure of nerve cells. Sources –Synthesized only by microorganisms, so traces only are present in plants; liver is a rich source. –B12 is found in organ and muscle meats, fish, shellfish, dairy products, eggs and in fortified foods like breakfast cereals.

30 It is derived from glucose via uronic acid pathway. Enzyme L-gluconolactone oxidase is responsible for conversion of gluconolactone to ascorbic acid. This enzyme is absent in primates, including humans, some bats…. The active form is ascorbic acid itself. Vitamin C (Chemical nature)

31 VITAMIN C Vitamin C is L-ascorbic acid, which is a colorless, crystalline acid with strong reducing properties. Functions Vitamin C has antioxidant properties similar to those of vitamin E, –Protects cells from free radicals. –Protects iron from oxidative damage, thus enhancing iron (Fe 2+ ) absorption in the gut. The main function is as a reducing agent. –It has the potential to reduce cytochrome a and c of the respiratory chain and molecular oxygen and nitrates. It is required for various hydroxylation reactions e.g. proline to hydroxypoline for collagen synthesis (see next slide).

32 Hydroxylation of proline and lysine residues in collagen Vitamin C is required for the maintenance of normal connective tissue as well as for wound healing because synthesis of connective tissue is the first event in wound tissue remodeling.

33 Other activities Several other metabolic reactions require vitamin C as a cofactor: –The catabolism of tyrosine and the synthesis of epinephrine from tyrosine and the synthesis of the bile acids. –It is also believed that vitamin C is involved in the process of steroidogenesis. The adrenal cortex contains high levels of vitamin C which are depleted upon adrenocorticotropic hormone (ACTH) stimulation of the gland.

34 Roles in the body Sources Citrus fruits and green leafy vegetables Vitamin C is readily absorbed and so the primary cause of vitamin C deficiency is poor diet and/or an increased requirement. Deficiency symptoms 1. Scurvy –Bleeding gums –Small red spots on skin –Rough skin –Wounds fail to heal –Weak bones and teeth –Anemia and infections 2. Stress (e.g., infections, smoking) –Mechanism unknown, but vitamin C requirements increase during stress 3. Common cold? 4. Disease prevention? –Cancer, heart disease

35 Periodontal disease

36 VitaminChemical name B 1 B 2 B 3 B 4 B 4 B 5 B 6 B 7 B 8 B 9 B 10 B 11 B 11 B 12 Thiamine Riboflavin Nicotinamide (niacin) Adenine (no longer considered a vitamin) Pantothenic acid Pyridoxine BiotinInositol Folacin (folic acid) p-aminobenzoic acid (PABA) / H1 L-carnitine / b-hydroxy-g-trimethylammonium butyrate (or choline) Cyanocobalamin Vitamin B-complex

37 8. Inositol (Vitamin Bh) Inositol is part of the vitamin B-complex. Since it is not essential in the human diet, it cannot be considered a vitamin. Inositol is naturally present in foods high in fiber (wheat, legumes, bran, etc). It is required for: –For proper formation of cell membranes. –For formation of lecithin –It is not a vitamin per se, but it works synergistically with many vitamins and nutrients. functions closely with a B complex vitamins, Choline, folacin, Vitamins B-6 and B-12. –Inositol is necessary for proper function of nerves, brain, and muscles in the body. –This nutrient is also often used to counter depression; indeed, serotonin needs inositol for proper functioning. –Exists in all human cells, where it plays an important role in cell proliferation and differentiation. Low levels of this nutrient may result in depression and some research has shown that increased levels of Inositol appear to be a promising treatment for depression.

38 10. P-amino benzoic acid (B x ) A substance required for the synthesis of folic acid by many organisms. PABA is an essential nutrient for some bacteria and is sometimes called Vitamin B X. Para-aminobenzoic acid is included in the B-vitamin complex, although it is not an essential nutrient for humans and it varies in its activity from other B vitamins. Although humans lack the ability to synthesize folate from PABA, it is sometimes marketed as an essential nutrient under the premise that it can stimulate intestinal bacteria. It also absorbs ultraviolet light and is used as aminobenzoic acid, as a topical sunscreen. Abbreviated PAB or PABA. The potassium salt is used as drug against fibrotic skin disorders.

39 Structure Folic acid PABA (vitamin Bx)

40 11. L-CARNITINE (B11) L-carnitine –Is made in the body from the amino acids lysine and methionine, –Is needed to release energy from fat. –It transports fatty acids into mitochondria, the powerhouses of cells. –In infancy, and in situations of high energy needs, such as pregnancy and breast- feeding, the need for L-carnitine can exceed production by the body. Therefore, L-carnitine is considered a "conditionally essential" nutrient.

41 L-carnitine L-carnitine’s actions appear to be particularly important in the heart. As an example, patients with diabetes and high blood pressure were given 4 grams of L- carnitine per day in a preliminary study. After 45 weeks, irregular heartbeat and abnormal heart functioning decreased significantly compared with nonsupplemented patients.

42 Sources of L-carnitine Dairy and red meat contain the greatest amounts of carnitine. Therefore, people who have a limited intake of meat and dairy products tend to have lower L-carnitine intakes. Carnitine deficiencies are rare, even in strict vegetarians, because the body produces carnitine relatively easily. Rare genetic diseases can cause a carnitine deficiency. Also, deficiencies are occasionally associated with other diseases, such as diabetes and cirrhosis. Most people do not need carnitine supplements. For therapeutic use, typical amounts are 1–3 grams per day.


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