Vitamin B-12 Chemistry and Mode of Action

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  • Cobalamin enzymes catalyze 3 types of reactions: intramolecular rearrangements, methylations, and the reduction of ribonucleotides to deoxyribonucleotides. The two reactions in mammals that require coenzyme B12 are: (1) the conversion of L-methylmalonyl CoA into succinyl CoA and (2) methylation of homocysteine to form methionine. Reaction (2) is particularly important as Met is necessary for the generation of coenxymes that play a role in the synthesis of purines and thymine. The basic structure of a cobalamin is pictured: the core consists of a corrin ring with a central cobalt atom.
  • Write this down, as this is not mentioned in the slides:
    In mammals, cobalamin is a cofactor for only two enzymes, methionine synthase and L-methylmalonyl-CoA mutase.
    Vitamin B 12 contains a cobalt metal ion bound to a porphyrin ring. Cobalt normally forms six coordinate bonds. Besides the four bonds to the nitrogens of the porphyrin, one bond is to a ring nitrogen of dimethylbenzamidine. The final bond is to a cyanide ion in the vitamin, or to the 5′ carbon of adenosine in the active coenzyme
  • itamin B12 is a substance whose biochemistry is complex. Basically it consists of a cobalt-containing porphyrin-like prosthetic group attached to a nucleotide (cobalt is a major trace metal in human physiology, with the average body containing 1.1 grams of the element, third in abundance after iron and zinc). The diagram at left shows the structure of cyanocobalamin, one the simpler forms of the vitamin. B12 has been called the most complicated molecule in the human body that is not simply a repeating chain of smaller units (like proteins and nucleic acids). The laboratory synthesis of this substance, not accomplished until 1971, capped off the distinguished career of Nobel-winning organosynthesist Robert Burns Woodward.
  • B12 is synthesised in nature by micro-organisms. Animal-derived foods are a primary source because animals eat other animal food, they produce B12 internally due to the intestinal bacteria (not present in humans), and they eat food contaminated with bacteria.
  • Please keep those in mind while we discuss B12 deficiencies:
    In humans, B12 exerts its physiologic effects on two major enzymatic pathways.
    First, methyl-cobalamin (m-B12) is a cofactor in the conversion of
    Homocysteine to Methionine . This reaction is essential for the conversion of
    dietary and storage ( methyltetrahydrofolate ) folates to tetrahydrofolate .
    Second, adenosyl-cobalamin (aB12) is a cofactor in the conversion of
    Methylmalonyl coenzyme A ( MMCoA ) to Succinyl-CoA .
     
    http://www.fao.org/docrep/004/Y2809E/y2809e0b.htm
    anemia
    nerve damage
    Whose at risk
    pernicious anemia
    B-12 injections often taken regularly
    HIV
    Chronic Fatigue Syndrome
  • Unsaturated and Odd-Chain Fatty Acids Require Additional Steps for Degradation
    Most fatty acids have an even number of carbon atoms due to the process by which they were synthesized, thus the beta-oxidation pathway can successfully complete the degradation of these molecules. However, there are more steps required for fatty acid chains that are not as simple, i.e. those that are unsaturated or which have an odd number of carbons.
    Vitamin B12 contains a cobalt atom and a corrin ring[edit]
    Cobalamin
    Cobalamin enzymes catalyze 3 types of reactions: intramolecular rearrangements, methylations, and the reduction of ribonucleotides to deoxyribonucleotides. The two reactions in mammals that require coenzyme B12 are: (1) the conversion of L-methylmalonyl CoA into succinyl CoA and (2) methylation of homocysteine to form methionine. Reaction (2) is particularly important as Met is necessary for the generation of coenxymes that play a role in the synthesis of purines and thymine. The basic structure of a cobalamin is pictured: the core consists of a corrin ring with a central cobalt atom.
  • During this rearragement, two groups attached to adjacent carbon atoms are excahnged, the process being catalyzed by coenzyme B12. The first step in these rearrangements is the carbon-cobalt bond of 5’-deoxyadenosyl being cleaved (a homolytic cleavage reaction). This creates the Co2+ coenzyme form and a radical of 5’-deoxyadenosyl (pictured).
  • Vitamin B 12 activates methyl groups for methionine biosynthesis by binding them to the Co ion at the sixth position. The methyl group donor to B 12 is 5‐methyl tetrahydrofolate. The methyl‐B 12 donates its methyl group to homocysteine,forming methionine. Besides being incorporated into proteins, methionine is the source of methyl groups for several important reactions, including the modification of cellular RNAs and the biosynthesis of lipids
    Figure taken from http://www.cliffsnotes.com/sciences/biology/biochemistry-ii/amino-acid-metabolism-carbon/1-carbon-metabolism
  • N5-METHYL-THF IS A STORAGE FORM OF FOLATE. THE REACTION REDUCTION OF N5,10-METHYLENE THF TO N5-METHYL-THF IS IRREVERSIBLE. TO GET THE FOLATE OUT OF STORAGE, B12 MUST CATALYZE THE CONVERSION OF HOMOCYSTEINE TO METHIONINE, RESULTING IN THE PRODUCTION OF THF FROM N5-METHYL THF.
    People with a folate deficiency can experience side effects relating to the fact that folate is needed for TMP production in dividing cells. They can present with anemia, hair loss, GI symptoms, etc. In fact, some cancer drugs exploit this and there are chemotherapeutic agents that target both dihydrofolate reductase and thymidylate synthase. Sometimes people are treated with supplemental folate for what is thought to be a folate deficiency, and they actually had a B12 deficiency. These people can experience certain neurological symptoms after they had experienced an initial relief in their folate deficiency symptoms. This phenomenon occurs because B12 impairs the ability to take the folate out of its ‘storage’ as the 5-methyl THF.
  • ype “vitamin B-12” into your favorite Internet search engine, and you’ll find an array of information and advertising sites touting various vague health benefits, including the “amazing” exercise-boosting ability of this complex compound. Despite its popularity as a general “energizer” for the body, mind and spirit, the evidence that vitamin B-12 should be taken either orally or parenterally by individuals who do not have a clinical diagnosis of deficiency is generally not convincing 
     A recent study also suggests that high vitamin B12 status may be associated with better treatment outcome. Folate and vitamin B12 are major determinants of one-carbon metabolism, in which S-adenosylmethionine (SAM) is formed. SAM donates methyl groups that are crucial for neurological function. Increased plasma homocysteine is a functional marker of both folate and vitamin B12 deficiency. Increased homocysteine levels are found in depressive patients. In a large population study from Norway increased plasma homocysteine was associated with increased risk of depression but not anxiety. There is now substantial evidence of a common decrease in serum/red blood cell folate, serum vitamin B12 and an increase in plasma homocysteine in depression. Furthermore, the MTHFR C677T polymorphism that impairs the homocysteine metabolism is shown to be overrepresented among depressive patients, which strengthens the association. On the basis of current data, we suggest that oral doses of both folic acid (800 microg daily) and vitamin B12 (1 mg daily) should be tried to improve treatment outcome in depression.
  • is the classic term used to describe the megaloblastic anemia which develops as a result of autoimmune destruction of the gastric mucosa (atrophic gastritis) and autoantibodies directed against intrinsic factor. PA is said to occur most commonly in elderly Caucasians of northern European extraction and in younger African-Americans
    methionine synthase activity slows down, reducing the rate of conversion of methyltetrahydrofolate to tetrahydrofolate, the active form of folate.
    Thus vitamin B-12 deficiency effectively induces a functional folate deficiency, with significant “methylfolate trapping
    Pernicious anemia also can cause other problems, such as nerve damage, neurological problems (such as memory loss), and digestive tract problems. People who have pernicious anemia also may be at higher risk for weakened bone strength and stomach cancer.
  • B12-dependent enzymes Methylmalonyl Coenzyme A mutase, and 5-methyltetrahydrofolate-homocysteine methyltransferase (MTR), also known as methionine synthase; and the buildup of their respective substrates (methylmalonic acid, MMA) and homocysteine.
    The Supply of folic acid for the production of thymine due to methyl transferring facilitated by b12
    In the form of a series of tetrahydrofolate (THF) compounds, folate derivatives are substrates in a number of single-carbon-transfer reactions, and also are involved in the synthesis of dTMP (2′-deoxythymidine-5′-phosphate) from dUMP (2′-deoxyuridine-5′-phosphate). It is a substrate for an important reaction that involves vitamin B12 and it is necessary for the synthesis of DNA, and so required for all dividing cells.[16]
    The pathway leading to the formation of tetrahydrofolate (FH4) begins when folic acid (F) is reduced to dihydrofolate (DHF) (FH2), which is then reduced to THF. Dihydrofolate reductase catalyses the last step.[90] Vitamin B3 in the form of NADPH is a necessary cofactor for both steps of the synthesis. Thus, hydride molecules are transferred from NADPH to the C6 position of the pteridine ring to reduce folic acid to THF.[91]
    Methylene-THF (CH2FH4) is formed from THF by the addition of a methylene bridge from one of three carbon donors: formate, serine, or glycine. Methyl tetrahydrofolate (CH3-THF, or methyl-THF) can be made from methylene-THF by reduction of the methylene group with NADPH.
    Another form of THF, 10-formyl-THF, results from oxidation of methylene-THF or is formed from formate donating formyl group to THF. Also, histidine can donate a single carbon to THF to form methenyl-THF.
    Vitamin B12 is the only acceptor of methyl-THF, and this reaction produces methyl-B12 (methylcobalamin). There is also only one acceptor for methyl-B12, homocysteine, in a reaction catalyzed by homocysteine methyltransferase. These reactions are of importance because a defect in homocysteine methyltransferase or a deficiency of B12 may lead to a so-called "methyl-trap" of THF, in which THF is converted to a reservoir of methyl-THF which thereafter has no way of being metabolized, and serves as a sink of THF that causes a subsequent deficiency in folate.[84] Thus, a deficiency in B12 can generate a large pool of methyl-THF that is unable to undergo reactions and will mimic folate deficiency.
    The reactions that lead to the methyl-THF reservoir can be shown in chain form:
    folate → dihydrofolate → tetrahydrofolate ↔ methylene-THF → methyl-THF
  • http://www.plosone.org/article/info%3Adoi%2F10.1371%2Fjournal.pone.0012244
    in fact, the most common Alzheimer’s drug works by boosting acetylcholine).
    First, the vitamins appeared to halve shrinkage across the whole brain compared with the brains of the people taking the placebo pill. But second, and very  significantly, the vitamins only benefited people who had a high homocysteine level — over 13 (a healthy level is said to be between about seven and ten).
  • FIGURE 23.16 The biosynthesis of cysteine in animals. (A stands for acceptor.)
    Methyl transfer from S‐AdoMet is highly favored chemically and metabolically. First, transfer of the methyl group relieves a positive charge on the Sulfur of S‐AdoMet. Secondly, the bond between the Sulfur and the 5′ carbon of the adenosine is rapidly hydrolyzed, leaving homocysteine and free adenosine. This last step is important, because the product remaining when S‐AdoMet gives up its methyl group, S‐adenosyl‐homocysteine, is a potent inhibitor of methyltransferases. Cleavage of this product removes the inhibitor from the reaction.
    Homocysteine itself is converted to methionine by the transfer of a methyl group from N5‐methyl‐tetrahydrofolate to homocysteine, regenerating methionine. The methyl group of N5‐methyl‐tetrahydrofolate is derived from serine, originally, so the net effect of this pathway is to move methyl groups from serine to a variety of acceptors, including homocysteine, nucleic acid bases, membrane lipids, and protein side chains. Serine itself is easily made from 3‐phosphoglycerate by an amino transfer reaction, followed by cleavage of the phosphate.
  • Glutathione id important it acts as a free radical scavengers
    Serine (α-amino-β-hydroxypropionic acid) is necessary for the condensation reaction with homocysteine to cystathionine (transsulfuration, cysteine) and also in the folic acid cycle during the reaction of tetrahydrofolate (THF) to 5,10 methylene-THF. Besides, serine is used as a precursor of the biosynthesis of purine bases and of certain phosphoglycerides (components of biological membranes). Therefore, the human body requires large amounts of it. Serine is produced from 3-phosphoglycerate, an intermediate product of glycolysis. Serine-hydroxymethyltransferase (SHMT) [EC 2.1.2.1.] transfers the hydroxymethyl group to THF by producing 5,10-methylen-THF, the original central linkage for the carbon atom transfer for the pyrimidine synthesis and the methylation cycle. Hence, SHMT plays an important role in the carbon metabolism.
    Serine and glycine (α-aminoacetic acid) directly depend on one another and can easily be converted into each other as long as there is availability of folate and vitamin-B6. During the glycine synthesis, the β-carbon atom of serine is transferred to THF whilst glycine can be converted from THF to serine by taking on a hydroxyl methyl group: Serine + THF « Glycine + Methylene-THF + H2O. This reaction is catalysed by the (equally vitamin-B6-dependent) enzyme serine-transhydroxymethylase. Glycine also is very significant as the (inhibiting) neurotransmitter in the spinal cord and the brain stem.
    http://www.benbest.com/health/Meth.html
  • The researchers assigned 390 Type 2 diabetes patients at the outpatient clinics of three nonacademic hospitals to take either metformin or a placebo pill three times per day for more than four years. The average study participant had been diagnosed with diabetes 13 years prior and had been undergoing insulin treatment for seven years. Average participant age was 61.Among those taking metformin, vitamin B12 levels began to steadily drop relative to those who were taking a placebo pill. The biggest drop occurred in the first few months, but the decrease continued over the course of the study.After four years, participants in the metformin group had undergone a 19 percent relative reduction in their levels of the nutrient. They were 11.2 percent more likely than placebo participants to suffer from B12 insufficiency and 7.2 percent more likely to suffer from deficiency.
  • In order to examine the action of vit.B12 on cells of the human immune system, lymphocyte subpopulations and NK cell activity were evaluated in 11 patients with vit.B12 deficiency anemia and in 13 control subjects. Decreases in the number of lymphocytes and CD8+ cells and in the proportion of CD4+ cells, an abnormally high CD4/CD8 ratio, and suppressed NK cell activity were noted in patients compared with control subjects. In all 11 patients and eight control subjects, these immune parameters were evaluated before and after methyl-B12 injection. The lymphocyte counts and number of CD8+ cells increased both in patients and in control subjects. The high CD4/CD8 ratio and suppressed NK cell activity were improved by methyl-B12 treatment. Augmentation of CD3−CD16+ cells occurred in patients after methyl-B12 treatment. In contrast, antibody-dependent cell-mediated cytotoxicity (ADCC) activity, lectin-stimulated lymphocyte blast formation, and serum levels of immunoglobulins were not changed by methyl-B12 treatment. These results indicate that vit.B12 might play an important role in cellular immunity, especially relativing to CD8+ cells and the NK cell system, which suggests effects on cytotoxic cells. We conclude that vit.B12 acts as an immunomodulator for cellular immunity.
    In conclusion, we found a significant decrease in the absolute number of CD8+ cells and suppressed NK cell activity in vit.B12-deficient patients. These abnormalities could be at least partly restored by methyl-B12 treatment. Moreover, augmentation of CD8+ cells by methyl-B12 treatment was observed even in control subjects. These observations may contribute to our understanding of the potential anti-tumor effects of vit.B12, and may partly explain the high risk of gastric carcinoma in PA; our data also provide a rationale for considering the use of vit.B12 for treating a variety of other immunological, neurological, and oncological disorders.
  • Effect of methyl-B12 administration on lymphocyte subsets and NK cell activity in patients and control subjects
    leucocyte counts and lymphocyte counts, CD4+, CD8+, CD56+ cell counts and NK cell activity were measured at the end of the 2-week treatment with methyl-B12. Results of statistical analysis of immunological parameters before and after methyl-B12 administration in both patients and control subjects are summarized in this table. The leucocyte counts and lymphocyte counts of patients were increased significantly after methyl-B12 treatment (P < 0.05). After treatment, the lymphocyte counts was still significantly lower in patients than in control subjects (P < 0.05). Interestingly, an increase in the lymphocyte counts was observed even in control subjects (P < 0.05).
  • The CD8 cell is an immune system T lymphocyte believed to "put the brakes on" the immune system, making the allergy patient less sensitive to allergens such as pollen, cats, and mold. Typically, allergic individuals have numbers of the CD8 suppressor cells that are low relative to CD4 aggressor cells.
    http://www.patentstorm.us/patents/6255294/description.html
    When Vitamin B12 is delivered parenterally, it passes into the circulation for distribution throughout the body before arriving at the liver. It is during this first pass in its native form that it is believed to exert its therapeutic effect.
  • Administer hydroxocobalamin (Cyanokit) or the Cyanide Antidote Kit if a diagnosis of cyanide toxicity is strongly suspected, without waiting for laboratory confirmation.
    Hydroxocobalamin, routinely used in Europe, has been approved by the US Food and Drug Administration (FDA) for treating known or suspected cyanide poisoning. Hydroxocobalamin combines with cyanide to form cyanocobalamin (vitamin B-12), which is renally cleared.[7, 8]
    The Cyanide Antidote Kit contains amyl nitrite pearls, sodium nitrite, and sodium thiosulfate. Amyl and sodium nitrites induce methemoglobin in red blood cells, which combines with cyanide, thus releasing cytochrome oxidase enzyme. Inhaling crushed amyl nitrite pearls is a temporizing measure before IV administration of sodium nitrite.
    Sodium thiosulfate enhances the conversion of cyanide to thiocyanate , which is renally excreted. Thiosulfate has a somewhat delayed effect and thus is typically used with sodium nitrite for faster antidote action.
    Borron SW, Baud FJ, Mégarbane B, Bismuth C. Hydroxocobalamin for severe acute cyanide poisoning by ingestion or inhalation. Am J Emerg Med. Jun 2007;25(5):551-8. [Medline].
    Borron SW, Baud FJ, Barriot P, Imbert M, Bismuth C. Prospective study of hydroxocobalamin for acute cyanide poisoning in smoke inhalation. Ann Emerg Med. Jun 2007;49(6):794-801, 801.e1-2. [Medline].
  • Not only does the cyanide in cyanocobalamin poison you like some crazy rendition of Arsenic and Old Lace, the cyanide actually depletes your body of stored methyl groups. At the same time, these methyls are needed to synthesize cobalamin in your liver.
  • he discovery of vitamin B(12), the elucidation of its role in metabolism, and the effects and treatment of its deficiency occurred in distinct phases over more than 100 years, and it was the subject of two separate Nobel Prizes. The valuable contribution of clinical reports and studies of patients with pernicious anemia throughout the 19th century resulted in enough clinical definition to allow Minot and Murphy to put together the first hallmark study on treatment of the condition, leading them to a Nobel Prize. These researchers were not the first to suggest that an inadequacy of nutrients was the cause of pernicious anemia, but their particular input was a carefully designed intervention in well-characterized pernicious anemia patients, of a special diet containing large amounts of liver. They found consistent improvement in the clinical and blood status of all subjects, most of whom remained on remission indefinitely. After the successful intervention studies, the next advance was made by Castle who discovered that a gastric component, which he called intrinsic factor, was missing in pernicious anemia. Many years later, intrinsic factor was found to be a glycoprotein that formed a complex with vitamin B(12), promoting its absorption through ileal receptors. The vitamin was isolated by two groups simultaneously and was crystallized and characterized in the laboratory of Dorothy Hodgkin, contributing to her Nobel Prize in 1964. Subsequently, the various biochemical roles of vitamin B(12) were elucidated, including its important interaction with folate and their common link with megaloblastic anemia. Many of the early clinical studies recognized that vitamin B(12) deficiency also caused a severe neuropathy leading to paralysis and death, while post mortem analysis demonstrated spinal cord demyelination. Vitamin B(12) is still the subject of intense research and, in particular, its role in preventing these irreversible neurological lesions remains unclear.
  • Vitamin B-12 Chemistry and Mode of Action

    1. 1. Vit.B12 Chemistry and Mode of Action
    2. 2. Outline Vitamins; Vit B-12 structure Sources Biological Glance Vitmain B-12 deficiencies and clinical implications. Applications Side effects
    3. 3. Vitamins- general concepts • What are vitamins? Any group of organic compounds that either our own bodies cannot synthesize them, or they are not synthesized in amounts sufficient for our needs. Thus we must obtain them from the foods we eat, or via vitamin supplements. 1 • What is the difference between fat-soluble and water-soluble vitamins? - Fat-soluble vitamins are stored in the liver and fatty tissues. These are not readily excreted from the body such as vitamin A, vitamin D, vitamin E and vitamin K. - Water-soluble vitamins travel in the blood and are stored in limited amounts. These are readily excreted from the body through urine such as, Vit C, Vit B12, thiamin, niacin, riboflavin, tryptophan, pantothenic acid, biotin, and folic acid.
    4. 4. Vit B12 (cobalamin)  Is a complex biochemical structure, but is water soluble.  Vitamin B12 is generic name for group of compounds called corrinoids (four pyrrole rings). ◦ corrin nucleus ◦ atom of cobalt in center ◦ attached are one of following     CN = cyanocobalamin (CNCbl) OH=hydroxocobalamin (OHCbl) 5’-adenosyl=adenosylcobalamin*(AdoCbl) -CH3=methylcobalamin* (MeCbl)
    5. 5. Figure1: B12 simple schematic diagram; functional groups are color-coded
    6. 6. Figure 2: B12 structure
    7. 7. Sources • • • • Seldom found in foods from plants Synthesis is limited to bacteria. Rumen microbial synthesis depends on the supply of cobalt in the diet Animal products ▫ Derive their cobalamin from micro-organisms; Animal derived foods are a primary source since animals eat another animal food, they produces B12 internally due to the intestinal bacteria (not present in humans), and they eat food contaminated with bacteria. ▫ Meat, poultry, fish, shellfish, eggs, milk, milk products ▫ Liver is a good source • Supplements Cyanocobalamin and hydroxycobalamin
    8. 8. B12 (Biological Glance)  Metabolizing fats and proteins. For example, it is important for amino acid incorporation; like Methionine (Sulfur containing amino acids.  1-Carbon Transfer. For Example, it is important for the sythesis of folate (vitamin B9; folic acid) and of methionine.  Proper nerve function  production of red blood cells.  DNA reproduction
    9. 9. Odd-Chain Fatty acids Catabolism Figure 3: The The oxidation of a fatty acid containing an odd number of carbon atoms.
    10. 10. Figure 3-1 Conversion of propionyl-CoA . to succinyl-CoA
    11. 11. Figure 3-2 The propionyl-CoA carboxylase reaction.
    12. 12. Figure 3-3 The rearrangement catalyzed by methylmalonyl-CoA mutase.
    13. 13. Methionine synthesis
    14. 14. The role of 5‐methyl tetrahydrofolate in such oxidation process 5-methyltetrahydrofolate Tetrahydrofolate
    15. 15. CLINICAL CROSSROAD Dee BB12 D 12 fifcc i iee i nn ccy y 11/29/13
    16. 16. Pernicious Anemia  • Is the classic term used to describe the megaloblastic anemia which develops as a result of autoimmune destruction of the gastric mucosa (atrophic gastritis) and autoantibodies directed against intrinsic factor which is needed for the absorption of B12 in our bodies and is mainly secreted from gastric parietal cells. • This type of anemia lacks the B12 which coplues with the folate to produce red blood cells. Otherwise, your red blood cells don't divide normally and are too large. They may have trouble getting out of the bone marrow—a sponge-like tissue inside the bones where blood cells are made.
    17. 17. Synthesis of dTMP from dUMP The salvage pathway to dTTP synthesis involves the enzyme thymidine kinase which can us either thymidine or deoxyuridine as substrate: thymidine + ATP <——> TMP + ADP deoxyuridine + ATP <——> dUMP + ADP The activity of thymidine kinase (one of the various deoxyribonucleotide kinases) is unique in that it fluctuates with the cell cycle, rising to peak activity during the phase of DNA synthesis; it is inhibited by dTTP.
    18. 18. Alzheimer &Memory loss (fact or fiction)  The possible link is that Vit.B12 effectively help in keeping & controlling the levels of homocysteine in our bodies. Normally we don’t have much of this because it is quickly turned into two important brain chemicals, including acetylcholine, which is essential for laying down memories.  There have been lots of studies showing that Alzheimer’s patients have unusually high levels of homocysteine in their bloodstream. They also have low levels of acetylcholine 3
    19. 19. Possible role of vitamin B12 in choline synthesis
    20. 20. The biosynthesis of cysteine in animals. (A stands for acceptor.) Fig. 23-16, p.642
    21. 21. Peripheral Neuropathy • Damage to one or more of the peripheral nerves in the body. The damage means that the messages that travel between the central and peripheral nervous system are disrupted. There are many different conditions that can lead to peripheral neuropathy. • Interestingly, diabetes is the most common cause of persistent (chronic) peripheral neuropathy. (What’s the link with B12??) • Noteworthy,  peripheral neuropathy is typically diagnosed as diabetic neuropathy, but this can also be a symptom of vitamin B12 deficiency! 4
    22. 22. Metformin induce B12 Deficiency • Common, potentially damaging, and well-documented complication of metformin (popular diabetes drug) is vitamin B12 malabsorption which is poorly recognized and not screened for or treated prophylactically by the majority of physicians who prescribe metformin. • Interestingly the clinical presentation of the neuropathic symptoms and clinical findings could be easily misdiagnosed as being due to diabetic neuropathy, which would have further prolonged the time to diagnosis and treatment of the neuropathy and resulted in further neurological damage. 4
    23. 23. Hot topics- Vit B12 applications! • It has been suggested that B12 has a vital role in regulating the immune system response, more specifically the cellular mediated immunity. In a study conducted in Gunma University School of Medicine, Japan in 1999 of 11 patients with B12 deficiency, the lymphocyte subpopulations and NK cell activity were evaluated. • The findings of this study has shown a considerable decrease in the total number of CD8+ cells and suppressed NK cell activity in vit.B12deficient patients Wherein, these abnormalities could be at least partly restored by methyl-B12 treatment. Moreover, augmentation of CD8+ cells by methyl-B12 treatment was observed even in control subjects 5
    24. 24. Vitamin B12 in IgE-mediated Allergic Reactions  The mechanism of action for Vitamin B12 in IgE-mediated allergic diseases, such as allergic rhinitis and asthma, may involve the maturation of certain immune system cells including polynucleated cells, natural killer (NK) cells, and CD8 cells.  These immune system cells may require a sustained and elevated serum Vitamin B12 concentration to develop from an immature state to a mature state in which they can exert their down-regulatory function on the immune system. Polynucleated cells are known to have memories that last many years, a concept consistent with controlled studies demonstrating reductions in symptoms and in specific IgE levels persisting many months after parenteral Vitamin B12 treatment.
    25. 25. Vit B12 and Cyanide poisoning  Vitamin B-12 has the largest and most complex chemical structure of all vitamins. On the same note, vitamin B-12 is the only vitamin that contains a metal, a cobalt(II) ion bonded to a porphyrin-like- chelating agent.  How does it work in treating Cyanide Toxicity? Hydroxocobalamin combines with cyanide to form cyanocobalamin (vitamin B-12), which is renally cleared.
    26. 26. Double faces! (B-12 as a Villain)  Most B-12 circulating in the blood is in the methylcobalamin form. Before the body can use the cyanocobalamin form, it must be converted by the liver to methylcobalamin.  Dark side of the industry? The history of vitamin B-12 and the switch from the methyl to the cyanide form of B-12 is the result of using charcoal to filter extracts during the isolation of B-12. Cyanide in charcoal rapidly converts all natural forms of B-12 into the cheaper "more stable" (but NOT better) cyanide form. Because of this fact, the discovery of B-12 coenzymes and their life-altering metabolic role was delayed for years. Once again, Big Money and sloppy science are helping destroy our health.
    27. 27. Side Effects?  Vitamin B12 is LIKELY SAFE for most people when taken by mouth or when the prescription-only, injectable product is used correctly.  In some people, vitamin B12 might cause diarrhea, blood clots, itching, serious allergic reactions, and other side effects.
    28. 28. References 1- Campbell M. K., Farrell S. O. (2009). Belmont, USA , Cengage Learning. 2- Toh B.-H., et al (1997). Pernicious Anemia, New England Journal of Medicine. 337:1441-1448. 3- A. D. Smith S.M., et al. (2010). Homocysteine-Lowering by B Vitamins Slows the Rate of Accelerated Brain Atrophy in Mild Cognitive Impairment: A Randomized Controlled Trial. PLoS ONE 5(9). 4- Callaghan B. C., Hur J., and Feldman E.L. (2012)Diabetic Neuropathy, Current Opinion in Neurology. 25(5):536-541.  5- Tamura, et al. Immunomodulation by vitamin B12: augmentation of CD8+ T (1999) lymphocytes and natural killer (NK) cell activity in vitamin B12-deficient patients by methyl-B12 treatmentClinical and Experimental Immunology. Clinical and Experimental Immunol. 116(1)28-32
    29. 29. Summary
    30. 30. History 1822: J.S. Combe described pernicious anemia. 1926: Minot and Murphy, treatment in lightly cooked liver 1928: W.B. Castle, intrinsic factor 1940s: Combs and Norris, close to isolation 1948: Isolation in USA and UK 1955: Elucidation of chemical structure 1970: de novo synthesis

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