Vit.BVit.B12 12 Chemistry and Chemistry and Mode of Action Mode of Action

Outline Outline

Vitamins; Vit B-12 structure

Sources

Biological Glance

Vitmain B-12 deficiencies and clinical

implications.

Applications

Side effects

Vitamins- general conceptsVitamins- 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.

Vit BVit B1212 (cobalamin)(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)

Figure1: B12 simple schematic diagram; functional groups are color-coded

Figure 2: B12 structure

SourcesSources• 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• SupplementsCyanocobalamin and hydroxycobalamin

BB12 12 (Biological Glance)(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

Odd-Chain Fatty acids Catabolism

Figure 3: The The oxidation of a fatty acid containing an odd number of carbon atoms.

Figure 3-1Figure 3-1Conversion of propionyl-Conversion of propionyl-CoA CoA

to succinyl-CoA to succinyl-CoA..

Figure 3-2Figure 3-2The propionyl-CoA carboxylase reaction.The propionyl-CoA carboxylase reaction.

Figure 3-3 The rearrangement catalyzed by methylmalonyl-CoA mutase.

Methionine synthesisMethionine synthesis

The role of 5‐methyl tetrahydrofolate in such oxidation process

5-methyltetrahydrofolate Tetrahydrofolate

B12 Deficiency

B12 Deficiency

04/10/23

CLINICAL CROSSROADCLINICAL CROSSROAD

Pernicious Anemia 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.

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.

Alzheimer &Memory lossAlzheimer &Memory loss (fact or fiction) (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

Possible role of vitamin BPossible role of vitamin B12 12 in choline in choline synthesis synthesis

Fig. 23-16, p.642

The biosynthesis of cysteine in animals. (A stands for acceptor.)

Peripheral NeuropathyPeripheral 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

Metformin Metformin induce B12 induce B12 Deficiency 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

Hot topics- Vit B12 Hot topics- Vit B12 applications! 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.B12-

deficient 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

Vitamin BVitamin B1212 in IgE-mediated Allergic in IgE-mediated Allergic ReactionsReactions

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.

Vit B12 and Cyanide Vit B12 and Cyanide poisoningpoisoningVitamin 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.

Double faces! (B-12 as a Double faces! (B-12 as a Villain)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.

Side Effects? 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.

ReferencesReferences1- 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

Summary Summary

History 1822: J.S. Combe described pernicious anemia.1926: Minot and Murphy, treatment in lightly cooked liver1928: W.B. Castle, intrinsic factor1940s: Combs and Norris, close to isolation1948: Isolation in USA and UK1955: Elucidation of chemical structure1970: de novo synthesis