Biochemical Aspects of Vitamin B12 Deficiency - Vitaminquick
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Biochemical Aspects of Vitamin B12 Deficiency - Vitaminquick
- 1. BIOCHEMICAL ASPECTS OF VITAMIN B12 DEFICIENCY By Vitaminquick
- 2. WHAT IS VITAMIN B12? • A collection of cobalt + corrin ring molecules that perform similar functions in the body • Essential water soluble biomolecule • Organometallic compound containing a cobalt ion, which colors the molecule red • Aids in the development of RBC’s, DNA production, myelin sheath fatty acid synthesis, and amino acid metabolism • Exists in a variety of forms called cobalamins • Manufactured by the microorganisms inside the stomachs of cows and sheep • Stored in the human Liver Cobalamin molecular formula = C63H88CoN14o14P
- 3. THE MAIN VARIETIES OF B12 Cyanocobalamin – used in vitamin supplements Methylcobalamin & 5-deoxyadenosylcobalamin – used in cellular metabolism
- 4. CORE OF THE MOLECULE Corrin Ring • The central metal ion is cobalt • Four of the six coordination sites are fulfilled by the Corrin ring • Dimethylbenzimidazole provides the fifth site • The sixth site is variable • Dark red color because of the cobalt-corrin complex
- 5. SOURCE AND STORAGE OF VITAMIN B12 • Not synthesized by plants and animals; humans do not manufacture B12 and must obtain it though dietary sources • Found in bacteria of animals in the intestines • Best sources: • Organs • Beef, Chicken, and Pork • Fish • Dairy products • Seafood • Nutritional Yeast • Fortified cereals and soy products • Liver stores B12 with enough for a 3 year supply • RDA: Children 0.2mcg/d, Adults 1mcg/d, Preg or lactating adult 1.5mcg/d,
- 6. ENZYMATIC & BIOLOGICAL IMPORTANCE • Vitamin B12 Folate and the relationship of Hyperhomocyctinemia • The cofactor adenosylcobalamin is required for the conversion of methylmalonyl coenzyme A to succinyl coenzyme A • Methylcobalamin is needed to convert 5-methyltetrahydrofolate to tetrahydrofolate and is necessary for DNA and red blood cell production • Formation of collagen
- 7. DEFICIENCY • Clinical deficiency is severe, exhibiting hematologic and/or neurologic signs and symptoms, cobalamin levels < 200 pg/mL, and levels for Hcy and methylmalonic acid (MMA) that are usually elevated. • Subclinical deficiency is the more common type & includes absent signs and symptoms, with only subtle changes in neurologic processes seen in some; low to low-normal cobalamin levels (200–350 pg/mL); and at least one metabolic abnormality (elevated homocysteine or elevated methylmalonic acid), usually mild. • Depleting stores can take 3-5 years • Deficiency is likely to happen in adults >65 years old, vegans, people with pernicious anemia, or who have had gastric surgery, gastritis, Crohn’s disease, HIV, or Celiac disease • Dietary B12 is absorbed in the ileum of the small intestine and requires the presence of R protein (haptocorrin from saliva), gastric acid, pepsin, and intrinsic factor
- 8. BIOMECHANICAL DISORDERS Pernicious Anemia- decreased ability of IF to bind to B12, treated with injections B12 malabsorption- caused by decreased stomach acid production and a resulting overgrowth of bacteria, treated with supplement B12 that is not bound to food B12 supplements can interact with certain medications
- 9. Methylation: the relationship of Folate and B12:
- 10. THANK YOU
Editor's Notes
- Vitamin B12 is the only essential biomolecule that contains a metal-carbon bond that is stable (organometallic compound). It is the most complex vitamin in existence. Vitamin B12 is actually a collection of cobalt + corrin ring molecules that perform similar functions in the body. They differ only by the side groups in the sixth coordination site position, which we will explore in further detail. These various forms of Vitamin B12 are called cobalamins (Encyclopedia Britannica, Inc., 2014. B12 is categorized as an essential, water soluble biomolecule. What makes this an organometallic compound is the fact that it contains a cobalt ion, which colors the molecule red (UC Davis, 2014). Vitamin B12 aids in some of the most important biological processes such as the development of RBC’s, DNA production, myelin sheath fatty acid synthesis, and amino acid metabolism (Ramsey, 2011). One of the most interesting facts amount this vitamin is that it is manufactured by the microorganisms inside the stomachs of animals such as cows and sheep. These animals possess the ability to digest insoluble plant fiber such as cellulose, which is made possible by the microbes, yeast, bacteria and fungi. The B12 then is stored inside the muscle of these animals and then humans consume the protein bound B12 from the animal (McKinley Health Center, 2008). Once digested, the vitamin is stored in the human Liver in large amounts in order ensure that there will be plenty in sufficient store for RBC & DNA production, myelin sheath and fatty acid synthesis, and amino acid metabolism.
- The three main and most commonly used varieties of vitamin B12 are cyanocobalamin, methylcobalamin, and 5-deoxyadenosylcobalamin. (Jaouen, G., ed. (2006) Cyanocobalamin is the man made form of B12 that is used in vitamin supplements. The structural formula for this variety is C63H89CoN14O14P. This form is manufactured by bacterial fermentation and can also be created in vitro. The process of fermentation by the microorganisms produce a variety of methylcobalamin, hydroxocobalamin, and adenosylcobalamin. These compounds are then subject to heat and sodium nitrate while adding potassium cyanide, which results in the conversion to cyanocobalamin. This supplemental version of vitamin b12 is given in an oral form, to patients who do not obtain sufficient amounts of the vitamin from their diet, and is also given intramuscular by injection to patients who can not absorb vitamin b12 in their small intestine (PubChem, 2014). Methylcobalamin (C63H91CoN13O14P) & 5-deoxyadenosylcobalamin (C72H100CoN18O17P) are the two active co-enzyme forms of B12 used in cellular metabolism. 5-deoxyadenosylcobalamin is manufactured from a fermentation process using beet molasses and mineral salts. Methylcobalamin exists in animal form but may also be manufactured (Thorne Research Inc., 2013).
- The structure is very complex so we will discuss the core of the molecule first. This is called the Corrin ring structure and is made of 4 pyrrole rings { a pyrrole ring has 4 carbons and 1 nitrogen, C4H5N }. This corrin ring is very flexible and more bulky than a typical porphyrin ring (Encyclopedia Britannica, Inc., 2014). The nitrogen in each of the pyrrole rings is facing towards the cobalt atom at the center. The color of the different forms of vitamin B12 is dark red because of the cobalt ion. Dimethylbenzimidazole provides the fifth site attached to the cobalt through its nitrogen atom, running down from the cobalt underneath the corrin ring. This benzimidazole is also connected to a pentose molecule, which attaches to a phosphate group and the rest of the structure. The bonding between the Cobalt and the 5,6-dimethylbenzimidazole is weak, which means it can sometimes be replaced by related molecules such as a 5-hydrozyl-benzimidazole, an adenine, or any other similar group. In the sixth position above the Corrin ring, is the active site of Cobalt which can attach several different groups. This is the location that determines the variety of B12 that will be formed. These groups include CN, which forms Cyanocobalamin, Methyl which forms methylcobalamin, 5’-deoxy adenosy group which forms adenosylcobalamin, and an OH group, which forms Hydroxycobalamin (UC Davis Geo, 2014).
- Vitamin B12 is not synthesized by plants and animals. Instead, it is synthesized by microorganisms inside the stomach of animals. Humans do not manufacture B12, therefore, humans must obtain B12 from dietary and/or supplement sources. Some of the highest amounts of B12 can be found in fish sources such as sardines, tuna, salmon, and cod. Beef and other meat sources such as chicken and turkey are also very good sources (The George Mateljan Foundation, 2014). Dairy is another natural source of B12. Milk has been shown to provide a highly bioavailable form of B12. However, people who follow a restrictive diet such as those with lactose intolerance or vegans, may not be able to include sufficient amounts in their diets. Supplements or alternative sources such as fortified cereals and nutritional yeasts may be necessary to sustain B12 stores. If oral supplements are used, it is recommended that 10mcg be taken daily or 2000mcg taken weekly. It is better absorbed when taken in lesser amounts so supplements should be taken in frequently in small amounts (Charest, RD, M.Sc, 2014).
- Methylcobalamin is a cofactor necessary to convert homocysteine to methionine. Methionine is an essential amino acid which is obtained through diet. Some methionine is turned into homocysteine. Homocysteine promotes cardiovascular disease at elevated levels due to oxidative and vessel wall damage. The body can usually turn homocysteine into methionine. However, if this pathway is blocked, levels if homocysteine will increase. Methylcobalamin is required by methionine synthase to convert homocysteine into methionine. If levels of B12 are insufficient, then homocysteine levels will rise. Thus, vitamin B12 deficiency increases homocysteine levels, which also increases risk of CVD. Dr. Greg gives a thoroughly entertaining explanation of this relationship in the youtube video in the slide. The entire video is about an hour long, so skip ahead to about the 47 minute mark for his homocysteine discussion (Greg, MD, 2013). Vitamin B12 is also important for bone health. Studies have shown a relationship between low B12 levels and bone fracture rates. B12 also helps iron absorption in plant foods and inhibits the formation of notrosamine by intestinal mucosa.
- Pernicious Anemia= patients that lack IF must receive parenteral B12 in the form of cyanocobalamin or high doses of oral B12 in the form of cobalamin (about 1% will be absorbed into the bloodstream) Depleting stores can take 3-5 years. Deficiency is likely to happen in adults >65 years old, vegans, people with pernicious anemia, or who have had gastric surgery, gastritis, Crohn’s disease, HIV, or Celiac disease. Atrophic gastritis= elderly patients produce less pepsin and hydrochloric acid in the stomach; can not free bound B12 from food. Dietary B12 is absorbed in the ileum of the small intestine and requires the presence of R protein (haptocorrin from saliva), gastric acid, pepsin, and intrinsic factor. Intrinsic factor is a protein produced by the stomach. If intrinsic factor is absent, the B12 will not be absorbed and will instead move through the body and be excreted. Gastric acid is required in order to be able to digest animal protein. If there is a decrease in secretion of gastric acid, the animal protein can not be properly broken down to release the vitamin B12 from the food (U.S. National Library of Medicine, 2013). Clinical deficiency is severe, exhibiting hematologic and/or neurologic signs and symptoms, cobalamin levels < 200 pg/mL, and levels for Hcy and methylmalonic acid (MMA) that are usually elevated. Subclinical deficiency is the more common type & includes absent signs and symptoms, with only subtle changes in neurologic processes seen in some; low to low-normal cobalamin levels (200–350 pg/mL); and at least one metabolic abnormality (elevated homocysteine or elevated methylmalonic acid), usually mild (CDC, 2009).
- Megaloblastic RBCs are large RBC’s with abnormal nuclei which can result from B12 anemia. Pernicious Anemia is the decreased ability of IF to bind to B12, which must be treated with injections of vitamin B12. B12 malabsorption caused by decreased stomach acid production and a resulting overgrowth of bacteria, is also treated with supplemental B12 that is not bound to food, making it easier to absorb (The Johns Hopkins University, 2013). Taking vitamin B12 supplements may interact with certain medications so it is important that health care providers are informed prior to the start of supplementation. Certain conditions such as diabetes involve medications like Metformin, which can result in a negative interaction and reduction in B12 levels. Other medications including Colchicine for the treatment of Gout, methotrexate used in chemotherapy, phenobarbital and other anti-seizure medicines, bile acid sequestrants, and proton pump inhibitors, may produce similar effects. Vitamin B12 may also reduce the effectiveness of certain antibiotics such as tetracycline, if taken at the same time (Ehrlich, N.M.D., 2007).
- Folate first becomes THF (Tetrahydrafolate). Glycine, Serine, and a cofactor Serine Hydroxymethyl transferase, all help convert THF to 5, 10-methylene THF. This molecule, 5,10-methylene THF, is next altered by Methylene THF reductase + FAD to become 5-methy THF. Cobalamin is now required to move the methyl group but if there is deficiency of B12 this can not occur. However, if enough B12 is present in the body, then the methyl group can attach to create methylcobalamin. Methylcobalamin then mixes with homocysteine with the assistance of methionine synthase to reduce the molecule down to methionine and replace the cobalamin for future use. The methionine can now be used in the body by combining with 1 ATP and methionine adenosyl transferase, which adds an adenine group to the methionine and removes the phosphate groups. S-adenosylmethionine (SAM) reacts with S-adenosylhomocysteine (SAH) and a methyl receptor to remove the methyl group and leaves behind S-adenosylhomocysteine. The SAH then becomes homocysteine, which is necessary to repeat the process and also necessary to continue the pathway to cysteine through the utilization of Vitamin B6 (Higdon, Ph.D, 2003).