Biochemistry of Vitamin B12 Kathleen Dorsch
Vitamin B12 Also known as Cobalamin Water-soluble vitamin Most complex structure and largest of the vitamins Only active substance in the human body to contain cobalt which gives the vitamin a red color
Vitamin B12 Image source: http://www.mikeblaber.org/oldwine/BCH4053/Lecture33/Lecture33.htm Core of Vitamin B12 (cobalamin) consists of a central cobalt atom surrounded by a corrin ring
Sources of B12 Vitamin B12 can only be obtained in the diet through meat and dairy products Only bacteria can synthesize B12 Animals consume bacteria and B12 through grazing, humans in turn consume B12 in animal products Although deficiency is rare, strict vegetarians or vegans are at risk for B12 deficiency Supplements are recommend for vegetarians and vegans Adults require intake of up to 3mcg/day; children require a minimum of 0.4mcg/day depending on age
Absorption of B12 Bound to protein in food and must be released through the action of pepsin in the stomach Once released, combines with cobalophilins and moves to the small intestine Intrinsic factor (IF), a specific binding protein for B12, binds the cobalamin Majority of B12 is absorbed in the manner, through IF and active transport Only 1% can be absorbed through simple diffusion Moves IF-B12 complex moves to ileum where it binds with transcobalamins (Tcs) which transport B12 to peripheral tissues
Absorption of B12 Image Source: http://www.aafp.org/afp/2003/0301/p979.html
Uses of B12 Two forms used in the body Methylcobalamin 5-deoxyadenosyl cobalamin Coenzyme required for two reactions Methylcobalamin cofactor for methionine synthase Methionine synthase needed for production of the amino acid methionine from homocysteine Methionine required for proper DNA synthesis 5-deoxyadenosyl cobalamin cofactor for methylmalonyl CoA mutase Methylmalonyl CoA mutase uses B12 as a cofactor for the conversion of L-methylmalonyl CoA to succinyl CoA for use in the Kreb's cylce
Uses of B12 Image Source: http://www.aafp.org/afp/2003/0301/p979.html Two reactions in the body require vitamin B12: succinyl-CoA synthesis and methionine synthesis
Methylcobalamin cofactor for methionine synthase Image Source: http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB12/figure9_2.html Conversion of homocysteine to methionine also requires folate B12 is needed during the conversion of 5-methyltetrahydrofolate (inactive) to THFA (active) Without B12, folate becomes trapped and the pathway cannot continue. THFA cannot form and 5-methyl THFA accumulates THFA is needed for conversion of deoxyuridylate to thymidylate, one of the four essential bases in DNA synthesis
Consequences of Methylfolate Trap DNA synthesis is interrupted Affects rapidly dividing cells such as erythrocytes formed in bone marrow Megaloblastic anemia occurs as a result Homocysteine levels elevated Linked to increased risk of cardiovascular disease
Megaloblastic Anemia Image Source: http://pathwiki.pbworks.com/w/page/14674016/HemaSlides9-10 Normal red blood cells on the left, megaolblastic cells on the right
Megaloblastic Anemia Megaloblastic anemia characterized by oversized or macrocytic, immature red blood cells Since folate and B12 work so closely together, folate deficiency is usually seen as the cause of anemia When treated with folate supplementation, anemia will improve but neuropathy often seen with B12 deficiency will not Megaloblastic anemia should not be treated before discovering the true cause
5-deoxyadenosyl cobalamin cofactor for methylmalonyl CoA mutase B12 is an important component of odd-chain fatty acid oxidation Oxidation of odd-chain fatty acids yields one propionyl CoA and one acetyl CoA Fatty acids with an even number of carbons yield two acetyl CoA molecules Pathway entails a rearrangement that requires B12 5-deoxyadenosyl cobalamin form of B12 is utilized
Succinyl CoA synthesis Propionyl CoA is carboxylated at the expense of the hydrolysis of a molecule of ATP to yield D-methylmalonyl CoA This reaction catalyzed by propionyl CoA carboxylase, a biotin enzyme similar to pyruvate carboxylase D-methylmalonyl CoA is then racemized to the L isomer Methylmalonyl CoA mutase, with B12 as its coenzyme, then catalyzes and intramolecular rearrangement to form succinyl CoA The -CO-S-CoA group migrates from C2 to methyl group in exchange for a hydrogen atom Image source: http://themedicalbiochemistrypage.org/fatty-acid- oxidation.php
Krebs Cycle/TCA Cycle Image Source: http://www.virtualmedstudent.com/links/biochemistry/krebs_cycle.html Succinyl-CoA produced through beta-oxidation of odd-chain fatty acids enters the Krebs or TCA cycle to produce energy
Deficiency of B12 and Succinyl CoA Pathway If B12 is deficient, either through diet or poor absorption, methylmalonyl CoA levels increase. As a result, the succinyl pathway is disrupted. Abnormal fatty acids may form and incorporate into neural lipids. This may lead to myelin breakdown and be responsible for neurological defects seen in B12 deficiency.
Causes of Vitamin B12 Deficiency Common causes of B12 deficiency include: Inadequate ingestion • Strict vegetarian or vegan diet for an extended number of years – Alcoholism – B12 stores usually last several years so inadequate ingestion is rarely the – cause of deficiency Inadequate absorption • – Pernicious anemia – Atrophic gastritis – Any condition that interferes with gastric acid/enzyme production or IF binding Older adults at a greater risk for deficiency due to decreased action of gastric • enzymes
Vegetarian or Vegan Diets The sole dietary sources of vitamin B12 come from animal sources Those individuals following a strict vegetarian or vegan diet can develop a B12 deficiency Vegetarians can obtain some of the daily B12 requirement from fortified foods such as cereal Pregnant or lactating women who are vegetarian/vegan are at risk of causing deficiency in infants if they do not obtain necessary requirements Strict vegetarians or vegans are encouraged to take a B12 supplement Because B12 is stored efficiently in the body, it takes several years of eliminating B12 food sources to develop symptoms of deficiency
Pernicious Anemia Megaloblastic macrocytic anemia caused by B12 deficiency, secondary to lack of IF. Vitamin B12 cannot be absorbed without IF, resulting in deficiency. Red blood cells become enlarged and abnormal.
Atrophic Gastritis Often seen in older adults, a condition of chronic gastritis with atrophy of mucous membranes and destruction of peptic glands. Sufficient stomach acid is required for absorption of B12 and can lead to deficiency. Atrophic gastritis is a leading cause of deficiency in older adults.
Consequences of Deficiency Two major consequences of B12 deficiency include: Megaloblastic anemia (see previous slides) Neuropathy
Neuropathy Long-term deficiency leads to impaired myelination or demyelination of the spinal cord and brain Leads to paresthesia (especially numbness/tingling in hands and feet) Diminution of senses of vibration and position Poor muscular coordination Memory loss Hallucinations
Medical Management Treatment of vitamin B12 deficiency involves intramuscular or subcutaneous injection of 100mcg or more of vitamin B12 once per week. Large oral doses of 1000mcg daily can also be effective, as 1% will be absorbed by simple diffusion. Injections must be maintained in patients with pernicious anemia, usually on a monthly basis. Neurological symptoms usually resolve with treatment, but prolonged effects may remain.
References Ashkenazi, S., Weitz, R., Varsano, I., & Mimouni, M. (1987, December 1). Vitamin B12 deficiency due to a strictly vegetarian diet in adolescence. Clincal Pediatrics, 26 (12), 662-663. doi:10.1177/000992288702601211 Brooks, V. (2012). Vitamin B12 & folate biochem physiology pharm A [PowerPoint Slides] Dietary supplement fact sheet: Vitamin B12 . (2011, June 24). Retrieved March 25, 2012, from Office of Dietary Supplements, National Institutes of Health website: http://ods.od.nih.gov/factsheets/vitaminb12/ Dror, D. K., & Allen, L. H. (2008). Effect of vitamin B12 deficiency on neurodevelopment in infants: Current knowledge and possible mechanisms. Nutrition Reviews, 66 (5), 250- 255. doi:10.1111/j.1753-4887.2008.00031.x Higdon, J., & Drake, V. (2007, August). Micronutrient information center . Retrieved March 25, 2012, from Linus Pauling Institute at Oregon State University website: http://lpi.oregonstate.edu/infocenter/vitamins/vitaminB12/ Mahan KL, Escott-Stump S. Krause's Food and Nutrition Therapy. 12 th Ed. St. Louis, MO: Saunders Elsevier; 2008. Truswell, A. S. (2007, September). Vitamin B12. Nutrition & Dietetics, 64 (Supp 4), S120- S125. doi:10.1111/j.1747-0080.2007.00198.x
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