Sources: made by bacteria, Meat, Fish Poultry, ONLY animal products! Forms: Cobalamin, generic for compounds called corrinoids, for B12 corrin has cobalt attached to it, active in human body= methylcobalamin and adenosylcobalamin. Meats: adenosylcobalamin & hydroxocobalaminMilks: methylcobalamin & hydroxocobalaminSupples: Cyanocobalamin& hydroxocobalaminDigestion & Absorption: Eaten in all formsStomach: -pepsin and HCL separate cobalamins from polypeptides.-R proteins (cobalophilins &haptocorrins made in stomach), found in saliva/gastric juices, binds to vitamins-Intrinsic Factors are made & released in stomach but fxn in intestine. Small Intestine: - cobalamin released from R protein by pancreatic proteases-Intrinsic factor binds to free cobalamin- Ileum: Huge doses= passive diffusion Dietary Doses: Cubilins-receptors for B12, then B12 & IF enter cell by receptor mediated endocytosis.Enterohepatic circulation: BILETransport: bound to 1 of 3 transocbalaminsTC1: circulating storageTC2: carries newly absorbed Co to tissuesTC3: delivery from tissues to liverTissues: uptake at tissues, receptor fro TC2, goes to receptor mediated endocytosis, lysosome degradesTC2 and get free B12 inside cell. Storage: liver is main site, stored as adenosylcobalamin less in: muscle,kidney,brain,bone,heart,spleen & in circulating blood as transcobalaminEnzymatic Reactions: 2 of them! Homocysteinemethionine 2 step process: formations of methylcobalamin the methlycobalamin donates methyl group to form cobalamin & methionine. Formation of Succinyl CoA from methylmalonylSuccinylCoA is a krebs intermediate, 5-deoxydenoslycobalaminExcretion: Urine: very little, Bile: enteroheptaic circulation, can be stored up to 11 years!B12: CobalaminAssessments: Main tests:Serum B12: serum levels can be falsely high/low with conditions or other diseasesMethylmalonic Acid: high with B12 deficieny, can be serum or urineHomocysteine: high with B12 deficiencyOthers:DUST: Deoxyuridine Supression Test: complicated and expensive, impaired thymidine synthesis dut to lack of B12TC2: lack of evidence to determine if it is a better indicator that serum B12Shilling Test: no longer done in US, determine problems wwtih absorp related to IF, give oral radioactive B12, measures urinary excretion, lower than normal urinary excretion= probs w/ absorp. Antibodies to IF: antibodies bind to protein then protein can’t fxn. Deficiency: In stages:1- serum: low levels of holotranscobalamin II2- cell concentrastions of vitamin diminish.3- biochemical deficiency occurs: decreased DNA synthesisa. Elevated homocysteine in serumb. high homocysteine= high risk factor for heart attackc. low methionine= low SAM (essential for nerve fxn)d. Elevated methylmalonic acid in serum4- Megaloblasic, macrocytic anemia (most common symp), may be caused by pernicious anemia, autoimmune conditions, anitbodies attack parietal cells, low IF production *pernicious anemia= lack of IF (gastric bypass, long term antacid)General Symptoms: pale skin, short breath, insomnia, dementia, fatigue, paresthesia, loss of concentration, palpitations, & neurological probsSevere B12 Deficiency Symptoms: neurological symptoms, degeneration of spinal cord, presentation of absent reflexes, ataxia, no sense of touch, results in severe irreversible brain & nervous system damage and death At Risk:Malabsorption: atrophic gastritis, gastrectomy, aclorrhydria (no acid in stomach), decreased absorptive rea in intestine, medications (proton pumps and H2 blockers)Deacreased intake: veggie dietsMutations of TC2: circulating storage, about 20 % of populationTreatment: oral supplements, intramuscular injectionsToxicity: none recorded, no UL setSources: mushrooms, green veggies, peanuts, legumes, citrus fruits, fortified products-1998 products had to be fortified w/ 140mg of folic acid/ 100g of product-Folacin= term used to describe compounds with similar structure and nutritional props as folate. Forms: Folic acid- synthetic & Folate- naturalMonoglutamates: one glutamic acid, found in supplements & fortified foods, transport form.Polyglutamates: 2-9 glutamates attached, found in cells, biologically active is tetrahydrofolate (THF)Structure: body can make all three pieces of compound but we can’t put them together.Digestion: Eaten as poly/monoglutamatesConjugases: cleave poly into mono, found in jejunal mucosa, brush border (Zn dependent), pancreatic juice & bile. Conjugases inhibitiors: prevent polys from breaking down into monos, legumes, cabbage, oranges. Require Zn= Metalloenzyme (conjugases)Absorption: proton coupled folate transporter (PCFT), genetic defect will cause a secondary B9 deficiency.Enterocyte: Folic acid and folateNADPH dihyrofolate reductaseDihydrofolateNADPH dihydrofolate reductaseTetrahydrofolateTransport: portal system= monoglutamates, sent to liver, Uptake at tissues= carries, reduced folate carries, proton coupled folate transporters (FR alpha, beta & gamma) Once inside cell 4-8 glutamates residues are attached (turn monos into polys) & now trapped in cell, conversion of coenzyme form.B9: FolateInvolved in:Mechanisms of Action: 1- accepts 1 C group from metabolic rxns2- donates the 1 C for synthesis rxnsAmino Acid Metabolism: (see sheet)1- histidine glutamate2- glycineserine3- glycine CO2 & NH44- homocysteinemethionineMethyl Folate Trap: B12 removes methyl group from 5 methyl THF, if no B12 the methyl group becomes trapped on the THFPurine and Pyrmidine Synthesis:Purines: adenine and guanine5-10methyl THF DHFPyrimidine: cytosine, thymine, uracil5-10methyl THF Formyl THFMethotrexate: binds to reductase enzyme, prevents cell division (DHFTHF)Excretion: Urine and used in bile, but most of bile is reabsorbed. Assessment: 1- serum and plasma levels : reflect recent dietary intake, RBC more indicative of tissue status, tells folate status at time RBC was synthesized. 2- N-formiminoglutamate (FIGLU) excretion: intermediate (histidineglutamate), B12 def, will also cause increased FIGLU excretion3- Deoxyuridine suppression test. 4- Plasma Homocysteine : functional marker, B12 def will also increase homocysteine. Deficiency: Megaloblastic macrocytic anemia: 1.clinical- low plasma folate, 2. 3-4 mons low folate intake= low RBC folate, 3. 4-5 mons. Bone marrow and other rapidly dividing cells become megaloblasic (immature)4. Blood cells are large in size & fewer in #, abnormal DNA syn., large immature cells w/ lots of hemoglobin. At
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