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| 8663005805 | Vitamin B12: History | 1849. English physician, Thomas Addison, describes a group of patients with a "remarkable form of anemia" 1871. Named "pernicious anemia" (i.e., fatal anemia) by Biermer 1920. Whipple describes treating experimental anemia in dogs by feeding raw liver 1926. Minot and Murphy successfully treat pernicious anemia in humans by feeding cooked beef liver (120 to 240 g/d) 1934. Nobel Prize in Physiology or Medicine Awarded jointly "for their discoveries concerning liver therapy in cases of anaemia". | 0 | |
| 8663038699 | Vitamin B12 Structure |  | 1 | |
| 8663043615 | Vitamin B12 (Cobalamin) | is the generic descriptor for corrinoid compounds exhibiting the biological activity of vitamin B12 | 2 | |
| 8663053246 | Corrinoid Compound | compound containing cobalt-centered corrin ring | 3 | |
| 8663098884 | Vitamin B12 Food Sources | -Synthesized solely by bacteria -Only dietary sources of B12 are animal products, which have derived their B12 from bacteria -Animal tissues that accumulate B12 (e.g. liver) are excellent food sources of the vitamin | 4 | |
| 8663110344 | Not Vitamin B12 Food Sources | -Plants do not synthesize B12 -Fruits, vegetables, and grains contain no B12 (unless contaminated by bacteria) | 5 | |
| 8663360564 | Foods Highest in B12 | -beef liver/kidney -chicken liver -clams -oysters -fortified foods (almond milk, cereal, tofu) | 6 | |
| 8663385078 | Natural B12 Absorption | bound to protein and must be released by gastric acid (HCl) to be absorbed | 7 | |
| 8663411162 | Synthetic B12 Absorption | not bound to protein | 8 | |
| 8663418691 | Vitamin B12-binding/ Transport Proteins | -R-protein -intrinsic factor -transcobalamin II | 9 | |
| 8663425479 | R-protein | (Also called haptocorrin or transcobalamin I) Glycoproteins secreted by salivary glands, binds to B12 and protects it from stomach acid | 10 | |
| 8663438307 | Intrinsic Factor | Glycoproteins secreted by gastric parietal cells, binds to B12 in intestine and transports it to IF receptor | 11 | |
| 8663446336 | Transcobalamin II | Main transport protein for B12 in plasma | 12 | |
| 8663453730 | Active Absorption: Stomach | -Food B12 is released from proteins by pepsin and HCl -Free B12 binds to R-protein, forming B12-R complex | 13 | |
| 8663472359 | Active Absorption: Duodenum | -B12-R is acted upon by pancreatic protease, releasing free B12 -Free B12 binds to intrinsic factor, forming B12-IF complex | 14 | |
| 8663480491 | Active Absorption: Ileum | -B12-IF binds to B12-IF receptor (cubilin) on intestinal cell -B12-IF-cubilin complex is internalized by endocytosis -B12 is released from IF-cubilin -Free B12 binds to transcobalamin II in portal bloodstream | 15 | |
| 8663496316 | B12 Passive Absorption | -Simple diffusion -Occurs throughout the small intestine -Inefficient (~1% absorbed) -Used in therapy ( >500 μg/day) -Usually given per os -Can be given intranasally | 16 | |
| 8663505614 | Atrophic Gastritis | -Chronic inflammation of gastric mucosa with loss of parietal cell function -Autoimmune disorder in which antibodies destroy parietal cells -Results in loss of intrinsic factor -*Most common cause of pernicious anemia* | 17 | |
| 8663530892 | Dr. William B. Castle | linked B12 deficiency and atrophic gastritis | 18 | |
| 8663549051 | B12 Transport Proteins | B12 in plasma is bound to transcobalamin (TC) proteins: -TCI -TCII -TCIII | 19 | |
| 8663555268 | TC | -(~80%) -Also known as haptocorrin -Circulating storage form | 20 | |
| 8663559987 | TCII | -(10-25%) -Main transport protein; delivers B12 to all cells | 21 | |
| 8663564694 | TCIII | function unknown | 22 | |
| 8663579715 | B12 Storage | -2-4 mg stored in body, mainly (~50%) in liver -70% stored as adenosylcobalamin | 23 | |
| 8663584679 | B12 Excretion | -Bile (~1.5 μg/day); about 70% reabsorbed -Patients with pernicious anemia do not reabsorb | 24 | |
| 8663591341 | B12 Function | -methyl group transfer reactions - mutases | 25 | |
| 8663598299 | Mutases | Exchange a hydrogen and some other groups between 2 adjacent carbon atoms | 26 | |
| 8663571571 | Cellular Uptake of B12 | B12 enters cells through receptor-mediated endocytosis B12 TCII in plasma--> enters endosome/lysosome by TCII receptor-->goes to methionine synthase OR methylmalonyl CoA mutase | 27 | |
| 8663648902 | Methionine Synthase (MS) | -Uses methylcobalamin as an intermediate methyl carrier at one active site of MS enzyme -Transfers methyl group from cobalamin to homocysteine at another active site | 28 | |
| 8663663338 | Methylmalonyl CoA Mutase (MCM) | -Located in mitochondria -Enzyme that catalyzes the isomerization of methylmalonyl-CoA to succinyl-CoA -Uses adenosylcobalamin in active site | 29 | |
| 8663670876 | Adenosylcobalamin | The Co-CH2 bond is relatively weak and can therefore be easily broken, forming a free radical that can abstract a hydrogen (i.e. from methylmalonyl CoA) | 30 | |
| 8663681702 | B12 Function: Remethylation of homocysteine | -Methylcobalamin -Occurs in cytoplasm | 31 | |
| 8663689557 | B12 Function: L-methylmalonyl CoA -> succinyl CoA | -Adenosylcobalamin -Occurs in mitochondria | 32 | |
| 8663700835 | B12 Deficiency Levels | -high homocysteine -high 5-CH3THF -low everything else | 33 | |
| 8663708762 | Megaloblastic Anemia | -DNA synthesis is needed for early erythroblasts to divide and mature -In folate/B12 deficiency, DNA synthesis is impaired; early erythroblasts cannot divide and escape into bloodstream -Early erythroblasts are large (megalo) and do not contain much hemoglobin | 34 | |
| 8663741314 | B12 Deficiency and MMA | -B12 is required for conversion of methylmalonyl CoA to succinyl CoA -In B12 deficiency, methylmalonyl-CoA accumulates and is hydrolyzed to CoA and methylmalonic acid (MMA) -*MMA accumulation is associated with neurodegeneration* | 35 | |
| 8663760674 | Masking of B12 Deficiency by Folic Acid | -B12 deficiency is often identified by megaloblastic anemia -Folic acid can correct megaloblastic anemia due to B12 deficiency—but cannot correct the other effects of B12 deficiency (i.e. neurologic effects) Thus, folic acid can "mask" or hide B12 deficiency -Folic acid treatment reverses anemia because B12 deficiency causes "secondary folate deficiency" because it reduces THF and thus 5,10-methyleneTHF for DNA | 36 | |
| 8663791947 | Anemia Due to B12 Deficiency | -degeneration of spinal cord -difficult to diagnose early stages -worsens without B12 therapy | 37 | |
| 8663800451 | B12 Status Indicators | -Diet and supplement history & medical history -Serum vitamin B12 (<300 pg/mL or <221 pmol/L mild def; <200 pg/mL or < 148 pmol/L- severe def) -Homocysteine increases: not specific but functional indicator -Methyl malonic acid increases: specific indicator, functional -Holotranscobalamin (<40 pg/mL or <30 pg/mL): newer method reflects serum levels -Megaloblastic anemia, not specific, severe deficiency | 38 | |
| 8692780881 | B12 Deficiency Causes | -severe malabsorption -abuse of nitrous oxide -inherited metabolic disorder -dietary deficiencies | 39 | |
| 8692809463 | Pernicious Anemia | Usually caused by lack of functional IF in stomach- autoimmune destruction of the gastric parietal cells (atrophic gastritis) Prevalence 2-3% of the population >65 years (rarely occurs in younger individuals) | 40 | |
| 8692829079 | Pernicious Anemia Treatment | -IM B12 injections (100 -1000 μg cyanocobalamin) Injections at monthly intervals -Oral B12 supplement (≥ 1000 μg) Daily dosing recommended | 41 | |
| 8692837429 | Food-Bound B12 Malabsorption due to Non-Autoimmune Gastritis | *Gastric atrophy* - Loss of stomach acid for extraction of B12 from food - Can absorb crystalline normally (have intrinsic factor) - May affect >30% of the elderly | 42 | |
| 8692847699 | H. Pylori | causes gastric atrophy | 43 | |
| 8692859005 | Vitamin B12 Status Elderly | -Elderly have lower serum vitamin B12 than younger individuals -Elevated serum methylmalonic acid concentrations common in elderly | 44 | |
| 8692867975 | Vitamin B12 and Nitrous Oxide | - Laughing gas, anesthesia - Oxidizes cobalt in B12 - Results in B12 deficiency and spinal cord degeneration as seen in classical B12 deficiency - Seen in dentists, dental assistants, individuals who use nitrous oxide as recreational drug | 45 | |
| 8692923651 | Macrobiotic B12 Deficient Diet | Diet consists of: - Grain cereals (mainly rice) - Vegetables - Pulses (mainly soy) - Sea vegetables - Small amount of fruit - Soup | 46 | |
| 8692955275 | Vitamin B12 Deficiency: Clinical Significance | -Impaired neurological function -Megaloblastic anemia -Neural tube defect increased risk | 47 | |
| 8692967419 | B12 Deficiency and Neurological Abnormalities | -Neurological degeneration of peripheral nerves-impaired touch and pain sensation -Ataxia- unsteady gait -Degeneration of spinal nerves | 48 | |
| 8692991830 | *B6* | 49 | ||
| 8693004617 | Vitamin B6: History | 1930's Scientists were characterizing vitamin B family members (vitamin B1, B2, B3) 1939 Chemical structured determined to be a pyridine derivative with several oxy (methoxy) groups; hence named "pyridoxin" 1934 Paul György identifies factor that cured dermatitis in rats; names it "vitamin B6 | 50 | |
| 8693047918 | PLP | pyridoxal phosphate, main form in the body | 51 | |
| 8693064947 | B6 Absorption | through passive diffusion | 52 | |
| 8857882770 | Alkaline Phosphatase | removes phosphate from PLP so that it can absorbed via passive diffusion as PL, PM, or PN | 53 | |
| 8693080384 | B6 Metabolism | in the liver | 54 | |
| 8693083061 | B6 Transport | main circulating form is PLP, mainly bond to albumin in plasma | 55 | |
| 8693099369 | Peripheral Tissue Uptake: Tissue Type | Plasma PLP is taken up mainly by muscle | 56 | |
| 8704363018 | Peripheral Tissue Uptake: B6 Location of Total Body PLP | 80-90% of total body PLP is in muscle | 57 | |
| 8704368664 | Peripheral Tissue Uptake: Glycogen Phosphorylase | Bound mostly to glycogen phosphorylase. One PLP molecule is found at each of the 2 catalytic sites. | 58 | |
| 8704390808 | Peripheral Tissue Uptake: B6 Overall Body Half-Life | ~25 days | 59 | |
| 8693127498 | Peripheral Tissue Uptake: B6 Total Body Storage | 60 -170 mg | 60 | |
| 8693131642 | B6 Excretion | urine, mainly as the metabolite 4-pyridoxic acid. ~50% of daily intake is converted to 4-pyridoxic acid | 61 | |
| 8693168468 | B6 Functions | PLP serves as a *coenzyme* in >100 enzymes | 62 | |
| 8693181083 | Main PLP-dependent Enzyme Reactions | -Transaminations -Decarboxylations -Transulfurations -R-group interconversions | 63 | |
| 8693189492 | Serine Hydroxymethyltransferase SHMT | Serine to glycine conversion, PLP is a coenzyme | 64 | |
| 8693240533 | B6 in Folate Cycle | shows up 3 times | 65 | |
| 8693258384 | PLP Enzymes | PLP-containing enzymes labilize specific bonds at the a-carbon atom of an amino acid substrate | 66 | |
| 8693266240 | Dopamine | -Neurotransmitter -Important in cognition, motivation, punishment, reward -Important for motor control -Produced in neurons -Parkinson's disease due to death of dopaminergic neurons | 67 | |
| 8693312230 | Transamination | -Key process in AA degradation -Catabolism of nearly all amino acids involves transfer of amino groups to a-keto acids | 68 | |
| 8857991325 | Transamination Mechanism | 1.) Amino acid's *nucleophilic* group attacks the Enz-PLP Schiff base carbon to form an amino acid-Schiff base with the release of Enz's Lys amino group 2.) Amino acid-Schiff base *tautomerizes* to a resonance-stabilized intermediate. The resonance stabilization facilitates the cleavage of the C=N bond 3.) Intermediate is *hydrolyzed to yield alpha-keto acid and PMP* |  | 69 |
| 8693318650 | Major Amino Group Acceptors | -a-ketoglutarate -pyruvate | 70 | |
| 8693327406 | PLP in Amino Transferases | PLP is bound to the enzyme through a Schiff base linkage to a Lys residue at the active site | 71 | |
| 8693334413 | Transamination Mechanism Steps | 1.) Amino acid's nucleophilic group attacks the Enz-PLP Schiff base carbon to form an amino acid-Schiff base with release of Enz's Lys amino group 2.) Amino acid-Schiff base tautomerizes to a resonance-stabilized intermediate. The resonance stabilization facilitates the cleavage of the C=N bond 3.) Intermediate is hydrolyzed to yield a-keto acid and PMP | 72 | |
| 8693357746 | B6 Status Assessment | Plasma PLP is best indicator • < 20 nmol/L = deficient • < 30 nmol/L = marginal | 73 | |
| 8693366509 | B6 Deficiency Occurrence | Relatively rare in US, Most common in elderly, alcoholics, individuals on certain drug therapies | 74 | |
| 8693373033 | B6 Deficiency: Clinical Symptoms | -Seborrhoeic dermatitis -Weakness -Neurological disorders -Seizures -Convulsions (infants) -Anemia | 75 | |
| 8693382598 | Drugs that interfere with Vitamin B6 Status | -Cycloserine/Isoniazid (Tuberculosis) -Hydralazine (High blood pressure) -Phenelzine (Depression) -Gentamycin (Antibiotic) -Penicillamine (Wilson's disease) -L-dopa (Parkinson's disease) -Oral contraceptives | 76 | |
| 8693398214 | B6 Toxicity | -Sensory & peripheral neuropathy (1-3 g/day) -Clinical misuse | 77 | |
| 8693404699 | B6 Prescription | -Asthma -PMS -Sickle cell disease -Carpal tunnel syndrome | 78 |
