S74: Folic Acid, Vitamin B12, and One Carbon Metabolism Learning Objectives 1) Understand the role of vitamin B12 and methionine as methyl donors in biological rxns. 2) Learn the role of Intrinsic Factor in vitamin B12 absorption and the consequences of the loss of intrinsic factor that can occur in the elderly. 3) Know how tetrahydrofolate (THF) functions as a one-carbon donor and the link between vitamin B12 and THF. 4) Recognize the consequences of folate deficiency and the importance of folate supplementation in avoiding those consequences. 1) Understand the role of vitamin B12 and methionine as methyl donors in biological rxns. - Amino acid biosynthesis!- 9 essential aa's that need to be eaten, but also 2 others we make need essential aa precursors so we can really only make 9 aa's from scratch!- almost all of the aa's that we can produce are involv. in biosyn. of other compounds- purines, pyrimidines, neurotrans!- use transaminases to go between aa's !- One-Carbon Metabolism= the transfer of 1 C - involves glycine, serine, methionine!- one carbon pool= all single carbon metabolites that can be used in biosyn. rxns (-CH3, -CH2OH, -CHO)!- involves 2 vits= folate and vitamin B12!- folate deficiency --> increased risk for neural tube defects!- vit B12 def. --> causes pernicious anemia - Structure of Vit B12= Cobalamin!- cobalt iron in corrin ring structure!- X group can be attached to diff. groups incl. methyl!- syn. only by bacteria!- major sources in diet: meat, eggs, dairy...!- Vit B12 dependent enzyme rxns!- cofactor in 2 enzyme rxns!1) an enzyme that syn. succinyl-CoA (intermed of TCA)!2) Methionine synthase --> catalyzes conversion of !homocysteine --> methionine !- critical rxn for resupplying methionine (major methyl !group donor) w/methyl groups!- Role of Methionine as a Methyl Donor!- methionine --> SAM --> gives CH3-product (methylated products) = a diff. product than it was before methylation !- the cycle of methylation is supported by methionine/homocysteine!!!! 2) Learn the role of Intrinsic Factor in vitamin B12 absorption and the consequences of the loss of intrinsic factor that can occur in the elderly.- Absorption of Cobalamin: Gastric Phase - complex absorption, problems assoc. with absorption= most common cause of Vit B12 deficiency!- stomach: low pH --> releases vit B12 from other proteins --> bind to R proteins (made by salivary glands and gastric mucosa) --> parietal cells release Intrinsic factor (glycoprotein)!- Absorption of Colbalamin: Lumenal Phase!- Pacreatic proteases digest R proteins --> release vit B12 --> Intrinsic factor resistant to digestive proteases --> intrinsic factor binds vit B12!- Absorption of Cobalamin: Mucosal Phase!- Vit B12/Intrinsic factor complex bound to specific receptor in ileum --> intrinsic factor not absorbed --> vit B12 passes thru intestional enterocyte into capillary bed!- Transport of Cobalamin!- transported in blood bound to carrier protein= transcobalamin!- about half of vit B12 is taken up by liver and half by peripheral tissues via specific transcobalamin receptor protein!- Excretion of Cobalamin!- is NOT metabolized, but is excreted as is into bile!- most of excreted B12 is rebound to intrinsic factor and reabsorbed!- vit B12 is highly conserved in our bodies!- Vit B12 Deficiency Disease: Pernicious Anemia - deficiency is rare, we only need a little and conserve it!- most common form of def. = pernicious anemia --> results from failure of parietal cells to secrete intrinsic factor!- prevalence increases w/age!- vit B12 malabsorption from: surgeries, autoimmune diseases (gastritis) that targets parietal cells, H. pylori infections!- Symptoms of vit B12 deficiency - Megaloblastic anemia= maturation of hematopoietic precursor cells disrupted due to defect in DNA synthese, WBCs and RBCs are enlarged, many cells die in bone marrow --> anemia!- folate deficiency causes identical condition!- Neurologic abnormalities due to demyelination of nerves (mental slowness, poor memory) 3) Know how tetrahydrofolate (THF) functions as a one-carbon donor and the link between vitamin B12 and THF. - Folate= precursor for methyl donor Tetrahydrofolate = FH4 - B12 has to be recharged w/a methyl group too, gets it from FH4 which is made from folate!- Vit B12 doesn't come in form that is preloaded w/CH3 group --> it acts as an intermed., picking up CH3 from FH4 made from vitamin folate!- Conversion of Folate to Tetrahydrofolate!- folate: in dark green leafy veggies, legumes, some fruit!- pteridine ring of folate can accept 4 e-'s (from NADPH) ---> to form tetrahydrofolate !- reduction of folate done by dihydrofolate reducatase using NADPH as e- donor!- One Carbon Metabolism!- THF= FH4= tetrahydrofolate can help make many diff. products (including purines, methionine,and TMP (from dUMP) by picking up and transferring different groups (incl. methyl groups) 4) Recognize the consequences of folate deficiency and the importance of folate supplementation in avoiding those consequences. - Folate Deficiency - chronic and severe fd assoc. w/megaloblastic anemia= large, abnormally nucleated RBCs that accum. in bone marrow and decreased # of WBCs and platelets that are abnormally large!- anemia from fd hard to tell apart from pernicious anemia!- req. of FH4 for syn. of PURINES and PYRIMIDINES = likely basis for dev. of anemia because hematopoiesis req. a lot of new DNA syn. for continuing cell production!- Vit B12 is NOT used as methyl donor for rxns involved in DNA syn. BUT still causes a similar condition because of the methyl trap hypothesis!- if you don't have vit B12 you get stuck in this trap --> so folate isn't happening --> so DNA syn. problems because of that !- folate= beginning methyl transfer molecule --> req. for nucleotide syn. --> req. to copy genome/cell division!- Methyl Trap Hypothesis!- w/o B12 --> folate gets trapped in its fully reduced 5-methyl tetrahydrofolate form --> insuffi. THF is available to support DNA syn!- THUS vit b12 def. --> metabolic folate def.!- Neural Tube Defects!- folate def. esp. during 1st trimester= assoc. w/increased risk of NTDs in fetus (e.g. spina bifida)!- folate supplementation decreases incidence of NTDs!- 1998: US decided to supplement all cereal grains and mixed food w/grains w/folate --> incidence of NTDs down by 19%!- Folate Supplementation--Associated Public Health Risk!- Symptoms of vit B12 def. in elderly= cognitive so if folate supplementaion resolves the anemia, only the
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