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INMD 6802Folic Acid, Vitamin B12and One-Carbon MetabolismLincoln R. [email protected], Oct. 27, 20148:00 –8:50 Class 74!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Summary of Major Lipoprotein Functions• Chylomicrons: Produced in the intestinal enterocytes. Carrier of dietary fat (triglycerides) and cholesterol. Synthesized with ApoB-48; picks up ApoC-II and ApoE from HDL. • Very Low Density Lipoprotein (VLDL): Produced in the liver. Carrier of triglyceride and cholesterol to extra-hepatic tissues. Synthesized with ApoB-100; picks up ApoC-II, and ApoE from HDL.• Low Density Lipoprotein (LDL): Produced from VLDL after loss of triglyceride. Primary carrier of cholesterol and cholesterol esters to peripheral tissues or to liver for excretion. Since coming from VLDL, it is synthesized with 1 molecule of ApoB-100 (binds LDL receptor), which is its main lipoprotein but also has ApoC-II and ApoE.• High Density Lipoprotein (HDL): Active in reverse cholesterol transport. Produced in liver and intestine. Exchanges lipid and apolipoproteins between particles. Uses ApoA-I, ApoCII and ApoE. 2!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Learning Objectives• Understand the role of vitamin B12and methionine as methyl donors in biological reactions.• Learn the role of Intrinsic Factor in vitamin B12absorption and the consequences of the loss of Intrinsic Factor that can occur in the elderly• Know how tetrahydrofolate (THF) functions as a one-carbon donor and the link between vitamin B12and THF• Recognize the consequences of folate deficiency and the importance of folate supplementation in avoiding these consequences !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Amino Acid Biosynthesis• Recall that humans only have the ability to synthesize 11 of the 20 amino acids, the remaining 9 essential amino acidsneeding to be consumed in the diet• Actually 2 of the amino acids that we can synthesize can only be made from an essential amino acid precursors, so we can only make 9 starting from scratch– tyrosine is made from the essential amino acid - phenylalanine– cysteine biosynthesis requires methionine for its S group• Almost all of the amino acids that we can produce are involved in the biosynthesis of other compounds – purines, pyrimidines, neurotransmitters !!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Overview of Amino Acid SynthesisTA = transaminase!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!One-Carbon Metabolism• Were going to focus our attention on the area of one-carbon metabolism, which involves the amino acids glycine, serine and methionine• The term one-carbon pool refers to all single carbon metabolites that can be used in biosynthetic reactions in its various oxidation states (e.g., -CH3, -CH2OH, -CHO)• One-carbon metabolism involves two important vitamins: folate and vitamin B12• Why should you care?– folate deficiency – increased risk for neural tube defects– vitamin B12deficiency – causes pernicious anemia!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Structure of Vitamin B12-CobalaminCobalamin is unusual in that it contains a cobalt ion complexed in a ring structure (a corrin ring) similar to a porphyrin ring.The X group (red circle) can be attached to various groups including a methyl group to yield–methylcobalamin.Cobalamin is synthesized exclusively by bacteria – it is not made by plants or animals.The major sources of cobalamin in our diets are meat, eggs, dairy, fish and seafood – all of these pick up cobalamin from the bacteria in their food supply!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Vitamin B12-dependent Enzyme Reactions• Cobalamin is used as a cofactor for only two enzyme reactions:• The first is an enzyme that synthesizes succinyl-CoA, an intermediate of the TCA cycle• The second is methionine synthase, which catalyzes the conversion of homocysteine into methionine• This reaction is critical for resupplying methionine, the major methyl donor in our bodies, with methyl groups!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Role of Methionine as a Methyl DonorSome of the specific reactions in which SAM functions as a methyl donorThe cycle of methylation supported by methionine / homocysteineSAMCH3!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Gb!!!!!!Absorption of Cobalamin – Gastric Phase• The absorption of vitamin B12is complex and problems associated with this process are the most common cause of vitamin B12deficiency• In the stomach, the low pH serves to release vitamin B12from other proteins and it binds to R proteins produced by the salivary glands and gastric mucosa• Parietal cells release another protein called Intrinsic Factor that will become important further down!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Absorption of Cobalamin – Luminal Phase• Pancreatic proteases digest R proteins releasing vitamin B12• Intrinsic Factor is a glycoprotein that is resistant to the actions of digestive proteases• Intrinsic Factor binds to vitamin B12!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Absorption of Cobalamin – Mucosal Phase• Vitamin B12-Intrinsic Factor complex is bound be a specific receptor found in the ileum• Vitamin B12is taken up by receptor, while Intrinsic Factor is not absorbed• Vitamin B12passes through intestinal enterocyte into capillary bed!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Tr a n s p o r t of Cobalamin • Vitamin B12is transported in blood bound to a specific carrier protein – transcobalamin• Approximately half of vitamin B12is taken up by the liver and the other half by peripheral tissues via a specific transcobalamin receptor protein!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Excretion of Cobalamin • Vitamin B12is not metabolized, but excreted as is into bile• Most of the excreted vitamin B12is rebound to Intrinsic Factor and reabsorbed• Vitamin B12is highly conserved in our bodies!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!Vitamin B12Deficiency Disease –Pernicious Anemia• Dietary deficiency in vitamin B12is rare because we need so little and are so good at conserving it– This is one vitamin that the true vegan needs to take in a supplemental form; however, many meat substitute foods and cereals are supplemented with vitamin B12• The most common form of vitamin B12deficiency is pernicious anemia – a disease that results from the failure of parietal cells to secrete Intrinsic Factor• This disease occurs in all ethnic groups and its prevalence increases with age
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