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36 Cards in this Set

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What causes iron deficiency anemia?
- Inadequate levels of iron for synthesis of various proteins such as hemoglobin and myoglobin
- Also inadequate for use as a cofactor for enzymatic reactions
What are the iron sources?
Heme Iron
- Red meat
- Shellfish and fish

Non-heme iron
- Enriched cereals
- Beans
- Tofu
- Seeds
- Potatoes
- Green vegetables
- Dried fruits
How much iron is absorbed in the diet? Where?
- 1 mg
- Duodenum
How is heme iron absorbed?
Heme iron is taken up by the heme transporter
What is required for non-heme iron absorption?
Vitamin C is required in diet for efficient uptake of dietary non-heme iron
What happens to dietary iron before it can be taken up into the epithelial cells of the duodenum?
Duodenal cytochrome B - a ferrireductase - on epithelial cell membrane reduces Fe3+ (ferric) to Fe2+ (ferrous) through a Vitamin C dependent mechanism
What happens after ferric iron (Fe3+) is converted to ferrous iron (Fe2+) in the duodenum?
Fe2+ is transported into intestinal epithelial cells by DMT1 (divalent metal ion transporter 1)
What can happen to Fe2+ after being taken up by DMT1 in duodenum?
- Directly transported across basal lateral membrane into portal vein by Ferroportin 1
OR
- Stored until needed in the cells by Ferritin present in the cells
How is Fe2+ oxidized back to Fe3+?
Hephaestin on basal lateral epithelial cell membrane
What happens after Fe3+ is made again by hephaestin?
- Fe3+ is transported out of epithelial cell by Ferriportin
- Next, it binds to Transferrin and is distributed to the rest of the body
- All cells that take up Fe3+ use the Transferrin Receptor for uptake through endocytosis
What molecule does Fe3+ bind in the plasma for transport through the rest of the body?
Transferrin
What peptide regulates the release of iron from the duodenal epithelial cells? Where is it synthesized?
- Hepcidin
- Synthesized by liver
What influences the levels of Hepcidin?
When iron levels in the liver increase, Hepcidin is released and binds to Ferroportin inducing endocytosis and degradation of Ferroportin (preventing additional release of iron into the plasma)
Where is iron stored?
- Liver takes up iron and stores it inside the hollow ball structure of the protein Ferritin
- 1 ferritin can contain ~5000 Fe(OH)3 molecules

- Iron can also be stored in Hemosiderin granules made up of partially degraded ferritin-iron complexes
What happens to Hemosiderin under normal iron conditions? Excess iron?
- Normal conditions, very little iron is found in Hemosiderin granules
- Iron overload conditions, excess iron is mainly stored in this form
What happens to iron in degrading RBCs?
- Most of it is recycled
- Macrophages recycle iron back to bone marrow for synthesis of new RBCs
What are the ways to lose iron? How much?
- Normally through shedding of intestinal and skin cells (~1 mg/day)
- During menstrual cycle, women lose ~0.5 mg iron / day
- During pregnancy, women lose 500-1000 mg of iron
- Abnormal bleeding (variable loss)
What are the locations of iron?
- Hemoglobin (~60% or ~2500 mg)
- Myoglobin (~8%)
- Ferritin in liver (~25%)
- Remaining is bound to Transferrin or enzymes (eg, cytochromes, catalase, and aconitase)
What causes Megaloblastic Anemia?
- Inability to synthesize adequate amounts of purines and thymidylate triphosphate for DNA synthesis
- Deficiency of folate, Vitamin B12, or a methionine synthase leads to impaired DNA synthesis
How is synthesis of purines and thymidylate triphosphate implicated in the basis of Megaloblastic Anemia?
- Synthesis of these molecules involves 1C units attached to folate derivative Tetrahydrofolate
- Deficiency of folate, Vitamin B12, or a methionine synthase
How is folate converted to the form which can donate 1C units for DNA synthesis?
- Folate is converted to THF by sequential reduction reactions by Dihydrofolate Reductase
- Folate → Dihydrofolate → Tetrahydrofolate
How is folate critical to the synthesis of Thymidylate Triphosphate?
- Methylene-THF donates a 1C group to dUMP → dTMP using enzyme Thymidylate Synthetase
- THF reductase is oxidized to dihydrofolate, which must be reduced by DHF reductase to form THF
What drug inhibits purine and thymidylate synthesis? Implications?
Methyltrexate - causes drug induced Megaloblastic Anemia
What are the sources of a 1C unit for the folate and S-adenosylmethionine pathways?
- Serine is the major source
- Histidine, glycine, and formate can also contribute 1C units
How is folate critical to the synthesis of Purines?
De novo synthesis of purines (Adenine and Guanine) depends upon donation of two 1C units in the form of formate from formyl-tetrahydrofolate
De novo synthesis of purines (Adenine and Guanine) depends upon donation of two 1C units in the form of formate from formyl-tetrahydrofolate
Why is Vitamin B12 critical for the synthesis of purines and dTMP?
- Synthesis of methionine requires methyl-THF (from folate pathway) and Vitamin B12 as cofactor 
- Without Vitamin B12 methyl-THF is not utilized, methionine synthesis is inhibited, and THF is not regenerated
- Leads to megaloblastic anemia
- Synthesis of methionine requires methyl-THF (from folate pathway) and Vitamin B12 as cofactor
- Without Vitamin B12 methyl-THF is not utilized, methionine synthesis is inhibited, and THF is not regenerated
- Leads to megaloblastic anemia
How is Methionine synthesized?
- Methionine Synthase - transfers a methyl group for methyl-THF to vitamin B12 which acts as a co-enzyme
- Methyl group is then transferred to Homocysteine forming Methionine
- Methionine Synthase is the only known enzyme to use Methyl-THF as a ...
- Methionine Synthase - transfers a methyl group for methyl-THF to vitamin B12 which acts as a co-enzyme
- Methyl group is then transferred to Homocysteine forming Methionine
- Methionine Synthase is the only known enzyme to use Methyl-THF as a substrate and thus the only way to regenerate THF
What are the implications of deficient Vitamin B12?
- Methyl-THF is not utilized
- Methionine synthesis is inhibited
- THF is not regenerated
- Methyl-THF is not utilized
- Methionine synthesis is inhibited
- THF is not regenerated
What is the necessity of Methionine?
Formation of S-adenosylmethionine required for methylation of DNA, RNA, and for synthesis of creatinine, melatonin, and epinephrine
What are the sources of folate in the diet?
- Most vegetables (especially dark leafy greens)
- Fruits
- Grains
- Nuts
- Beans
- Dairy products
- Seafood and meats

Since 1998: cereals, flour, rice, and their products are fortified w/ folate
What happens to dietary folate (folic acid) once ingested?
- Converted from polyglutamic folate to monoglutamic folate in intestine by Folate Hydrolase
- Folate is released into blood in complex w/ Folate Binding Protein as either monoglutamate folate or monoglutamate THF
What are the sources of Vitamin B12 in the diet?
- Meat
- Shellfish
- Milk
- Eggs

(not at significant levels in vegetables and fruits)
How do vegans obtain folate and Vitamin B12 in their diet?
Folate through food:
- Most vegetables (especially dark leafy greens)
- Fruits
- Grains
- Nuts
- Beans
- Dairy products

Vitamin B12 often needs to be supplemented because it is not found in significant levels in fruits and vegetables)
What happens to dietary Vitamin B12 once ingested?
- Vitamin B12 is bound to proteins in diet and released in stomach at acid pH
- Absorbed in process involving salivary Haptocorrin (R-protein), Intrinsic Factor, and Cubulin
What can cause a Vitamin B12 deficiency?
- Low intake of vitamin
- More often d/t impaired absorption or transport of vitamin (eg, Pernicious Anemia)
What happens in Pernicious Anemia?
- Lack of intrinsic factor
- Leads to vitamin B12 deficiency