Sblwk1- 11-2 Biochem Iron/folate/b12

Front 1

What is iron used for?

Back 1

Ideal catalyst for oxidation-reduction reactions
Heme – much of iron is in red blood cells (1 mg Fe/1 ml packed RBCs)

Front 2

How is iron stored/Distributed in body

Back 2

1. Hemoglobin 67%
2. Storred as ferritin (water soluble), hemosiderin (water insoluble), 27%
3. myoglobin 5%
4. Iron requiring proteins 1% (cytochroms, iron sulfur clusters, enzymes using non-heme iron)

comes in and little is lost

Front 3

Normal iron in RBC?
in body?

Life of RBC?

Back 3

1. rbc- 2.7 g
2. 3-5 g in body

3. 120 destroyed then macrophages grab iron released

Front 4

Two types of iron?

Back 4

Ferrous 2+
Ferric 3+ (dietary)

Front 5

How does iron transport? (name transporters)

Back 5

– Ferrireductase
– DMT1 (divalent transporter-1)
– HEPHAESTIN
– FERROPORTIN

Front 6

Dietary iron (Fe+3) is reduced to Fe2+ by what?

Back 6

DCytb (duodenal cytochrom-like b)

Front 7

Describe the transport process of iron in enterocyte...

Back 7

1. Fe +3 is reduced by Dcytb to Fe+2
2. DMT-1 transports Fe+2 on apical surface of enterocyte in microvili region

Front 8

What happens to mouse without DMT1?

Back 8

microcytic anemia (no iron in RBCs)

Front 9

Describe the transport of iron out of enterocyte picking up after it was brought in my DMT1...

Back 9

1. iron moves to basolateral side of enterocyte
2. transported out by ferroportin, which requires a ferroxidase (Hephaestin) to help
3. Once out amount absorbed in body and liver controlled by hepcidin

Front 10

1. What carries iron to the tissues and in what form?

2. How does iron get into erythroblast?

Back 10

1. Fe +3 carried by transferrin

2. (TfR) transferrin receptor mediated endocytosis

Front 11

Describe the importance of the kiss and run hypothesis

Back 11

Endosome docks onto mitochondria and iron is removed because mitochondria is more acidic causing TfR to hold ferritin tightly but lets go of iron

Front 12

Protein involved in reducing Ferric to ferrous Fe after it leaves endosome...

Back 12

Steap3 (ferrirductase)

Front 13

What transports iron out of an endosome?

Back 13

DMT1

Front 14

What are main causes for iron deficiency?

Back 14

1. Insufficient Dietary iron
2. Menstruating women
3. Aspirin abuse
4. Ulcers of the GI tract (Blood loss)
5. Hypochromic microcytic anemia

Front 15

Describe the two main causes of iron overloading...

Back 15

1. Genetic causes: when things are wrong with the transport system and Fe absorption is increased (hereditary hemochromatosis)
2. Conditional: repeated blood transfusions (sickle cell anemia_

Front 16

What is the clinical definition of HHI

Back 16

Organ dysfunction due to iron overload: cirrhosis, arthritis, endocrinopathy, skin pigmentation, cardiomyopathy; usually manifests in 6th decade

Front 17

Genetic definition of HH1?
a. inheritance
b. gene
c. functional probs

Back 17

a. AR 1/250 MC AR in man
b. HFE gene, Cys 282--> Tyr (C282Y) secondary mutation is His 63 Asp (H63D)
c. Malregulation of iron uptake and export by enterocyte

Front 18

What tests are used to diagnose HH?

Back 18

serum ferritin (protein storage of iron) >400ng/ml (normal is 20-300)
- CT, MRI, or histo exam of liver (

Front 19

What does hepcidin do as far as regulatory roles?

Back 19

Negative controller
binds to ferroportin and destroys it
- without ferroportin can not bring iron into the rest of the body

Front 20

What causes Hepcidin levels to increase or decrease (assuming no pathology)?

Back 20

Hfe via signal transduction
1. Hfe binds normally to Tfr1 and when there are higher levels of iron Hfe bound to Tfr1 are replaced by iron and then bind to hepcidin signaling complex (TfR2)
2. Via signal transduction (Smad pathway) induces hepcidin expression and prevents iron expression

Front 21

Explain how a mutation in Hfe leads to iron overloading

Back 21

mutated Hfe cannot bind to TfR2 and therefore hepcidin cannot be expressed and ferroportin cannot be regulated leading to iron overload

Front 22

Besides Hfe there are a few other ways HH can be caused.... what are they?

Back 22

1. A77D (auto dominant): Alanine to aspartic acid inactivates ferroportin, which increases iron in enterocytes and macrophages

2. Val 162 deletion: ferroportin hepcidin interactions is disabled

3. TfR2 mutation (Auto recessive) leaves inability to release hepcidin

Front 23

What gene(s) is/are found mutated in juvenile hemochromatosis?

Back 23

HJV- (hemojuvelin) which is part fo signaling pathway to hepcidin

could also have Rare (HAMP mutation) hepcidin antimicrobial peptide

Front 24

Gene/chromosomes mutated in the types of hemochromatosis?
a. Type I (classical)
b. Type II (Juvenile)
c. Type III
d. Type IV

Back 24

a. Hfe chr 6
b. HJV- chr. 1 and sometimes HAMP- Chr. 19
c. TfR2- Chr 7
d. Ferroportin def. chr. 2

Front 25

Which protein is being looked at as possible treatment for iron and why?

Back 25

Tmprss6 due to fact that it downregulates hepcidin transcription, and therefore could be used in iron overload therapies

Front 26

What is role of Ttc7 and the idea in role of iron problem treatments?

Back 26

causes loss of iron and may be used in future HH1 treatment

Front 27

What vitamins does the production of RBCs depend on?

Back 27

Vit B12 (cobalamin) and folate (folic acid

Front 28

Deficiencies in B12 and folate can cause sever anemia called?

Back 28

megaloblastic anemia

Front 29

What causes megaloblastic anemia?

Back 29

slowed synthesis of DNA in in developing RBC in bone marrow and a nuclear maturation defect (which is mandatory for RBC to be released)
Decreased B12 or folate prevents syntesis of adequate amounts of DNA

Front 30

What lab findings with megaloblastic anemia?

Back 30

Large erythrocytes
MCV > 100fL (norma= 80-100)
MCHC (mean cell hemoglobin content)= normal

Front 31

What is clinical presentation of megaloblastic macrocytic anemia

Back 31

lethargy weakness, yellow or waxy pallor, loss of weight and appetite, diarrhea
Also neuro- pins and needles (peripheral neuropathy)

Front 32

Back 32

Front 33

Describe in words folate metabolism to DNA synthesis... Also how does it all start up again...?

Back 33

1. Key players... (N5) of THF and serine (transfers carbon kicks N5,10 methylene-THF)
2. Carbon of N5,10 methylene-THF transferred to deoxyuridylate (dUMP) and makes deoxythymidylate (dTMP), which is used to make DNA
3. Dihydrofolate (DHF) is formed as a biproduct of #2 and is reduced by dehydrofolate reductase to THF

Front 34

What are the two proteins required for transport of folate in cells?

Back 34

1. High affinity folate receptor- concentrates folate in vescicles
2. membrane folate transporter- transfers from vescicle to cytosol

Front 35

What does N5-methyl- THF need to enter folic acid cycle as THF?

Back 35

Vit. B12 (cobalamin) - demythylates it

Front 36

B12 aka cobalamin is transported by what in the blood?

Back 36

transcobalamin

Front 37

Back 37

Front 38

Describe in steps the absorption of dietary B12...

Back 38

1. B12 binds to R-binders made by gastric mucosa
2. IF (made from parietal cells of stomach) carry B12 to ileum after B12 is released from R-binder protein which was degraded by proteases from pancreas
3. Receptors (cubulin) in the ileum bring B12 to body

Front 39

Lack of IF can cause what?

Back 39

pernicious anemia due to failure to absorb vitamin B12
- parietal cells in stomach fail to make it

Front 40

What is gold standard to determine if it is IF or just B12 that is deficient?

Back 40

Schilling test