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HMS Chemical Biology and Biochemistry > Iron Transport > Flashcards

Flashcards in Iron Transport Deck (34)
1

Iron Goldilocks zone

2

Fenton chemistry

Iron reactions with water producing free radicals

3

Most of the elemental iron that we eat is present in our body in the form of

rust!

 

Particularly rust sequestered in ferritin.

 

4

Transferrin

5

Ferritin

6

Low transferrin saturation

Iron deficiency

7

Overloaded transferrin saturation

iron toxicity

8

High serum ferritin

Ferritin is primarily a cellular protein.

 

However, some ferritin leaks in the blood and thus high serum ferritin can be associated with iron overload. Other diseases of the liver can also cause elevated serum ferri:n.

9

Major components of iron economy

60-70%:  In erythrocytes as hemoglobin.

25%:  In liver cells (hepatocytes and Kupffer cells) and macrophages as ferritin stores.

7.5%:  In tissues

0.1%:  As blood transferrin

 

~1% is recycled daily.

 

10

Iron steady state

Iron loss = Iron gain = 1-2 mg per day

 

~4g per adult male human body

11

Macrophage iron regulation

12

Intestinal Epithelium iron regulation

13

Reticulocyte iron regulation

14

DMT1

Divalent metal transporter 1

15

FPN1

Ferroportin 1

16

How is secretion of iron regulated by liver and kidneys?

It's not!!!!!!!

 

Only absorption is regulated, and it is regulated on the transcriptional level (upregulation of DMT1 and FPN1) and the mRNA stability level

17

Why is DMT1 upregulation insufficienct to absorb iron?

Without FPN1 upregulation as well, the iron cannot diffuse into the lamina propria in a timely manner before the enterocyte is sloughed off and the iron is lost

18

FPN1 expression in an iron replete vs iron deficient mouse

19

Duodenal iron staining in an iron replete vs iron deficient mouse

Note that in the replete condition the iron clusters in the location of the ferritin storage clusters.

20

Hepcidin

21

The human body's iron sensor

22

How hepcidin regulates enterocytes

Hepcidin binds to FPN1 directly via the basolateral surface of enterocytes.  It induces phosphorylation and endocytosis.  The endocytosed FPN1 is ubiquitinated and targeted for lysosomal degradation (NOT proteasomal)

23

What controls serum iron availability?

24

Each maturing erythrocyte needs approximately ____ iron atoms before it is mature.

Each maturing erythrocyte needs approximately 3 billion iron atoms before it is mature.

25

Transferrin cycle in a maturing erythrocyte

Once mature, erythrocytes cease to produce Transferrin receptor and eventually lose all expression.

 

Note that transferrin loses its affinity for iron at the low pH of the lysosome!

Also note that heme metabolism takes place in the mitochondrial matrix.

26

Negative feedback. . .

resists change.

 

This is the easiest way to remember positive vs negative feedback.

27

In cases of iron toxicity, how are erythrocytes affected?

Heme synthesis in erythrocytes is found to be normal to high, but the number of erythrocytes is totally unaffected.

28

In FPN1 loss of function, hepcidin levels are found to be 

HIGH

 

paradoxically.  Possibly because iron stores in the hepatocytes are still great despite low circulating iron.

29

If there is more iron in macrophages than hepatocytes, think

FPN1 loss of function

30

How do you treat iron toxicity?

Phlebotomy

31

How do you treat FPN1 LoF-mediated iron deficiency

Phlebotomy, but carefully observed phlebotomy.

 

The problem with FPN1 LoF is that there is a low level of circulating iron, but iron toxicity in the tissues.

32

Why does ferritin associate with both iron oxidases and iron reductases?

An oxidase must oxidize Iron II that comes through FPN1 to Iron III in order for it to bind to transferrin or ferritin.  In order to remove Fe III from the ferritin lattice, it must be reduced to Fe II, which can no longer bind. 

33

HFE loss of function mutation

HFE is part of the iron sensing apparatus on hepatocytes.  If HFE loses function, iron cannot be detected, and as such hepatocytes stop all Hepcidin transcription in order to signal to the body to acquire more iron.

 

This leads to chronic iron toxicity.

34

Hereditary Hemachromatosis