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BIOC2005 CH > 6. Iron Metabolism > Flashcards

6. Iron Metabolism Flashcards

1
Q

How many grams of iron does the average adult contain?

A

3-4g

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2
Q

What is the most common worldwide nutritional deficiency?

A

Iron deficiency

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3
Q

Describe the oxidation states of iron. How many unpaired electrons are there?

A

2 stable oxidation states 2+ and 3+

4 unpaired electrons in the D orbital

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4
Q

What is the ferrous and ferric forms of iron?

A

Ferrous: 2+

Ferric: 3+

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5
Q

Why would it be bad for free iron to be present in cells? What is used to prevent free iron?

A

Free iron can catalyse formation of free radicals which damage cell components.

Iron transporters and management systems required to prevent free iron build up

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6
Q

Who first showed that redox-active metals can generate ROS?

A

James Fenton in 1894 showed that Fe2+ with H2O2 can oxidise tartaric acid

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7
Q

What is the Haber-Weiss reaction equation? What two equations are combined to form it?

A
  1. Fe2+ + H2O2 –> Fe3+ + .OH + OH-
  2. Fe3+ + O2- –> Fe2+ + O2

1 + 2 = 3 (Haber-Weiss)

  1. O2- + H2O2 –> O2 + .OH + OH-
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8
Q

Is the Haber-Weiss reaction only catalysed by Fe?

A

No, Copper ions can do the same

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9
Q

What are the 6 functions of iron in the body?

A
  1. Haemoglobin in RBCs - Oxygen transportation
  2. Myoglobin in RBCs - intracellular oxygen storage
  3. Cytochrome in ETC
  4. Cytochrome P-450 - detoxification
  5. Catalase/Peroxidase - prevention of free radical cell damage
  6. Energy metabolism enzymes - NADPH dehydrogenase
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10
Q

How much iron is lost every day?

A

1-2mg

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11
Q

What percentage of dietary iron is absorbed?

A

10% (30% of total iron uptake is haem)

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12
Q

How is the amount of iron in the body regulated?

A

Amount of iron absorbed is regulated (as there is very little iron excretion)

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13
Q

What is the definition of bioavailability?

A

Proportion of a particular nutrient present in food that the body is able to absorb and utilise by incorporation into physiologically functional pools

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14
Q

How does the bioavailability of iron compare in a vegetarian and mixed diet?

A

Veg (5-12%) has lower iron bioavailability than a mixed (14-18%) diet

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15
Q

Which cells are specialised to transport iron?

A

Villus epithelial cells from the duodenum and upper jejunum transport haem/non-haem iron

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16
Q

How is haem iron bioavailability affected? How does this compare to non-haem iron bioavailability?

A

Haem is only affected by amount of haem present

Non-haem affected by amount, individuals iron status, calcium levels, organic acid meal content (increases b/a), animal protein (increases b/a), alcohol (increases b/a),

phytic (decreases b/a)
polyphenols (decrease b/a)

Diseases

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17
Q

In which form is Fe absorbed?

A

ONLY in the Fe2+ form, best absorbed as haem iron

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18
Q

What vitamin stimulates iron uptake form the gut?

A

Vitamin C (and alcohol…)

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19
Q

Give an example of some polyphenols which inhibit iron absorption

A

Oregano, spinach, tea, coffee, wine

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20
Q

How does iron absorption occur?

A
  1. Fe3+ converted into Fe2+ by Fe-reductase (and dietary reducing agents)
  2. Fe2+ transported into the cell along with H+ by DMT1 (divalent metal transporter 1), DMT1 expression is regulated by bodily iron stores to maintain iron homeostasis
  3. If the iron is in haem form then Haem transporter (HT) transports it into the cell where haem oxygenase converts it to Fe2+
  4. Fe2+ passed to either ferritin (–>3+) or the labile iron pool
  5. LIP passes Fe2+ to IREG (iron response element G) which can transport Fe2+ out of cell
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21
Q

How is DMT1 expression regulated?

A

By bodily iron stores

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22
Q

What does the Labile iron pool (LIP) consist of?

A

A pool of transitory (labile), chelatable and redox-active iron which serves as a crossroad of cell metabolism

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23
Q

What reaction does ferric reductase/cytochrome b561 catalyse? Where is it present?

A

Present on the intestinal brush border (before Fe2+ gets into cell)

2Fe(III) + NADH + H+ –> 2Fe(II) + NAD+

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24
Q

What is the mRNA structure of DMT1 like?

A

Made up of two differentially spliced mRNAs - one containing an iron response element (bound by IRP and controls transcription in response to iron levels)

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25
Q

Which tissue has the highest DMT1 expression?

A

Duodenum

26
Q

What is the structure of the IREG1/Ferroportin mRNA like? Where is it expressed?

A

Two differentially spliced mRNAs - one with an IRE and on without (kinda like DMT1)

Placenta, duodenum, liver, spleen, macrophages, kidney

27
Q

Which two proteins help export iron from cells?

A

IREG1(ferroportin) and hephaestin

28
Q

Which protein is hephaestin homologous to?

A

Caeruloplasmin - copper carrying protein in the blood which is also a ferrooxidase

29
Q

What is transferrin?

A

Iron binding blood plasma glycoproteins that control the levels of free iron in biological fluids

30
Q

Describe the transferrin cycle (6)

The transferrin cycle is responsible for iron movement between cells. Uptake of iron from the gut uses a different process.

A
  1. Holotransferrin binds to transferrin receptors in clathrin coated pits on cell surface
  2. The clathrin coated pits invaginate to form endosomes containing transferrin
  3. Endosomes become acidified with proton pump
  4. Acidification of endosome leads to protein conformational changes which release iron from transferrin
  5. Acidification also causes DMT1 to export Fe2+ and H+ from endosome where it is stored in mitochondria or as ferritin
  6. Apotransferrin and transferrin receptor return to cell surface
31
Q

Describe the transferrin receptor 1

A

Two identical disulphide linked 90kDa subunits. Expressed in all iron requiring cells.

Each subunit consists of: Cytoplasmic domain, membrane anchoring (h’phobic) region and transferrin recognition site

32
Q

How does TfR2 vary from TfR1?

A

TfR2 has two versions (alpha and beta) whereas TfR1 has only one version. TfR2 is also only expressed in liver cells.

33
Q

What is ferritin?

A

Iron storage protein which prevents free iron from forming reactive oxygen species

34
Q

What is the structure of ferritin?

A

2 subunits, heavy (21kDa) and light (19kDa) chains. Can form heteropolymers with 24 subunits in total - these subunits can hold 4500 iron atoms. IRE is in the 5’ UTR.

35
Q

How many iron atoms can the heteropolymer of ferritin hold?

A

4500

36
Q

What are the three proteins required for storage and transport of iron?

A

Ferritin, haemosiderin (ferritin polymer) and transferrin

37
Q

How many iron atoms can transferrin store?

A

2

38
Q

Which two proteins regulate cellular iron levels?

A

IRP1 and IRP2

39
Q

Which mRNA does IRP1 bind to?

A

Ferritin and Ferroportin

40
Q

Which mRNA does IRP2 bind to?

A

TfR (transferrin receptor) and DMT1

41
Q

How is the transcription of ferritin mRNA affected at high/low intracellular iron concentrations?

A

At high intracellular iron concentrations, IRP1 has Fe-S cluster bound to active site so cannot bind to ferritin mRNA and ferritin is transcribed and translated producing high ferritin levels. Thus leading to adequate iron storage.

At low iron levels no Fe is present in the IRP1 active site so it is able to bind to the IRE (loop) upstream of the ORF, this prevents RNA polymerase from transcribing the mRNA and thus ferritin levels decrease.

42
Q

How is the transcription of TfR mRNA affected at high/low intracellular iron concentrations?

A

At high intracellular iron concentrations IRP2 cannot bind (and is degraded) and protect the TfR mRNA so the mRNA is quickly degraded.

At low iron levels, the IRP2 can bind to the IRE (loops) in the 3’ UTR, this stabilises the TfR mRNA so TfR is transcribed. Thus leading to increased iron intake into the cell (through the transferrin receptor)

43
Q

How is the transcription of ferroportin mRNA affected at high/low intracellular iron concentrations?

A

Exactly the same method as ferritin.

At high intracellular iron concentrations, IRP1 has Fe-S cluster bound to active site so cannot bind to ferroportin mRNA and ferroportin is transcribed and translated producing high ferroportin levels. So more Fe2+ is exported from the cells through the ferroportin.

At low iron levels no Fe is present in the IRP1 active site so it is able to bind to the IRE (loop) upstream of the ORF, this prevents RNA polymerase from transcribing the mRNA and thus ferroportin levels decrease.

44
Q

How is the transcription of DMT1 mRNA affected at high/low intracellular iron concentrations?

A

At high intracellular iron concentrations IRP2 cannot bind (and is degraded) and protect the DMT1 mRNA so the mRNA is quickly degraded.

At low iron levels, the IRP2 can bind to the IRE (loops) in the 3’ UTR, this stabilises the TfR mRNA so DMT1 is transcribed. This leads to Fe2+ cellular import (along with H+), increasing Iron levels.

45
Q

What does binding of IRP1/IRP2 cause?

A

IRP1 binding at high concentrations causes increase in ferritin/ferroportin levels, this causes a decrease in iron concentration in the cell by storing it/exporting it

IRP2 binding at high concentrations causes decrease in TfR/DMT1 levels, this causes a a decrease in iron importing

46
Q

What is HIF?

A

Hypoxy inducible factor

47
Q

What does HIF do? How?

A

HIF up regulates DMT1, Dcytb and ferroportin (any genes with HIF response element - HRE). In normoxic conditions HIF is hydroxylated and degraded so up regulation does not occur, but in hypoxic conditions HIF cannot be hydroxylated (no oxygen) so builds up and up regulates DMT1, Dcytb and ferroportin. This causes more cellular import and export of Fe2+.

48
Q

What happens to HIF when O2 levels increase?

A

HIF binds to VHL and Ub and degrades

49
Q

What is Hepcidin?

A

A key negative regulator of the entry of iron into the circulatory systems of mammals.

50
Q

What does hepcidin do? How was this discovered?

A

Prevents iron coming through ferroportin from intestine/macrophages by causing internalisation and degradation of ferroportin.

Hepcidin gene was locked out in iron-loaded mice, led to haemochromatis (iron overload)

51
Q

What causes elevated hepcidin levels?

A

Inflammation and increased iron levels

Inflammation can therefore lead to anaemia

52
Q

What is the receptor for hepcidin?

A

Ferroportin

53
Q

Describe the structure of hepcidin

A

Cysteine rich cationic peptide, precursor protein of 84 AA, distorted beta sheet and loop, expressed mainly in liver.

54
Q

What does hepcidin cause to happen to ferroportin?

A

Causes internalisation and degradation of ferroportin

55
Q

How is transcription of hepcidin induced by high Fe levels?

A

In hepatocyte

  1. Fe-Tf (Transferrin) complex binds to Transferrin Receptor 1 (TfR1)
  2. Fe-Tf binding dislodges Hfe from TfR1 and allows it to bind to TfR2
  3. Binding of Hfe to TfR2 (hepcidin signalling complex) transduces a signal to the hepcidin gene causing it’s transcription
56
Q

How is transcription of hepcidin induced by inflammation?

A
  1. IL-6 binds IL-6 receptor on hepatocyte
  2. Stimulates gp130/JAK1/2 to phosphorylate STAT3
  3. activated STAT3 binds to hepcidin promoter and leads to increased hepcidin transcription
57
Q

Give an example of two iron deficiency diseases and three iron overload diseases?

A

Deficiency:

  1. Iron deficiency anaemia (nutritional,
  2. Anaemia of chronic disease (infection, inflammation, cancer)

Overload:

  1. Hereditary hemochromatosis
  2. Iron-loading anaemias
  3. Common acquired diseases (parkinson)
58
Q

What effects do iron deficiency and overload cause?

A

Deficiency: lack of hematopoiesis (making of blood cells) and cell growth

Overload: Damage of cells and tissues by oxidative stress caused by excess reactive oxygen species

59
Q

What is hereditary hemochromatosis caused by? what does it lead to? What may it cause?

A

Genetic Iron overload disorder - 1 in 8 carrier frequency.

Results in low hepcidin expression (Hfe and TfR2 genes not expressed) so too much dietary iron is taken up by ferroportin into liver and not enough iron provided for other regions of the body.

Liver cirrhosis, cancer, heart failure, endocrinopathy

60
Q

What are the types of hereditary hemochromatosis?

A

Common - hepcidin deficiency

Rare - Ferroportin resistance to hepcidin

BIOC2005 CH (13 decks)

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