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Body systems 2 > iron > Flashcards

iron Flashcards

1
Q

proteins that contain iron - haemoproteins

A
  • haemoglobin - oxygen binding (oxidases, peroxidases, catalases) - oxygen metabolism

a lot of the body’s iron is contained within the haemoglobin in the body.
- It’s continuously circulating in your red blood cells and it is the way in which we carry oxygen around the body.

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2
Q

non-heme - iron-containing proteins

A
  • mitochondrial aconitase - energy metabolism
  • Fe-S proteins in electron transport chain - energy metabolism
  • ribonucleotide reductase - DNA synthase
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3
Q

specialised molecules for iron transport

A

we have specialized molecules - they are efficient at taking the iron, transporting it around the body, storing it
- and it is a highly coordinated process.
- so dependent on the situation of the individual and then the person’s body and a particular time you are ensuring that you are uptaking sufficient iron, you’re storing and you’re transporting to ensure that you’re delivering iron to where it’s needed.
– So we’re able to in a way, balance. Those mechanisms to ensure that iron is where we need it at a particular time.

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4
Q

different types of iron in the body - duodenal absorption

A

In our diet, We have different types of iron
- some are soluble some are insoluble.
- We generally find fe3 + or heme iron in the diet, and we have absorbed that in the duodenum and
- We absorb around 1 to 2 milligrams per day
- So we should have enough in our dietary intake in order to be able to absorb that
when we take it in then we will either store it Or transport it or use it.

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5
Q

liver iron

A
  • liver parenchyma
    -1000 mg
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6
Q

muscle - iron

A

muscle myoglobin - 300 mg

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7
Q

bone marrow iron

A

300 mg

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8
Q

reticuloendothelial macrophages

A

600 mg

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9
Q

how do we transport iron

A

transferrin is the way that we transport the iron to those cells that have a transferin receptor
and that will take the iron in to the cell for utilization.

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10
Q

where do we store iron that isnt used

A
  • If we don’t need to use it all so if we want to store some we can store it for example in the liver.
  • So the main storage protein for iron is feritin.
    ○ If we have too much iron, we can store it in a pathological form, which is called hemosiderin, but feritin is our main storage protein.
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11
Q

where do we use iron

A

-We can find it in myoglobin in muscles For our muscular activity
○ the main place that we find this being utilized is in the bone marrow.
○ So you’ve got to have a constant production of red blood cells, So those are produced from the bone marrow in the hematocrit stem cell producing fully functional red blood cells, and those contain a lot of iron

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12
Q

how is iron broken down

A
  • they will then be broken down. So at the end of their 120 days lifespan, they’ll be broken down by macrophages.
    • And that iron will then be recycled and reused and will be transported back to either be stored or used.
  • So we’ve got a really nice cycle of iron within the body,
    but we do need to ensure that we have an intake that allows us to maintain that cycle
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13
Q

iron excretion

A
  • average 1-2 mg per day
  • sloughed mucosal cells, skin loss (desquamation), menstruation, other blood loss
  • the level of control is absorption rather than loss and that allows us to maintain that balance.
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14
Q

iron handling proteins

A

recent discovery that iron ‘handling proteins are present in the kidney and that they also help us to regulate the amount of iron that we have in the body

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15
Q

iron form that we consume

A

the inorganic iron we consume is Fe3+ and is insoluble
Fe2+ is known to be the form that is transported

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16
Q

transferrin bound iron

A

when we have transferrin bound iron, it has to be 3+

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17
Q

How do we get iron into the body

A
  • We’ve got fe3 Plus in our diet and it’s in this form this insoluble form of fe3 Plus.
  • There are certain features within the gut help the conversion of fe3 plus to fe2 plus
  • the acidic environment of the gut helps that conversion from fe3 to fe2.
    ○ vitamin C in our diet is also a co-factor - that can also help the process of conversion from fe3 to fe2 Plus.
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18
Q

DcytB aka Cybrd1

A

a ferric reductase expressed in the intestinal mucosa
- in mouse, DcytB is a 286 amino acid protein with 45-50% similarity to cytochrome b561 family of plasma membrane reductases, hence the name duodenal cytochrome b.
- promotes reduction of dietary ferric iron to ferrous iron so it can be. transported across the apical enterocyte membrane.
- Ascorbate (vitamin C) acts as a co-factor
- strongly unregulated when dietary ion is restricted, during anaemia, and in response to hypoxia.
- all are drivers for upregulation of iron acquisition

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19
Q

how is iron transported across biomembranes

A

early studies on non transferring bound iron transport
- uptake into vesicles had the characteristics of a carrier mediated process - it involved transport proteins
- the kinetics of the apical and basolateral transporters differed

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20
Q

what protein is used to get iron across the membrane once its been converted

A

divalent metal transporter 1
- important for moving Fe2+ into the enterocte in the duodenum

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21
Q

divalent metal transporter 1

A
  • Km for Fe 2+ - 6 micrometres
    -pH dependent
  • transports Cd2+ -> Fe2+ -> Co2+, Mn 2+ -> Zn 2+, Ni 2+, VO 2+ and Pb 2+

Divalent metal transport 1 is vital for the transport of iron into the gut.

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22
Q

mouse model without DMT1

A

So we were able to find out the characteristics of this particular transporter by looking at another a mice model that didn’t have DMT 1 so it lacked this intestinal divalent metal transporter,
- when we removed dmt1, it produces a severe iron deficient anemia in the mice
So therefore the iron wasn’t being transported into the enterocyte, so it wasn’t available for transport around the body in order to produce those red blood cells

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23
Q

molecular characteristics of divalent metal transporter 1

A
  • 561 amino acid polypeptide - 60 kDa
  • predicted to have 12 membrane spanning domains
  • glycosylated extracellular loop
  • N- and C- termini in cytosol
  • A consensus transport motif in fourth intracellular loop
  • Iron responsive element - sensitive to iron - helps to increase the divalent metal transporter synthesis when cellular iron is low and allows us to increase the amount of iron that we intake into the body.
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24
Q

DMT1 in the kidney

A

DMT is mainly found in or on the apical membranes of the early distal tubules in the kidney.
- we may see that there’s reabsorption of iron in that area

25
Q

heme iron

A

absorbed more efficiently than non - heme iron

it might contribute up to about 50% of the iron that we absorb in our diet.

26
Q

haem transporter

A

the haem transporter is not just specific for that particular molecule.
- It also transports folic acid.
- folic acid is also needed for healthy production of hemoglobin.
So this is a combined transporter
- so it also allows us to ensure that we can transport folic acid into the body for production of hemoglobin

27
Q

what happens to iron when it enters the cell

A

So how does it get from the enterocyte Over the other side across the basolateral side into the circulation.
- the fe2 plus binds to something called poly(RC) binding protein and it’s basically a Metallo chaperone
- So it binds to it and it appears that it mediates the transfer of the free Iron to ferritin. For it to be stored.
- But not all of our iron needs to be stored as ferritin, We do need to transport some of it across and we need to be able to take it across this basolateral membrane here into the circulatory system for transport to wherever it is required.

28
Q

basolateral membrane iron transporter - ferroportin/IREG1/ MTP1

A

only known iron exporter from the basolateral side of the enterocyte
- 570 amino acids
- ten predicted transmembrane domains
-predicted to be a 62 kDa protein

29
Q

functional properties of ferroportin

A
  • mediates saturable and temperature dependent Fe efflux
  • maximal activity extracellular pH = 7.5 and inactivated at extracellular pH <6.0
  • also, mediates efflux of Zn and Co, but not of Cu, Cd, or Mn
30
Q

ferroportin 1a

A

d ferroportin 1a has a 5 Prime Iron response element.

31
Q

ferrportin 1b

A
  • Ferroportin 1 B lacks that 5 Prime Iron response element and it’s not repressed in iron-deficient conditions
32
Q

variants of ferroportin

A

2 variants of ferroportin - We’ve got 1 a and 1 B.

they allow a balance in Ferroportin and how it moves iron out of the enterocyte having the 2 variants
- we find that both of them are expressed in the duodenum And hopefully they will balance.
- but they’re also found in erythroid tissue which is really important for the production of your red blood cells and the healthy red blood cells

- So those are also regulated by the iron content in your diet and the export of iron from the enterocyte into the circulatory system.
33
Q

where is ferroportin localised

A

localised in the basolateral membrane

it is also localized to the basolateral renal proximal tubular membrane.
this is evidence again that the kidney is involved in some way in Iron homeostasis

34
Q

hephaestin

A

A molecule that allows us to transport iron by transferrin
- a multicopper oxidase with ferroxidase activity which promotes egress of iron from intestinal enterocytes into circulation by facilitating binding to transferrin

heph is a relatively large protein consisting of 1166 amino acids. it is predicted to have one membrane spanning domain

35
Q

function of hephaestin

A

highest expression is in the small intestine
- limited to enterocytes of the villi
- almost absent in crypt cells
- converts iron (II) state, Fe 2+, to iron (III) state, Fe 3+, and mediates iron efflux most likely in cooperation with basolateral iron transporter, ferroportin 1
- has been detected in colon, spleen, kidney, breast, placenta and bone trabecular cells

36
Q

cellular delivery of iron

A

pretty much almost all of the cells in your body and tissues in your body will have receptors that will accept iron when we transport it to where it’s needed.

37
Q

transferrin

A

transferrin functions to transport iron between sites of absorption, storage and use

transferrin consists of 2 homologous domains each contains one high affinity pH dependent Fe (III) - binding site

so we transport iron in the fe3 format.

38
Q

apotransferrin

A

when we do not have iron bound to transferrin

39
Q

monoferric

A

fully saturated transferrin

40
Q

transferrin receptor

A

recognised as the gate-keepers responsible for physiological iron acquisition by most cell types

receptor is a disulphie linked transmembrane glycoprotein homodimer. each subunit is 90KDa
- And that will accept the transferrin and allow it to be taken into the cell that requires the iron at that particular time.

41
Q

how do transferrin and the transferrin receptor interact with each other

A
  • receptor mediated endocytosis.
  • we have our fe3 binding to transferrin and the receptor on the cell surface.
  • there is inwards invagination of the plasma membrane and it forms a vesicle then when it takes in the absorbed substances and it forms an endosome.
  • Takes in the receptor and the transferrin - This is obviously in our fe3 form.
  • in order for us to be able to get it out to the other side of the endosome. It will then be transported by a divalent metal Transporter one
  • But it has to be converted back to fe2 Plus.
42
Q

what converts the iron back to Fe 2+ after the receptor-mediated endocytosis

A

that is done by STEAP 1
- and it allows it then to be transported across at the dmt1 and it becomes this labile pool.
- So it’s like a Transit pool. It’s neither being transported nor stored, but it’s thought to be that it’s kind of at a Crossroads of iron metabolism.

43
Q

what happens to Fe 2+ once its in the labile intracellular pool

A
  • it can go a number of different ways.
  • it can form free radicals so it can be quite dangerous To the body so that labile pool has to be controlled in terms of the levels
44
Q

ferritin

A
  • sequester and store iron. iron is stored as a solid phase mineral
  • it’s a large protein and it’s made up of 24 symmetrically related subunits of 2 types - a heavy and a light subunit
  • inside that ferritin, iron is stored in the ferric state so ferric oxyhydroxide and it’s a massive storage protein.
  • So 1 ferritin molecule can store up to 4 and a half thousand atoms of iron.
  • ferritin synthesis is inducibe by iron
45
Q

cellular iron balance

A
  • this balance between ferirtin on one side (how much we store) and then the transferrin receptor (how much we are transporting around the body at any one time) so transport versus storage.
    It can depend obviously on your body requirements and Your body situation So there’s quite a lot of things that do actually influence the cellular iron balance.
46
Q

iron balance - when intracellular iron pool is increased

A

when the intracellular pool is increased. We will want to transport as much iron as we can. We want to be able to transport that out.

47
Q

iron responsive elements

A

iron-responsive proteins, helps us to control These 2 levels
the transferrin receptor and your ferritin.

48
Q

IREs - low iron

A
  • if there are low iron levels that results in increased Iron response proteins which interact with your iron-responsive elements and that inhibit ferritin translation.
  • So when you have low iron in your body, your body does not want to store iron, We want to transport it.
  • So this basically blocks any translation here in terms of feritin
    However, you do want to be able to transport the iron that you have So therefore this is where transferrin receptor production is increased.
49
Q

IREs - high iron

A
  • We will be storing more
  • therefore high iron- it binds to the iron response protein and that basically stops the translation of our transferrin receptor, but it starts the ferritin production.
  • the active translation is happening here.
  • That allows us a place within the body to store that high iron.
50
Q

Hepcidin

A

it is thought to be the key regulator of our metabolism in the body.
- the 25 amino acid protein Hepcidin was first purified from human blood and urine as an antimicrobial peptide and was found to be predominantly expressed in the liver
- hepcidin is a repressor of iron absorption
- it interacts with ferroportin so that it kind of prevents the iron being able to be transported across that side of the enterocyte into your circulation.
- expression of hepcidin is decreased when body iron demands are high

51
Q

orchestration of iron homeostasis

A

-overexpression of hepcidin leads to iron-adequate anaemia, whereas knockout leads to iron overload

  • hypothesis is that the liver may be able to control duodenal iron uptake by modulating the amount of circulating hepcidin
  • increase dietary iron is associated with increased hepcidin. hepcidin then downregulates duodenal iron transport

increased hepcidin -> decreased iron absorption

52
Q

regulation by hepcidin

A

hepcidin can be increased by inflammation, infection.
- They can all increase or trigger the increase of hepcidin production and essentially It will decrease the absorption of iron.
What’s important for us is what the impact might be then in the body
- So if you’re going to block the absorption, you’re essentially can pretty much block all of this happening here so the transport of iron, the storage of iron, the function

it can maintain the levels of iron in the body quite nicely for us.

53
Q

hypochromic microcytic anaemia

A
  • hypochromic means They’re pale - it lacks colour
    ○ so you’ve got a very pale Center here and you’ve got a very thin rim of nicely stained sort of hemoglobin.
  • Microcytic - smaller cell in comparison to your normal red blood cell - mean cell volume below 80 centiliters
  • most common anaemia
54
Q

hypochromic macrocytic anaemia

A
  • Cells larger than normal
    They will not be fully functional there may be issues with their hemoglobin concentration
55
Q

response to low iron - hypoxia inducible factor

A

if you have low iron, you will have low oxygen delivery
-your hemoglobin concentration and the iron contained within defines the amount of oxygen you can carry around the body.
- So if you have a low haemoglobin you have low iron you are essentially at risk of hypoxia.
- So this particular hypoxic inducible factors were found and it responds to the low oxygen and the low iron s
-the iron response elements, will respond to that low iron also and in combination with the low oxygen, this will essentially trigger the transcription of genes That are involved in a number of processes, but the process were interested in is erythropoiesis
- so it will trigger the production of epo within the kidney.

56
Q

the response of the hypoxic inducible factor 2 Alpha, in conjunction with the hypoxia response

A

the response of the hypoxic inducible factor 2 Alpha, in conjunction with the hypoxia response element Alongside the little iron affecting the iron response protein and iron response Element - These will then trigger the synthesis of epo which will then feed forward into the eryhtropoetic process taking place in the bone marrow.
- Hopefully increase the production of erythrocytes

57
Q

low iron - production of ErfE

A
  • because we have this low iron being detected we want to increase the absorption and
    to ensure that hepcidin is not influencing the absorption of iron in the gut.
    • so we have the production of something called ErfE which can act on hepcidin
      ○ that comes from the bone marrow and that blocks the translation or synthesis of hepcidin, which then allows us in the duodenum to be able to take up The iron and be able to transport it by ferroportin Across the basolateral membrane.
58
Q

epithelial response to low iron

A

at the epithelia the net result of increased HIF alpha is to increase the expression of DcytB, DMT1 and FPN1 in the duodenum and inhibit hepcidin production.
more Duodenal cytochrome B, which allows us to convert more fe3 to fe2 plus
ore dmt1 which allows so transport more iron across the membrane

then we have increased expression of ferroportin 1 at the basolateral side and that allows us to then obviously transport more iron around the body
- And it also inhibits pepsin, which we now know controls the absorption at that basal side through ferroportin

59
Q

effects of high altitude

A

we’ve got 21% oxygen available to us in the atmosphere, but it’s obviously going to be dependent on the oxygen in the air.
- Oxygen in the air decreases the higher the altitude
- So your body must adapt to that low oxygen.

So your body needs to adapt to that particular level of oxygen in the blood and therefore needs to ensure that you have sufficient red blood cells in order to carry that amount around

And that’s where again we have this response element within the body.

Body systems 2 (19 decks)

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