Topic 2&3: Iron Metabolism Flashcards
what two states does iron exist in?
reduced ferrous (Fe+2) state
oxidized ferric (Fe+3) state
how is iron both good and bad?
iron can be combined with enzymes for reduction-oxidation (redox) reactions that generate energy or neutralize drugs
BUT
as a solo catalyst iron can generate free radicals that destroy cellular components
What is the difference between ferrous and ferric iron?
Reduced ferrous iron is missing two electrons whereas oxidized ferric iron is missing three electrons. This means that ferrous iron has one more electron than ferric iron.
what’s the main dietary source of ferrous iron?
meat
exists in a heme-bound form
Fe+2
what’s the main dietary source of ferric iron?
vegetables
exists in a non-heme-bound form
Fe+3
how is ferrous iron imported into the body?
heme-bound ferrous iron is imported directly into duodenal enterocytes by heme carrier protein-1 (HCP1)
once inside, the surrounding heme structure is degraded to release the ferrous iron.
how does ferric iron enter the enterocytes?
trick question: iron does not enter the enterocyte in the ferric state!!
Non-heme-bound ferric iron must first be reduced to ferrous iron by the intestinal brush border enzyme ferroreductase before it is imported into the enterocyte by divalent metal transporter 1 (DMT-1)
what happens to iron once it’s absorbed into the enterocyte?
not immediately transported to the blood
it remains within the enterocyte bound to the protein ferritin
what does ferritin do?
iron remains within the enterocyte bound to the protein ferritin
ferritin acts as both a catalyst neutralizer to prevent iron from producing pesky free radicals and as a storage reservoir to pack iron within the cell.
what two signal molecules regulate iron influx into the bloodstream from the enterocyte?
hepcidin and erythropoetin
what does hepcidin do?
it’s secreted by hepatocytes in response to adequate iron concentrations
as long as there are adequate iron levels, hepcidin prompts the internalization and degradation of ferroportin
hepcidin essentially prevents iron influx into the blood by blocking ferroportin from shuttling iron across the cell membrane so iron remains sequestered in the enterocytes
what is ferroportin?
transports iron across the cell membrane into the bloodstream
what does erythropoietin do?
when iron concentrations are low, erythropoietin down-regulates the synthesis of hepcidin in hepatocytes
the suppression of hepcidin by erythropoietin, allows iron to be transported into the bloodstream via ferroportin
What is the effect of hepcidin on enterocytes?
Hepcidin leads to the internalization and degradation of ferroportin, preventing iron transport into the bloodstream
what happens to Fe+2 once it’s in the blood?
Once in the blood, ferrous iron is converted into ferric iron by hephaestin, an enzyme present in the basolateral membrane of the enterocyte
Fe+3 is then bound to transferrin for transport in the bloodstream
how does transferring reflect the body’s current iron requirement?
concentration of transferrin is inversely proportional to the concentration of iron in the bone marrow
high transferrin correlates to low bone marrow iron, thereby indicating insufficient iron stores
low transferrin correlates to high bone marrow iron, thereby indicating overabundant iron stores
what do increased transferrin levels cause?
creates a chemical gradient that facilitates an influx of iron into the bloodstream for subsequent delivery to the bone marrow
what do decreased transferrin levels cause?
create a chemical gradient that limits the influx of iron into the bloodstream, thereby preventing overload
influx of iron can come from enterocyte absorption, mentioned above, or macrophage mobilization, discussed below
what does transferrin saturation tell you?
if transferrin levels best reflect the body’s current iron requirement, then the transferrin saturation best reflects the body’s ability to meet that requirement
transferrin saturation is the percent of transferrin binding sites currently occupied by iron (two binding sites per one transferrin molecule)
when the body is not meeting its iron requirement, transferrin saturation is low
in what diseases is transferrin saturation low?
during iron deficiency anemia and anemia of chronic disease
the body is not meeting its iron requirement
when is transferrin saturation low?
when the body is not meeting its iron requirement
this occurs during iron deficiency anemia and anemia of chronic disease
when is transferrin saturation high?
when the body is exceeding its iron requirement
how do you calculate transferrin saturation?
Transferrin saturation is calculated by dividing the serum iron by the total iron binding capacity (TICB), which is basically a fancy way of saying the total amount of transferrin available to carry iron.
in iron deficiency does the liver make more or less transferrin?
the liver makes extra transferrin to create a favorable gradient for iron influx into the blood
TCIB is high!
what happens to the TICB during anemia?
the body actually sequesters iron in storage sites to hide it from scavenging pathogens, thus it does not make extra transferrin
TICB is correspondingly low
where is iron normally stored?
within liver and spleen macrophages
how does iron enter the liver and spleen?
when the iron-transferrin complex reaches the liver and spleen macrophages, the complex is detected by transferrin receptor-1 and then undergoes receptor-mediated endocytosis
what happens to iron once its inside the liver and spleen?
once inside, iron is released from transferrin and then transferrin is recycled back into the bloodstream
the remaining iron is stored within the macrophage again bound to ferritin
how does ferritin act as a storage reservoir for iron?
iron is stored within the liver and spleen macrophage bound to ferritin
by acting as a storage reservoir it buffers against iron deficiency or overload
in times of deficiency, ferritin can release some of its iron; conversely, in times of overload, ferritin can sequester more iron within cells
on an iron panel, what do ferritin levels best reflect?
total body iron storage
what do low ferritin levels indicate?
meaning low iron stores
used to diagnose iron deficiency anemia
what do high ferritin levels mean?
high iron stores
used to diagnose anemia of chronic disease
what is mobilization of iron? what’s it controlled by?
the release of iron from macrophages
whether or not Fe remains within the macrophage is regulated by hepcidin
mobilization is controlled in conjunction with iron serum levels
What two physiological conditions promote the synthesis of hepcidin by hepatocytes?
- increased inflammatory cytokines in bloodstream
2. increased iron serum levels
why does increased inflammatory cytokines in bloodstream decrease hepcidin synthesis?
iron is just as valuable to pathogens as it is to humans!
as a protective response, the body has hijacked its iron storage mechanism to also hide iron from scavenging pathogens
unfortunately this means that under prolonged inflammatory conditions like during chronic infections, the blood doesn’t deliver enough iron to bone marrow to make new RBCs
what causes anemia of chronic disease?
iron is just as valuable to pathogens as it is to humans!
as a protective response, the body has hijacked its iron storage mechanism to also hide iron from scavenging pathogens
unfortunately this means that under prolonged inflammatory conditions like during chronic infections, the blood doesn’t deliver enough iron to bone marrow to make new RBCs
this culminates in anemia of chronic disease
what are the two functions of iron?
- when bound to the relevant proteins, the redox properties of iron aid in the generation of energy and metabolism of harmful substances
- when bound to heme, the positive charge of iron aids in the transportation of oxygen
what are the two purposes of redox reactions?
- generate energy through ETC
2. metabolism of harmful substances
how do redox reactions of Fe generate energy through the ETC?
As a part of the proteins involved in the ETC, iron can accept electrons from carrier molecules
By accepting the electrons iron becomes reduced (ferrous iron = Fe+2) while the carrier molecules become oxidized
From here iron can donate the electrons to lower energy complexes that also usually contain an iron core - here the donating iron atom becomes oxidized to Fe+3 and the accepting iron atom becomes reduced to Fe+2
passing down e- releases energy to fuel a hydrogen gradient that can be used to generate adenosine triphosphate (ATP)
how does iron metabolize harmful substances through redox reactions?
accomplished through the cytochrome P450 system in hepatocytes
cytochrome enzymes use iron to preform redox reactions on harmful substances, like drugs or toxins we ingest, ultimately converting them into water-soluble byproducts ready for excretion
what oxidation state is iron in the heme core of Hb?
ferrous Fe+2
there is sufficient positive charge on ferrous iron to gently hold the dense valence electron cloud of oxygen (O2) during transport, but then release oxygen (O2) during delivery to the tissues
why isn’t Fe+3 used in heme to transport O2?
ferric iron has too strong of a positive charge causing it to bind oxygen (O2) so tightly that it cannot easily release it upon delivery to the tissues = methemoglobinemia
how is oxygen stored in muscle cells?
Fe+3
iron is also used to store oxygen (O2) in muscles cells on the related protein myoglobin
how does the body control the serum concentration of iron?
the ONLY way the body can control the serum concentration of iron is by regulating its absorption from enterocytes or its mobilization from macrophages
there is no true regulated mechanism for the excretion of iron!!
what is hereditary hemochromatosis?
a substitution of cysteine for tyrosine at the amino acid 282 in the HFE gene controlling hepcidin
hepcidin controls both iron absorption from enterocytes and its mobilization from macrophages
mutated hepcidin is malformed and cannot down-regulate iron absorption
over decades, the extra iron gradually deposits in the heart, liver, pancreas, and skin
is iron excretion regulation?
No
iron excretion is not regulated. Iron can only be excreted via the regular sloughing off on intestinal enterocytes
what is the Fenton Reaction?
when not bound to an enzyme iron can act as a solo catalyst performing redox reactions on hydrogen peroxide (H2O2) which is called the Fenton Reaction
mobile valence electron on reduced iron attacks the valence electrons on hydrogen peroxide (H2O2). This causes iron to become oxidized and hydrogen peroxide (H2O2) to break down into a hydroxide ion and a hydroxyl radical (OH )
Fe+2 + H2O2 –> Fe+3 + Oh- + OH(radical)
how does iron cause cellular damage?
Iron can cause damage through the Fenton reaction. In this reaction iron catalyzes redox reactions on hydrogen peroxide (H2O2)
This reaction generates damaging hydroxyl free radicals (OH ).
Inside enterocytes or macrophages, ferric iron (Fe+3) is bound to which one of the following storage proteins?
ferritin
The synthesis of transferrin is prompted by what?
Low levels of iron in the bone marrow
The synthesis of transferrin is controlled in coordination with the concentration of iron in the bone marrow. Low iron levels in the bone marrow prompt increased transferrin synthesis whereas high iron levels in the bone marrow prompt decreased transferrin synthesis
transferrin synthesis does not change in response to serum iron levels!!
what is the mechanism by which dysfunctional hepcidin causes hemochromatosis?
Decreased hepcidin leads to increased iron absorption
