Fe
functions of Fe
*functions as parts of proteins -heme and iron sulfur cluster proteins * hemoglobin and myoglobin *cytochromes -ETC- enzymes move single electrons down the chain by oxidizing and reducing Fe -cytochrome P450 proteins-ER proteins involved in detox of drugs and alcohol (esp imp in liver) *aconitase (Fe-S cluster)- in krebs *many, many others
mRNA has what kind of shape
-1 strand, but it can form a 2 dimensional shape -can base pair (CG AU) and fold onto itself to form a stem loop or hair pin
explain the 3 segments of an mRNA
-5 prime untranslated region (UTR) -coding region -3 prime untranslated region
explain Transferrin receptor mediated endocytosis
1. Cell needs Fe so it puts transferrin receptors to its plasma mem 2. Transferrin receptor will bind transferrin, entire complex is endocytosed 3. endosome is formed, pH is dropped in endosome in order to separate receptor from transferrin 4. Fe is pulled from the protein itself and the Fe is exported from the endosome for storage in the cell (as it leaves it is reduced, can be used in the cell or bind into ferritin)
how is animal (heme) fe abs
1. Hb and Mb enter the stomach and are denatured and digested by HCl and proteases to release the heme portion. if needed the proteases of the pancreas can finish the job 2. heme interacts with hcp1 (heme carrier protein 1) on the surface of the BBM, a specific transporter for heme. 3. once the heme is in the enterocyte, heme oxygenase removes the Fe to form free Fe2+ and protoporphyrin 4. almost immediately that free fe binds to a ligand (ex: aas, and mobilferrin) 5. Fe is moved to basolateral mem through a exporting transporter protein called ferroportin 6. As the Fe moved through ferroportin into the pv, it is oxidized by hephaestin (a cu containing enz that oxidizes Fe to allow it to bind apotransferrin) 7. Fe3+ binds apotransferrin in the pv to make transferrin-Fe complex
explain plant nonheme abs and digestion
1.heme bound to protein, protein is digested by HCl and proteases and pancreatic proteases if needed to release Fe 2.Some of that Fe will be in the Fe2+ form, that Fe can then bind to a transporter called Divalent Mineral Transporter 1 (DMT1) 3. Some the Fe will be or is oxidized in the SI to Fe3+. in this case, that Fe3+ can be reduced to Fe2+ by Dcytb reductase (duodenal cytochrome b reductase) it can then be abs by DMT1 (ascorbic acid can also reduce it) 4. Some of the Fe3+ not reduced, abs depends on what ligands it is bound to (like phytates and oxalates) but some of that Fe3+ iron can bind to integrin transporter, then once in the cell reductases reduce it to Fe2+ 5. rest is the same as heme Fe
in general what form of Fe is abs at a higher eff
2+
how many binding sites for transferrin
2, so it can bind up to 2 Fe atoms
the human body contains how much Fe
2-4 g
how many subunits does ferritin have?
24
explain iron regulation of transferrin receptor and ferritin in iron overload
FERRITIN -pro will function as aconitase in high levels of Fe, no IRE-BP not binding to IRE and translation is not blocked -ferritin levels increase with increased translation, makes sense with high Fe levels TRANSFERRIN RECEPTOR -functions as aconitase, does not bind IREs in 3 prime UTR and therefore does not protect transferrin receptor mRNA because it does not bind the IRE -therefore transferrin receptor levels will go down with decreased translation and increased TR mRNA degradation. makes sense
what is the most common nut def in the world
Fe
what is the trace mineral that is the highest amount in our body?
Fe
in Cu def, what is common
Fe def anemia, including Cu accumulation in the liver. this is because the Fe stays in the liver because it cannot leave to other tissues
what are the states of Fe in the body
Fe2+ (reduced, ferrous) Fe3+ (oxidized, ferric) can go back and forth between these states
what kind of molecule is transferrin
a dimer
heme iron is what kind of structure?
a ring structure called metalloporphyrin
what is hemosiderin
a storage protein for iron that is made from ferritin
source of heme iron specifically. and what percent in that food is heme Fe
derived mainly from Hb and Mb in animals (about 50% of Fe in meat, fish, and poultry=heme)
symptoms
fatigue, weakness, reduced productivity
who has less Fe storage females vs males
females
unbound Fe can participate in the...
fenton rxn
hemosiderin is from
ferritin
in cells Fe tends to be in what form
ferrous Fe2+
unbound Fe in a cell can lead to prodcution of
free radicals and oxidative damage
hemochromatosis is caused by what
genetic form of Fe overload, abnormality in HFE gene required for hepcidin synth in the liver (abs Fe 2-3x normal and not down reg when accumulate Fe in tissues)
ferritin is thought to be modified to become
hemosiderin
what are the storage proteins intracellular for Fe
hemosiderin and ferritin
if a cell needs more iron how can it get more
increase transferrin receptors
prevalence of hemochromatosis
is the most common genetic disorder in US, 1.5 million people
what organs do RBC breakdown and turnover
liver and spleen
what is a chelator
metal binding pro
what is the interchanging between aconitase and IRE-BP called
mineral molecular switch-status of minerals in cells determine function of a protein
is HCP-1 regulated like DMT-1
no
when Fe is fortified it is added as...
nonheme Fe same for supplements
what is the source of about 90% of dietary iron
nonheme iron, 10% heme
where can you find transferrin receptors
on nearly all cells
what is the fenton rxn
one rxn where Fe can generate free radicals
why is the classic def symptom is fatigue
part of ETC (enzymes themselves and oxygen transport) and krebs
what tissues need iron
pretty much all of them
sources of nonheme iron
primarily plants
Fe is almost always bound to...
proteins
nonheme Fe is bound to...
proteins
what is a Fe-S cluster and what is its function
proteins wrap around these in order to function, so some proteins in the body cannot function without a Fe-S cluster. The Fe-S cluster is different based on Fe status, the 4Fe-4S cluster is when Fe status is adequate.
what is metalloporphyrin minus the Fe
protoporphyrin
what is ceruloplasmin?
same as hephaestin but in other tissues than enterocytes for ex the liver
what happens to ferroportin levels when hepcidin is increased?
they go down and therefore iron uptake decreases
why can you find transferrin receptors on nearly all cells?
they need Fe
high Fe in the liver means what for hepcidin levels
they will increase
what is the main Fe transporter in the blood
transferrin
After traveling through the blood, Transferrin binds to...
transferrin receptors on cells and is endocytosed
what is the function of transferrin?
transport Fe in the blood
diff in funct bet Hb and Mb
transport vs transient storage of oxygen
what are some reasons abs eff would go up
when iron needs go up like in adolescence and pregnancy if you have adequate stores abs eff will go down
how often is accidental iron overload a problem, what can it cause
when kids get ahold of Fe supplements can be lethal, can cause liver dysfunction
who has less Hb men or women
women
RDA for women and men
women premen: 18 mg/d postmen: 8 mg/d men: 8 mg/day
can we make heme?
yes as long as we have enough iron
Fe regulation (3 types)
-Fe-S clusters -mRNA structure -Fe regulated translation
what does this have to do with classic symptoms of Fe def (fatigue)
-aconitase is a enz in the krebs cycle and it works with 4Fe-4S clusters, if there is a shift to 3Fe-4S clusters (Fe def), the protein shifts to IRE-BP. therefore krebs cycle activity goes down and E production goes down
what are enhancers of nonheme Fe abs and what are the mechanisms of each
-ascorbic acid (because it reduces Fe) -Fructose (increases abs by improving solubility) -Meat, Fish, poultry factors (increases abs by improving solubility, during digestion of contractile proteins like actin and myosin, commonly found aas bind to Fe and keeps it soluble (ex: histidine, cys)
what happens to the Fe after RBC breakdown
-back into blood bound to transferrin back to bone marrow to be recycled
explain why high Fe levels causing ferritin to increase is a good thing
-can be protective against free fe damage (binds Fe) in any type of cell -in enterocyte, it will control toxicity because once ferritin binds, Fe will not be abs, and so therefore ferritin decreases abs efficiency and will be excreted in feces when enterocyte is sloughed
how long does mRNA stay around in the cell. why?
-degraded fairly quickly -this is because it allows the cell to adapt to diff conditions
what is an example of a pro that changes function based on Fe status?
-depending how much Fe is present to make a certain Fe-S cluster this protein can either be iron response element binding pro (3Fe-4S, low) or aconitase (4Fe-4S, high) (changes its funct based on number of Fe atoms in Fe-S cluster)
what are 2 regulation points in Fe abs
-high Fe levels in the body cause Ferritin to increase -high Fe levels will decrease DMT-1
what is hepcidin and what is its function in general terms, what makes it
-hormone made by liver that travels through the blood to regulate Fe met and abs
explain iron regulation of transferrin receptor and ferritin in iron def
-in Fe def, more IRE-BP than aconitase FERRITIN -Ferritin mRNA has IRE in 5 prime UTR with a IRE-BP bound to it -ribosome cannot bind to 5 prime end and therefore translation will be blocked (cant move through coding region) -IRE-BP can bind with highe enough affinity to displace and prevent binding of ribosome -ferritin levels go down which makes sense, if Fe low we dont need a lot of ferritin TRANSFERRIN RECEPTOR -IREs are at 3 prime UTR -this is imp because IRE-BP is bound, it protects the mRNA from 3-5 prime RNAases -now stable mRNA, stays around longer' -makes sense, Transferrin receptor pro levels goes up with increased translation, can take in more from the blood and increase cell Fe levels
where are IREs present
-in several genes including transferrin receptor and ferritin as well as DMT-1 on BBM (regulated based on Fe status and therefore iron clusters)
Fe intake is frequently inadequate in 4 groups explain each
-infants and young children: low Fe content in milk, high growth rate, insufficient reserves -adolescents: rapid growth, expansion of RBC mass -females in childbearing years: menstral loss -pregnant women: expanding blood volume, fetal dev, blood losses at birth
what happens to the iron as it enters ferritin
-it is oxidized to Fe3+ as it comes back out it is reduced
treatment of hemochromatosis
-limit Fe intake -consistent blood draws -give a chelator, binds Fe and increases urinary excretion
Sources of Fe
-meats, beans, green leafy vegetables, fortified foods like pastas, breads, cereals, flours
what are inhibitors of nonheme Fe abs explain each
-polyphenols (in tea and coffee, can decrease Fe abs by 40%) -oxalates, phytates (neg charged organic molecules that can bind Fe and decrease its abs, in plants like spinach) -other divalent cations (ex: Ca)
what is the prevalence of Fe def: waht percent of the world pop and what percent have Fe def anemia? In dev countries and the US, how common among preschooled aged as well as pregnant women have Fe def anemia?
-the most common nutr def in the world -as much as 80% of the worlds pop -about 30% have Fe def anemia -in dev countries and US: about 1/2 preschool children and pregnant women have Fe def anemia
what is the enz that degrades the RNA and how does it do it
3 prime to 5 prime RNAases -degrades from 3 to 5 prime end
transferrin in the blood is about how saturated
30%
diff in structure bet Mb and Hb
4 vs 1 subunits both have heme
Fe toxicity, what is the UL
45 mg/day
how many Fe atoms can ferritin store
4500
the trace mins are about what percent of total body wt
<0.01%
why dont we want to take a ca and fe supplement at the same time
Ca will decrease Fe abs, will outcompete Fe for abs
Assessment of Fe status stages of def
STAGE 1- -Fe stores in spleen, liver and bone marrow decline or depleted -assessment: plasma ferritin goes down (plasma prop to cell levels) STAGE 2- -transport Fe declines -assessment: (serum transferrin receptors go up) STAGE 3- -functional or cellular Fe becomes limiting -assessment: plasma Fe decreases STAGE 4- -anemia occurs- RBCs become microcytic hypochromic -assessment:
true or false, Fe def can be with and without anemia
T
in US stats, why are we lower
about 10% of young children, adolescent girls, and women of childbearing age have Fe def anemia less common in US, enrichment and fort program and increased heme Fe intake
abs eff of nonheme iron
about 17%
what is the estimated overall avg abs eff?
about 18% but may range from about 10-35% depending on Fe status
what is the abs eff of heme iron
about 25%
what is the avg content of Fe in the western diet
about 5-7 mg per 1000 kcal---> tends to be fairly low in the diet, more problematic for women
where is the iron in the body and in what percents
about 65% Hb about 10% Mb 1-5% part of enzymes
ferritin without Fe is called
apoferritin
why is iron so imp in the Fe-S cluster
because Fe presence can alter shape and function of a pro -this is because the Fe is what bonds to the Sulfurs in the cysteine aas in the pro it is interacting with. The Fe is actually how the pro attaches to the Fe-S cluster