Fe Metabolism And Diseasw Flashcards by Anna Safrankova

Why is fe stored / deposited

Can’t be excreted

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Which state does fe need to be in for acquisition into cell

Fe2/ soluble ferrous form

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Why is fe toxic

Fenton chemistry

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What enzymes convert it into redox states

Fe2 to fe3 by cu containing oxidases for transport
Fe3 to fe2 by reductases

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Which 2 ways is fe from diet

As ferritin - caged fe3 ion

Heme (from meat)- in protoporphyrin ring

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Why is fe needed more in cell than cu and give examples

Mroe enzymes

Cox haem
Ferrochelatase
Helicases
Enzymes for nucleotide synthesis
Translation

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Same amount of fe taken in by gut is removed from body everyday. How

Removal Dead skin cells/ mucous

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Where does fe go for storage

Liver

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Why would fe go to bone marrow

For heme synthesis and rbc incorporation

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Which reductase for fe3 to fe2 in enterocytes lumen side

Dcytb

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What does this allow fe2 to bind

Dmt1 (duodenal importer)

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Heme can also be imported into enterocytes from diet. How

Hcp1 transporter and fe is released by Heme oxidase 1 HO1

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What can fe then do if in excess enterocytes

Either enter ferritin or get oxidised back to fe3 via cu containing oxidases back onto ferroportin exporter

Then binds transferrin

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What is the fe oxidase called in enterocytes vs mitochondria

Hephaestrin

Ceruloplasmin in mt

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What is fe from the fe-Tf complex endocytosed from blood into and which receptor

Tfr1 receptors into clathrin coated endosomes

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What happens in the endosome

Ph change to 5.5 via proton pump mediated by steap3 fe reductase , releasing fe

Fe reduced to fe2 transported out of endosome by dmt1 and incorporated into enzymes

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What happens to ferroportin after

Recycled back up

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Which types of cells need this tfr1 uptake for fe

Erythroid cells

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Which enzyme do macrophages have to breakdown heme

HO1

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What proteins allow it to endocytose free heme or hb

Hemopexin and haptoglobin

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Which cu containing oxidase does mt have and what exporter

Ceruloppasmin

Also has a ferroportin

Then binds transferrin in vlood

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Which protein needed for mrna / translational level regulation of fe metabolism

Irp1

What does dissassembly of fe-s in low fe cause for irp1

It’s change from aconitase enzyme to irp1 and conformational change to open conformation = binds ires on mrna

What does irp1 binding in low fe at 5’ end cause

Block of translation in low fe of genes like aconitase, ferritin storage, heme synthesis , fe efflux ferroportin

What does binding to 3’ end do only in low fe

Protects transcripts for tfr1 and dmt1 for import

Why is irp2 different to irp1 when fe is high

Irp1 just changed to close confirmation whereas irp2 is degraded by fbx15 e3 ligase complez

What are ires

A-helices which have a c bulge/loop

Which event causes fe-s dissassembly even when fe can be high, causing irp1 binding even if fe is already high in cells

Oxidative stress

What backup system degrades it because of this

Fbx15 e3 ligase complex

Which tf is used for txn level regulation

Hif2a

What happens when fe is low or hypoxia occurs

Hif2a translocates to nucleus and activates txn of genes like dmt1, reductases like dcytb

What happens to Hif2a in normoxia or high fe levels

Targeted for degradation by ubiquitination which needs hif to be hydroxylated first by phd1-3

Why does phd1-3 only work to hydroxylate hif when fe is high

They are fe containing proteins

During high fe levels mainly in blood, what happens to regulate ferroportin export of fe in eg liver, enterocytes and macrophages

Hepcidin

What does fe bound transferrin bind in high fe levels

Tfr2 instead of tfr1

What else recruited to tfr2 in high fe which altogether with transferrin-fe and tfr2 causes erk1/2 signalling and helcidin txn

Hfe- hemachormatoais protein

What does hfe bind to in low fe and be sequestered = no erk signalling

Tfr1

Why would hepcidin be reduced in exp during fe deficiency

Ferroportin needed and hepcidin usually binds ferroportin and internalises and degradation occurs

Explain the other pathway of hepcidin activation

Bmp6 increases when fe increases Binds hjv bmpr receptor complex Causes smad 1,5,8 phos Recruits smad 4 Activates txn of hepcidin

What 2 protease actions occur in this pathway during low fe to block hepcidin txn

Hjv degraded protease Hjv cleavage of a soluble subunit which then binds to bmp6 and sequesters it outside of cell = no smad signalling

To stop accumulation of fe in cell when ferroportin ia blocked, what happens

Down reg of dmt1 transporter No irp binding = ferritin increase for storage, heme synthesis etc Hif2a block of txn of usual genes like dmt and dcytb

Ferroportin sexretion during excess fe in cell happens, which other export can get rid of fe in cell

Heme secretion

How much fe can ferritin hold

4500 fe3

What chaperone loads fe to ferritin

Pcbp1

What is h ferritin for

Ferroxidase/ oxidises fe2 to fe3 for incorporation into ferritin

What is phosphorylated when hepcidin binds ferroportin for internalisation and degradation

Jnk2

What hormone ensures ferroportin is not blocked by hepcidin to get fe to weythroid cells

Erythropoietin

What protease is blocked by the tfr2,hfe,fetf complex

Furin which cleaves soluble hjv part

Where does the hepcidin txn regulation occur

In the liver

What is the evidence for erk smad cross talk

Inhibition of erk blocks phos of smad 1,5 and 8

Explain the pathogenesis of hemochromatosis

Disregulated fe absorption movement and deposition due to mutations in the Hepcidin/ferroportin pathway

What sort of mutations causes it

Hepcidin itself, tfr2, ferroportin, hfe, hjv

What is the opposite of it

Anemia where fe is deficient due to high hepcidin low ferroportin