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LAST MEDCHEM OF UR LIFE > 40/41 - Iron Uptake & Distribution > Flashcards

40/41 - Iron Uptake & Distribution Flashcards

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1
Q

TRANSFERRIN
Function

A

Fe2+ –FPN1–> Fe2+ in Blood –HEPH–> Fe3+

CARRIER OF IRON
though the Plasma / ECF
BINDS ONLY Fe3+

2 Fe3+ irons per transferrin

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2
Q

What happens when
IRP binds IRE in the 5’-UTR region?

A

5=stop
Iron Depleted Cells
VVVVV
BLOCK ribosomal binding & interrrupt protein synthesis
VVVVVV

translational REPRESSION
of FERRITIN
LESS IRON STORAGE

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3
Q

Hemochromatosis

A

Excessive ABSORPTION of dietary IRON
&
ALTERED Iron Storage

Iron storage disorder

treated by:
reducing dietary iron / avoiding High VIT C Intake

blood removal

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4
Q

How does TRANSFERRIN assist IRON transport?

A
  • *Fe3+ is relatively
  • INSOLUBLE*and isReactive**

Transferrin:
INCREASES SOLUBILITY
&
reduces its REACTIVITY & iron-mediated redox toxicity

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5
Q

Morphological Adaptations

that occur during IRON DEFICIENCY

A

In order to maximize capacity of small intestine
overall increased surface area

INCREASED
MUCOSAL THICKNESS
VILLUS LENGTH + WIDTH
ENHANCED:
MITOSIS of stem cells in crypts

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6
Q

Iron
General Info

A

SECOND most abundant metal, after Aluminum

Main Role:
Enzymes involved in DNA Replication / repair / translation
rely on iron in the Fe-S Clusters & Heme

Second Main Role:
oxygen-binding characteristic of HEME
crucial for the oxygen-carrying capacity of hemoglobin + myoglobin

Bacteria & Cancer cells LOVE IRON

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7
Q

What causes
HYPOXIA?

A

hypoxia –> direct effect on gut –>
Increase Iron absorption & High Hematocrit (# RBC)

SMOKING
CO2 –> hemoglobin –> outcompetes oxygen

HIGH ALTITUDE
takes 12 weeks for haematological adaptation

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8
Q
  • *CD163**
  • *FUNCTION**
A

Expresed by MACROPHAGES
specialised to take in
HEMOGLOBIN in complex w/ HAPTOGLOBIN

Haptoglobin binds free Hg

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9
Q

MALARIA & FPN/HEPCIDIN

A

Malaria parasites invade RBCs –> consume Hemoglobin
& severely disrupt iron regulation in humans

Iron Supplementation –> MADE DISEASE WORSE
VVVV
UPREGULATE Hepcidin
VVVV
_decrease in Ferroportin expression_
VVVV
less protection against MALARIA

FPN protects RBC’s
against OXIDATIVE STRESS + Malaria Infaction

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10
Q

Function of HEME OXYGENASE

A

After HEME IRON is endocytized into an endosome

LIBERATES IRON (Fe2+) from HEME
inside an endosome

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11
Q

HEPH
Location / Function

A

HEPHAESTIN @ Basolateral Membrane = BLM
of the duodenum

  • *FERROOXIDASE**
  • *Fe2+ –oxidation–> Fe3+**

Transferrin will ONLY bind Fe3+

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12
Q

TRANSFERRIN - TFR1
Internalization PATHWAY

A

Transferrin-TFR1 is internalized via
CLATHRIN-MEDIATED ENDOCYTOSIS
VVVVV
Fe3+ is liberated from transferrin,
as a result of drop in pH –> 5.5 within the vescicle
proton pump on endosome –> acidifies endosome
VVVVV
STEAP3
Fe3+ –reduced–> Fe2+
VVVVV
DMT1
transports Fe2+ into the cytoplasm

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13
Q

Ferritin IMPORT

A

UNKNOWN MECHANISM
Ferritin –> Duodenal Enterocyte –> Lysosome
VVVVV
CIP / LIP

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14
Q
  • *HEME IRON**
  • *Compunds + Functions**
A

HemoGlobin + MyoGlobin
oxygen transport

  • *Cytochrome ABC + P450**
  • *ETC** - oxidative energy + drug metabolism

Catalase + Peroxidase
electron acceptors

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15
Q

TFR1
FUNCTION

A

Transferrin Receptor 1
membrane bound

Binds to IRON-BOUND TRANSFERRIN @ phys. PH
not for APO-transferrin = ironfree transferrin
VVVVV
to be internalized via clathrin mediated endocytosis

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16
Q

What is the MAIN UTILIZERS of
Circulating Iron

A

BONE MARROW** + **Muscle MYOGLOBIN

Humans ONLY ABSORB:
1-2 mg of iron per day
(from duodenum)
which compensates for the iron loss
which is 1-2 mg /day from sloughed cells / menstration

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17
Q

NHE
Function / location

A

Sodium / Hydrogen Exchanger
@ Brush-Border of duodenum enterocytes

PROVIDES PROTON (H+) for DMT
pumps Na+ in // H+ out
proton coupled w/ Fe2+ –> DMT1 –> enter cell

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18
Q
  • *Ceruloplasmin**
  • *Location + Function**
A

FERROOXIDASE
that is located everywhere
EXCEPT** for the **duodenem (hephaestin)

Fe2+ –oxidation–> Fe3+
to be bound by TRANSFERRIN in the BLOOD

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19
Q

Hepcidin
Synthesis

A

encoded by HAMP GENE
which is highly expressed in the LIVER

is the MASTER REGULATOR of systemic iron metabolism

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20
Q
  • *What does IRON SUPPLMENTATION** do to
  • *FERROPORTIN?**
A

SUPPRESS ITS ACTIVITY

Iron Supplementation
VVVV
MORE Hepcidin
VVVV
_downregulate FPN_

Oxidative stress / More Severe Malaria infection

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21
Q

How is NTBI
UPTAKEN?

A

Non-Transferrin-Bound Iron
there are 3 cellular membrane transporters involved:
DMT1 // ZIP14 // ZIP8

Bring NTBI –> Cells
still requires a ferrireductase to reduce Fe3 –> Fe2
before internalization

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22
Q

How is Hepcidin Expression REGULATED

by HYPOXIA / ANEMIA & Erythroid Factors

A

Anemia / Hypoxia
VVVV
INCREASE in Erythopoietin = EPO expression
VVVVV
ERYTHROPOIESIS is STIMULATED
VVVVV
decreases HEPCIDIN gene expression
VVVVV
MORE IRON for HEME / RBC PRODUCTION

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23
Q

What happens when
IRP binds IRE in the 3’-UTR region?

A

“3THREE = inCREEEase” mRNA translation

Iron DEPLETED CELLS
VVVVV
stabilize the transcript
PREVENT mRNA degradation
VVVV
INCREASE mRNA Translation & Protein Synthesis
of TfR1
to stimulate acquisition of IRON

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24
Q

Function & Location of

DCYTB

A

FerriREDUCTASE @ the Brush-Border Membrane
duodenal cytochrome B = DCYTB

REDUCES NON-HEME IRON
Fe3+ –> Fe2+
VVVV
DMT1

at the expense of a intracellular Ascorbate = Vit C

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25
* *Iron-Sulfer Clusters** * *ROLE**
**_Mitochondrial Electron Transport_** **Fe-S** **Oxidation-Reduction Reactions**
26
**FERROPORTIN = FPN** **Function / Location**
Only known **_Cellular EXPORTER_ of _UNBOUND IRON_** * *Hepcidin** --\> binds to **ferroportin** --\> **endocytosis + degradation** * prevents iron EGRESS from the cell* found mostly in : **enterocytes** in **duodenum** // **hepatocytes** // **macrophages**
27
What **INCREASES Iron Absorption?**
**_HEME IRON_** \>\> better absorbed vs *non-heme iron* ***_low pH_*** enhances iron absorption * *_ERYTHPOIESIS_** **stimulation** * *blood loss / acute hemolysis** * *_HYPOXIA_** - -\> hypoxia exerts a **direct effect on the GUT** **_PREGNANCY_**
28
* *Ferritin & Hemosiderin** * *Iron Stores**
**20-30% of Iron** in the body inside **_Hepatocytes**_ & _**RES Macrophages_** **3mg** of iron is bound to **transferrin** *but plasma transferrin compartment* **functions as TRANSIT** flows about **20mg of iron/day**
29
**Iron FUNCTION as a COFACTOR**
**_Cytochrome_** in **ETC** helps transport electron --\> O2 * *_CYP450_** * *Oxidative degradation** of drugs **_Mitochondria_** **_ACONITASE_** (Fe-S) as **TCA enzyme** Citrate --\> Isocitrate
30
What **BLOCKS iron absorption?**
**_PHYTATES_** **_TANNINS_** **_ANTACIDS_**
31
**LIP / CIP / FREE IRON**
*after cellular iron UPTAKE --\> LIP* **_Pool of IRON complexed w/ Low affinity ligands_** Citrate / ATP / AA's / Vit C / unknown chaperones **IRON2-Glutathione** = **dominant componant of the pool** **\<5%** of total cellular iron the **dynamic** compartment that supplies iron to the **MITCHONDRION** for **HEME + Fe-S Clusters** *excess iron --\> stored in FERRITIN*
32
**MITOFERRIN 1 & 2** Function
specialized transporters that * *Move IRON** (usually from the **LIP/CIP)** - -\> the **_MITOCHONDRIA_** where Iron can assist in: **cellular respiration** & **synthesis of Fe-S clusters + HEME**
33
What is an **IRE?**
**_Iron-Responsive Element_** conserved **hairpin structures of mRNA** (25-30 NT) that bind to **_IRP 1 // IRP 2_**
34
* *FLVCR1B Pathway** * *Function**
Another pathway for the **SECRETION OF HEME** **_EMERGENCY VALVE_** to prevent heme overload & **Route for _MACROPHAGES_** to **directly supply HEME --\> developing erythroblasts**
35
**TFR1 Location**
**_Transferrin Receptor 1_** expressed by **ALL iron-requiring cells** *but it's _levels of expression VARIES GREATLY_* ## Footnote **_Highly Expressed on:_ immature erythroid cells // rapidly dividing cells placental tissue**
36
**STEAP3 Function / Location**
**_FerriREDUCTASE_** located inside the **endosome** **Fe3+ --reduced--\> Fe2+** which is then brought --\> cytoplasm by **_DMT1_**
37
**Factors that ALTER Iron Digestion / Absorption**
**Individual's Iron Status** Level of **dietary iron consumption** **TYPE** of iron in foods Amount of **STOMACH ACID** for digestion **Dietary factors** enhance or inhibit absorption
38
**_4 Major Pathways_** **_in HEPCIDIN REGULATION_**
* *_IRON Stores / Status / Dietary_** * *HIGH IRON** --\> MORE HEPCIDIN - -\> *less FPN --\> restrict iron availability* **_INFLAMMATION**_ / _**INFECTION_** induces HAMP *--\>* MORE HEPCIDIN * **_HYPOXIA / ANEMIA_*** * decrease HEPCIDIN* * **_ERYTHROID FACTORS_*** * decrease HEPCIDIN*
39
How is **Intracellular IRON (Fe2+) transported to the BLOOD?**
RAPIDLY transferred across the Basolateral Membrane = **_BLM_** by **_FPN1_** *when body iron demands are HIGH* VVVVV **Fe2+ --\> BLOOD** VVVVV **_HEPH_** Fe2+ --oxidized--\> Fe3+ VVVV **_TRANSFERRIN_**
40
**Iron DISTRIBUTION** What is the **most abundant form of iron?**
* *_HEMOGLOBIN_** * *60-70%** iron in the body body has around **5g of iron** Functional Iron Hemoglobin \> myoglobin \> enzymes Storage: **Ferritin \> hemosiderin = 20-30%** in hepatosites / RES macrophages
41
**Mutations in the FERROPORTIN GENE do what?**
**Ferroportin =** only **iron exporter** BLM of duodenal enterocytes / RES macrophages / hepatocytes / placental cells Affect **IRON EXPORT from MACROPHAGES** VVVVV **_TYPE 4 HEMOCHROMATOSIS_**
42
How is **HEME iron** **Absorbed?**
**Heme = more soluble** **_ENDOCYTOSIS_** intestine --\> membrane VVVVV **ENDOSOME** ​VVVVV iron is then liberated from heme within the endosome by **_HEME OXYGENASE_** = **HO** ​VVVVV **Fe2+** for CIP/LIP
43
How is **Hepcidin Expression REGULATED** by **INFLAMMATION?**
Inflammation: --\> **_IL-6**_ + other _**CYTOKINES_** VVVV **JAK1/2 - STAT3** activation VVVV **HAMP expression** VVVV **Hepcidin --\> *_restricts iron availability_***
44
**_HEPCIDIN_** **_FUNCTION_**
**MASTER REGULATOR** of **systemic iron metabolism** regulates the systemic flux of iron by **modulating the levels of _FERROPORTIN_** Hepcidin --\> **Ferroportin's Extracellular domain** VVVV **_ENDOCYTOSIS_** VVVV **_DEGRADATION_ OF FERROPORTIN (IRON)** *preventing iron egress from the cells*
45
**Things that INHIBIT IRON UPTAKE**
chronic use of **_PPI's_** --\> INCREASE pH (less absorbed) **H.Pylori** / **Celiac's Disease** for non-heme **_Full body stores of Iron_** * *_IRON CHELATORS_** * *POLYOPHENOL -** tea / coffee / lagumes * *OXALATE** - spinach / rhubarb / chocolate * *PHYTATES** / **TANNINS -** wheat / teas * *Egg Yolk / _Fiber_ / Oxalates** * *CARBONATES - Calcium for heme**
46
**Things that PROMOTE IRON UPTAKE**
Duodenal lumen --\> MUCOSA (lining--\>blood) **Amino Acids / Animal Proteins** **_VITAMIN C_** HCL / Organic **Acids** **low pH** **Sugars** --\> form **iron chelates** fructose / sorbital
47
* *Link between** * *IMMUNITY & IRON METABOLISM**
**Infections / Inflammation** VVVVV **IL6 / Cytokines** that **_INDUCE HEPCIDIN SYNTHESIS_** *less iron availability for Bacteria/pathogens/cancer growth* **bacterial pathogens / cancer** require **iron to multiply**
48
**Dietary Iron Absorption & Where?**
**1-2** **mg** of Iron from diet/day some is **lost through cell sloughing & bleeding** **bone marrow = main consumer** * *OCCURS @ _SMALL INTESTINE_** * *duodenum / proximal jejunem**
49
**IRP1** **FUNCTION** Iron-Regulatory Protein
* *Ubiquitously expressed** cytosol * *_IRON-SULFUR_** **protein** **_Iron Replete / Enough Iron:_** IRP1 acts as an **_ACONITASE_** *lacks **_RNA binding activity_*** in the ***_absence of iron --\> binds to IRE_*** **more TfR1** & *less **_ferritin_*** synthesis more IRON acquisition & less iron storage
50
* *4 General Pathways** for individual cells to * *INTERNALIZE IRON**
* *_TFR1_** * *Transferrin** bound iron = MOST COMMON **_DMT1_** _&_ **_ZIP14+8_** bring in **NTBI's** **_CD163**_ + _**LRP1_** + **HRG1** bring in **Haptoglobin + Hg** /// **heme + hemopexin** **_SCARA5_** internalizes **Ferritin**
51
**Systemic IRON METABOLISM PATHWAY _HIGH IRON_**
**High Iron / FERRITIN stores --\> SMAD Signaling** **_HAMP TRANSCRIPTION_** VVVVV upregulates **_HEPCIDIN production_** ​VVVVV hepcidin ***_INHIBITS_*** **_Ferroportin_ expression** VVVVV *less FPN to* **intake Iron** back into the: **systemic iron pool** from macrophages / enterocytes / hepatocytes
52
**DMT1 Function / Location**
Divalent Metal-Ion Transporter 1 @ _Brush Border of Duodenal Enterocytes_ **_Proton-Coupled Uptake of Fe2+ Ferrous_** with the help of **NHE = sodium/hydrogen exchanger** that provides the **Proton**
53
How is **TFR1 + APO-Transferrin RECYCLED?**
**Apotransferrin = *_unbound/no-iron_*transferrin** due to the **pH difference** (**low 5.5 pH)** they are **recycled back to the CELL SURFACE** where the **pH is physiological** transferrin can make around 100-200 cycles of iron transport
54
* *HEME** * *Food Sources**
Animal origin: * *MEAT / FISH / POULTRY** * less dominant in standard diet = 10%* * *_BETTER ABSORBED_*vs than non-heme iron*** * *5-25%** are absorbed Iron-porphyrin Prosthetic Group Hemoglobin / myoglobin / cytochromes
55
How does **VITAMIN C** ***_INDIRECTLY_*** assist **Non-Heme Absorption?**
**_ASC_** --\> Ascorbyl Radical (AR) **_donates an ELECTRON for DCYTB_** **Fe3+ --\> Fe2+** ferrireductase
56
Where are **IRE's LOCATED?**
**_TFR1 mRNA_** has **multiple** IRE's within **3'UTR** ***PREVENT Degredation*** --\> **more TFR1** **_H/L Ferritin mRNA_** contain a **SINGLE** IRE in their **5'UTR** ***repress translation / protein synthesis*** --\> *less Ferritin*
57
**IRP2** **FUNCTION iron-regulatory protein**
* *only** functions as a: * *_RNA BINDING PROTEIN_** * *_Replete Iron / Enough Iron_** * DEGRADED / not used* **"IRP2 = NOT YOU"**
58
How is **NON-HEME Iron Absorbed?**
**_DCYTB = FerriReductase_** **Fe3+** --\> **Fe2+** VVVVV **_DMT1_** = **symporter** ​VVVVV **Fe2+** enters the **membrane** **CIP / LIP**
59
**Ferritin Function**
**MAJOR INTRACELLULAR _IRON STORAGE PROTEIN_** stores **~4,500 iron atoms** **_LIVER_** - **60%** of ferritin in body Muscle / Reticuloendothelial - 40% Ferritin is **always being loss​** due to the **apical cells** --\> **sloughed off / exfoliated**
60
How is **Hepcidin Expression REGULATED** ## Footnote **by IRON STATUS in Hepatocytes?**
HIGH IRON VVVVV **_BMP6 RECEPTOR**_ + _**HJV_** bone morphogenic protein 6 // haemojuvelin VVVVV **downstream SMAD signaling** VVVVV **Nucleus** ---\> **_HAMP_** --\> more **hepcidin** *reduction in iron availability*
61
**Non-Heme Iron Food Sources**
**Vegetable Origin** cereal / veggies / molasses **90% of DIETARY iron** *but is _HIGHLY INSOLUBLE_* only **2-5% is absorbed** Transferrin / Ferritin / Enzymes with iron @ active site Iron-sulphur proteins
62
**IRON** **TOXICITY**
**Accidental Iron Overdose** = **MOST COMMON** cause of poisining deaths in children **High Iron** content in **_prenatal multivitamins_** toxicity is a function of the **# of iron per KG of weight** so children can QUICKLY reach a toxic dose --\> destroys **LINING OF GI TRACT** **Hemochromatosis**
63
Where does **MOST of the iron RECYCLED?**
**_RES MACROPHAGES_** in the **SPLEEN** Reticuloendothelial System Recycle **10-20x** **more IRON** vs **intestine absorbs** * *RBC / Heme --\> HO1** --\> * *_IRON via ferroportin_ - -\> transferrin**
64
How is **IRON LOSS?**
After Iron --\> **epithelial cells:** transported for **circulation or** sequestrated as **Ferritin** last only **2 DAYS** before being **USED** or **SHED into intestinal lumen** lost by * *_EXFOLIATION OF INTESTINAL EPITHELIUM_** * *1-2mg / day**
65
What do **IRP1 & IRP2 have in COMMON?**
***_in the absence of iron_*** VVVV **_binds to IRE_** VVVV **more TfR1** --\> **more IRON acquisition** from plasma & ***_steric blockade_*** to ***_FERRITIN mRNA translation_*** ---\> ***obsolete iron storage***
66
**NON-Heme Fe2+** **Source / Absorpition**
**Fe2+ = FERROUS** * *MORE SOLUBLE** than **Ferric Fe3+** * LESS ABUNDANT though,* * *Fe3+ is reduced to Fe2+ for transport**
67
How does **VITAMIN C** **DIRECTLY** assist **Non-Heme Absorption**?
*just a HYPOTHESIS* **ASC** crosses the **membrane --\> EXTRACELLULAR** reacts **DIRECTLY** w/ **Fe3+** to produce **Fe2+**
68
**NON-Heme Iron Compounds + Functions**
**NAD Dehydrogenase** **Xanthine Oxidase** **Ribonucleotide Reductase** **Succinate Dehydrogenase**
69
* *NON-Heme Fe3+** * *Source / Absorption**
**Fe3 = FERRIC** Found in **both meat + plant** foods * *MORE DOMINANT form of Non-Heme IRON** * needs to be converted to **ferrous Fe2+** before transport* ***_HIGHLY INSOLUBLE_*** only about **2%** absorbed from meal
70
**FPN1 Function / Location**
**Ferroportin 1** @ **_Basolateral Membrane = BLM_** on **all tissues** that **export iron --\> plasma** rapid **IRON EXPORTER** **_Fe2+ --\> BLOOD_** CIP/intracellular Iron --\> into the blood

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