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

40/41 - Iron Uptake & Distribution Flashcards

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
Q
  • *Iron-Sulfer Clusters**
  • *ROLE**
A

Mitochondrial Electron Transport

Fe-S

Oxidation-Reduction Reactions

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26
Q

FERROPORTIN = FPN

Function / Location

A

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

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27
Q

What INCREASES
Iron Absorption?

A

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

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28
Q
  • *Ferritin & Hemosiderin**
  • *Iron Stores**
A

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

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29
Q

Iron FUNCTION as a
COFACTOR

A

Cytochrome
in ETC helps transport electron –> O2

  • *CYP450**
  • *Oxidative degradation** of drugs

Mitochondria
ACONITASE (Fe-S) as TCA enzyme
Citrate –> Isocitrate

30
Q

What BLOCKS iron absorption?

A

PHYTATES

TANNINS

ANTACIDS

31
Q

LIP / CIP / FREE IRON

A

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
Q

MITOFERRIN 1 & 2
Function

A

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
Q

What is an
IRE?

A

Iron-Responsive Element
conserved hairpin structures of mRNA (25-30 NT)
that bind to
IRP 1 // IRP 2

34
Q
  • *FLVCR1B Pathway**
  • *Function**
A

Another pathway for the SECRETION OF HEME
EMERGENCY VALVE
to prevent heme overload
&
Route for MACROPHAGES
to directly supply HEME –> developing erythroblasts

35
Q

TFR1
Location

A

Transferrin Receptor 1
expressed by ALL iron-requiring cells
but it’s levels of expression VARIES GREATLY

Highly Expressed on:
immature erythroid cells // rapidly dividing cells
placental tissue

36
Q

STEAP3
Function / Location

A

FerriREDUCTASE
located inside the endosome

Fe3+ –reduced–> Fe2+

which is then brought –> cytoplasm by DMT1

37
Q

Factors that ALTER
Iron Digestion / Absorption

A

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
Q

4 Major Pathways

in HEPCIDIN REGULATION

A
  • *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
Q

How is Intracellular IRON (Fe2+)
transported to the BLOOD?

A

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
Q

Iron DISTRIBUTION
What is the most abundant form of iron?

A
  • *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
Q

Mutations in the FERROPORTIN GENE
do what?

A

Ferroportin = only iron exporter
BLM of duodenal enterocytes / RES macrophages / hepatocytes / placental cells

Affect IRON EXPORT from MACROPHAGES
VVVVV
TYPE 4 HEMOCHROMATOSIS

42
Q

How is HEME iron Absorbed?

A

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
Q

How is Hepcidin Expression REGULATED

by INFLAMMATION?

A

Inflammation:
–> IL-6** + other **CYTOKINES
VVVV
JAK1/2 - STAT3 activation
VVVV
HAMP expression
VVVV
Hepcidin –> restricts iron availability

44
Q

HEPCIDIN

FUNCTION

A

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
Q

Things that INHIBIT
IRON UPTAKE

A

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
Q

Things that PROMOTE
IRON UPTAKE

A

Duodenal lumen –> MUCOSA (lining–>blood)

Amino Acids / Animal Proteins

VITAMIN C
HCL / Organic Acids
low pH

Sugars –> form iron chelates
fructose / sorbital

47
Q
  • *Link between**
  • *IMMUNITY & IRON METABOLISM**
A

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
Q

Dietary Iron Absorption
& Where?

A

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
Q

IRP1

FUNCTION

Iron-Regulatory Protein

A
  • *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
Q
  • *4 General Pathways** for individual cells to
  • *INTERNALIZE IRON**
A
  • *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
Q

Systemic IRON METABOLISM PATHWAY
HIGH IRON

A

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
Q

DMT1
Function / Location

A

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
Q

How is TFR1 + APO-Transferrin
RECYCLED?

A

Apotransferrin = unbound/no-irontransferrin

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
Q
  • *HEME**
  • *Food Sources**
A

Animal origin:

  • *MEAT / FISH / POULTRY**
  • less dominant in standard diet = 10%*
  • BETTER ABSORBEDvs than non-heme iron***
  • *5-25%** are absorbed

Iron-porphyrin Prosthetic Group

Hemoglobin / myoglobin / cytochromes

55
Q

How does VITAMIN C
INDIRECTLY assist Non-Heme Absorption?

A

ASC –> Ascorbyl Radical (AR)

donates an ELECTRON for DCYTB
Fe3+ –> Fe2+
ferrireductase

56
Q

Where are IRE’s LOCATED?

A

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
Q

IRP2

FUNCTION
iron-regulatory protein

A
  • *only** functions as a:
  • *RNA BINDING PROTEIN**
  • *Replete Iron / Enough Iron**
  • DEGRADED / not used*

“IRP2 = NOT YOU”

58
Q

How is NON-HEME Iron Absorbed?

A

DCYTB = FerriReductase
Fe3+ –> Fe2+
VVVVV
DMT1 = symporter
​VVVVV
Fe2+ enters the membrane
CIP / LIP

59
Q

Ferritin
Function

A

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
Q

How is Hepcidin Expression REGULATED

by IRON STATUS in Hepatocytes?

A

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
Q

Non-Heme Iron
Food Sources

A

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
Q

IRON

TOXICITY

A

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
Q

Where does MOST of the iron RECYCLED?

A

RES MACROPHAGES in the SPLEEN
Reticuloendothelial System

Recycle 10-20x more IRON vs intestine absorbs

  • *RBC / Heme –> HO1** –>
  • *IRON via ferroportin
  • -> transferrin**
64
Q

How is IRON LOSS?

A

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
Q

What do IRP1 & IRP2
have in COMMON?

A

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
Q

NON-Heme Fe2+

Source / Absorpition

A

Fe2+ = FERROUS

  • *MORE SOLUBLE** than Ferric Fe3+
  • LESS ABUNDANT though,*
  • *Fe3+ is reduced to Fe2+ for transport**
67
Q

How does VITAMIN C
DIRECTLY assist Non-Heme Absorption?

A

just a HYPOTHESIS

ASC crosses the membrane –> EXTRACELLULAR
reacts DIRECTLY w/ Fe3+
to produce Fe2+

68
Q

NON-Heme Iron
Compounds + Functions

A

NAD Dehydrogenase

Xanthine Oxidase

Ribonucleotide Reductase

Succinate Dehydrogenase

69
Q
  • *NON-Heme Fe3+**
  • *Source / Absorption**
A

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
Q

FPN1
Function / Location

A

Ferroportin 1 @ Basolateral Membrane = BLM
on all tissues that export iron –> plasma

rapid IRON EXPORTER
Fe2+ –> BLOOD
CIP/intracellular Iron –> into the blood

LAST MEDCHEM OF UR LIFE (11 decks)

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