proteinin iron metabolism

1. Thirupathi Raja
Group 2

2.  1 to 2 mg of iron
enters the body each
day.
 Most of the iron in the
body is incorporated
into hemoglobin in
erythroid precursors
and mature red cells.
 Most of the iron found
in the plasma derives
from the continuous
breakdown of
hemoglobin in
senescent red cells by
RE macrophages.
 Each day,
approximately 1 to 2
mg of iron are lost
from the body.


3. Two types of iron-containing proteins:
1) Haemoproteins
2) Non-haem iron proteins

4. Haemoproteins: contain iron in the form of haem
Haem: iron inserted in a tetrapyrrole ring

5.  Ferritin - iron storage protein
 Transferrin: iron transport protein

6. Ferritin:
iron storage protein. In men, contains up to 1 gram of iron
450 kDa protein consisting of 24 subunits
Inside the ferritin shell, iron ions form crystallites together with phosphate and hydroxide
ions. The resulting particle is similar to the mineral ferrihydrite.
Each ferritin complex can store about 4500 iron (Fe3+) ions.
Reflects the amount of BODY IRON STORES
men: 20-275 μg/litre
women: 5-200 μg/litre
15 μg/litre and less: insufficient iron stores

7. Ferritin
x 24

8.  Transports iron in the blood
 Contains only 2 atoms of iron
 Transferrin is the only source of iron for hemoglobin
 Transferrin saturation is clinically useful for iron
metabolism studies
(iron-saturated Tf / total Tf)
Transferrin

9. Transferrin saturation:
Normal about 30-50 %
Transferrin saturation under 15 %= Iron deficiency

10. Transferrin

11. pH 5.5
A) Uptake
(TfR cycle)
C) StorageB) Metabolic
Utilization
Extracellular
Space
Cytoplasm
D) Export
Heme Iron Containing
Proteins
Ferritin
Protoporphyrin IX
5-Aminolevulinate
Succinyl-CoA + Glycine
Mitochondrion
The transferrin cycle
Dmt1

12. Protein Function Expression
Ft (H and L subunits)
( IREs 5’UTR )
Iron storage Most cells
TfR1
( IREs 3’UTR )
Iron uptake Erythroid cells, epithelial
cells rapidly growing
(intestinal crypt cells).
Other cells including
macrophages
TfR2 Iron uptake Hepatocyte, circulating
monocytes
DMT1 (Nramp2/DCT1)
( IREs 3’UTR )
Iron import; iron release
from endosome to
cytoplasm
Brush border of epithelial
cell of the intestinal villus.
Endodomal vesicles in
erythroid cells and other
cell types
FP1/IR1/MTP1
( IREs 5’UTR )
Iron export Basolateral membrane of
epithelial cell of the
intestinal villus; placenta;
other cell types

13. Protein, carriers, &
“regulators” in iron
metabolism
Protein Function Expression
Duodenal cytochrome b Ferric reductase Brush border of enterocytes of the
intestinal villus.
Ephaestin Ferroxidase Basolateral membrane and
vesicles of enterocytes of the
intestinal villus.
HFE (No IREs) Interacts with TfR1 Intestinal crypt cells and tissue
macrophages
Hepcidin (No IREs) Antibacterial activity; iron
homeostasis?
Liver; blood; urine
IRP1 AND IRP2 Posttranscriptional control of
target mRNAs (Ft, TfR1,
DMT1, FP1/IR1/MTP1,
mitochondrial aconitase,
erythroid aminolevulinate
synthase)
Mainly: Liver, spleen, kidney,
heart.
Also: duodenum, brain

15.  Fe 2+
Tf binds to TfR1 on RBC. Fe 2+
Tf/TfR1
complex localize to clathrin-coated pits
which invaginate to form endosomes. A
proton pump decreases pH leading to iron
release. DMT1 moves iron across
endosomal membrane to cytoplasm. Apo-
Tf& TfRl are recycled to the cell surface for
further use. In RBC most iron is
incorporateed into protoporphyrin to make
Heme (mitochondria).

17.  specialized transport systems and membrane
carriers have evolved in humans to maintain iron in
a "soluble" state suitable for circulation in the
bloodstream [i.e., bound to serum transferrin (Tf)] or
to transfer it across cell membranes [through metal
transporters such as divalent metal transporter
1 (DMT1) or ferroportin1/Ireg-1/MTP-1] for tissue
utilization.
 Since there is no mechanism for delibrate excretion
of iron through the liver or kidneys, iron homeostasis
is maintained primarily by the tight regulation of iron
absorption in the intestine and the high degree of
conservation of body iron stores.

18.  It is induced by iron deficiency.
 Mediates cellular iron egress in
conjunction with the ferroxidase,
hephaestin.
 Localizes to the basolateral membrane
of polarized cells.
 IREs are at the 5’UTR of FP1 mRNA.

19.  Ferroxidase activity.
 It oxidizes iron as part of the transmembrane
transfer process &/or the process of loading
iron onto plasma Tf.
 Mice hemizygous or homozygous for sex-
linked anemia (sla) mutation have partial loss
of hephaestin function & resultant iron
deficiency due in part to hephaestin
mislocalization away from basolateral
membrane.

23. Synthesized in the liver.
2000 LEAP-1 purified from human blood.
2001,isolated from human urine.
Lack of hepcidin expression--- iron overload.
No IREs identified in hepcidin transcript.
Is a negative regulater of iron absorption in
duodenum &of iron release from macrophage.

24.  Is secreted in response to change in the ratio
of diferric Tf in the circulation to TfR1.
 Changes detected by TfR2&HFE-TfR1.
 It directly influences the expression of DMT1 &
ferroportin in enterocytes, there by regulating
absorption in response to body iron
requirements.

25.  HC represent a common single-gene
hereditary disorder.
 C282Y mutation disrupts a critical disulfide
bond in HFE ptn & abrogates its binding to
B2microglobulin------reduced expression on
the cell.
 HFE Knockout &knockin mice recapitulate
the human disease.

26.  Paradoxically, the mRNA coding for the HC gene
product HFE, does not contain IREs nor is it
known to be regulated by iron status.Yet, HFE
has a dramatic impact on cell iron trafficking &,
indirectly, on intestinal iron absorption.

27.  The "information" on the erythron
and body iron status is transferred
to the crypt cells of the distal
duodenum by Tf: the extent of Tf
saturation with iron acts as the
"signal" that is transferred through
the transferrin receptor (TfR)/HFE
pathway to the stem cells of the
crypts. This sets the level of "free
iron pool" in the crypt cell that will
also be reflected in the mature
enterocytes on differentiation and
migration to the villus. The free iron
pool through the iron regulatory
proteins (IRP) will dictate the level
of expression of apical and
basolateral iron transporters in the
mature enterocytes of the villus
and, in turn, of iron absorption.

28.  B: in iron-deficiency anemia,
the circulating iron-poor Tf will
signal to RE cells the increased
erythron demands prompting
for iron release and diverting
iron from the periphery,
including intestinal cells, to the
erythron. Due to low availability
of circulating iron, the
decreased free iron pool in
crypt cells will signal the
mature enterocyte to activate
the iron uptake transfer
machinery.

29.  . C: during secondary iron
overload (e.g., transfusion
siderosis), iron-saturated
Tf will cause the RE cells
and crypt cells to retain
iron; this will then
downregulate iron carriers
in the mature iron-replete
enterocytes and decrease
iron absorption.

30.  D: in hereditary hemochromatosis, due
to the defective HFE and the faulty
HFE/TfR pathway, both RE cells and
crypt cells receive an incorrect signal
of "iron deficiency" despite increasing
saturation of circulating Tf with iron.
This, paradoxically, will lead, as in a
"true" iron-deficiency state, both
macrophages and duodenal
enterocytes to "release" more iron.
Duodenal cells will accomplish this by
activating the iron uptake transfer
machinery. DMT1, divalent metal
transporter 1.