1. Metabolism of heme and iron
Alice Skoumalová

2. Metabolism of heme

3. Heme structure:
a porphyrin ring coordinated with an atom of iron
side chains: methyl, vinyl, propionyl
Heme is complexed with proteins to form:
Hemoglobin, myoglobin and cytochromes

4. Mitochondria Cytosol Mitochondria
všechny tkáně, hlavně játra a kostní dřeň
8 molekul glycinu a succinyl-CoA
Porfyriny - bezbarvé - nestabilní, snadno oxidovány (světlem) na porfyny
Fettochelatáza - inhibice olovem
Mitochondria

5. Derangements in porphyrin metabolism: Disease state Genetics Tissue
Organ pathology
Acute intermittent porphyria
dominant
Liver
Nervous system
Hereditary coproporphyria
Nervous system, skin
Variegate porphyria
Porphyria cutanea tarda
Skin, induced by liver dis.
Erythropoietic protoporphyria
Marrow
Gall stones, liver dis., skin
Congenital erythropoietic porphyria
recessive
Skin, RES
Lead poisoning
All tissues
Nervous system, blood, others
Porfyria cutanea tarda - nejčastější, indukovaná požitím léků či alkoholu, fotosensibilita

6. Cutaneous porphyrias

7. Synthesis of δ-aminolevulinic acid:
Pyridoxal phosphate (vit. B6)
induced by: drugs (barbiturates), oral contraceptive pills

8. Formation of porphobilinogen:
inhibited by lead

9. Degradation of heme:
Kernicterus

10. Conversion of heme to bilirubin:
ER enzyme system
Cytoprotective role: CO
biliverdin
the major source is Hg

11. increase the water solubility of bilirubin
Formation of bilirubin diglucuronide:
increase the water solubility of bilirubin

12. Hyperbilirubinemia
Elevated bilirubin levels in the blood (>10 mg/l); bilirubin may diffuse into peripheral tissues, giving them a yellow color (jaundice)
Cause:
1. Pre-hepatic: excessive formation of bilirubin by increased degradation of erythrocytes (icterus neonatus, hemolytic anemia)
2. Hepatic: insufficient processing of bilirubin as a result of liver defects (hepatitis, liver toxic damage, cirrhosis, hepatic failure)
3. Post-hepatic: by impaired excretion of gall (obstructive jaundice due to gallstones, inflammation of biliary tract)
Unconjugated bilirubin can cross the blood-brain barrier, leading to brain damage
Jaundice in neonates (increased bilirubin degradation+immaturity of the conjugation enzymes): phototerapy – isomerization of bilirubin to more soluble pigments

13. Type
Cause
Example
Frequence
Prehepatic
Hemolysis
Autoimmune
Haemoglobinopathy
Rare
According to the region
Hepatic
Infection
Damage
Genetics
Newborn
Hepatitis A,B,C
Alcohol, drugs
Gilbert´s syndrome
Wilson´s disease
α1-Antitrypsin deficiency
Chronic hepatitis
Physiologic
Very common
Common
1 in 20
1 in
1 in 1000
Posthepatic
Intrahepatic
bile ducts
Extrahepatic
Drugs
Primary biliary cirrhosis
Cholangitis
Gallstones
Pancreatic cancer

14. ↑↑(UC) N ↑ ↑↑(both) ↑ N ↑↑(C) ↑ ↓ Bilirubin
blood urine deriv. in feces
Urobilinogen
blood urine
Prehepatic
↑↑(UC) N ↑
↑ ↑
Intrahepatic
↑↑(both) ↑ N
↑↑ ↑↑
Posthepatic
↑↑(C) ↑ ↓
↓ ↓

15. Summary:
Synthesis of heme:
from glycine and succinate
induction by drugs and ↓ glucose; inhibition by lead
intermediates → porphyrinogens (porphyrins)
porphyrias
Degradation of heme
to bilirubin (hydrophobic)
conjugation in liver
conversion to urobilinogen in intestine
hyperbilirubinemia (differential diagnosis)

16. Metabolism of iron

17. Iron in an organism:
total 3-4 g (2,5 g in hemoglobin)
heme, ferritin, transferrin
two oxidation states: Fe2+, Fe3+
Function:
1. Heme iron:
hemoglobin, myoglobin, cytochrom-c oxidase, catalase
2. Non-heme iron:
Fe-S complexes (xanthine oxidase), DNA synthesis (ribonucleotide reductase)
Free iron is toxic !
Regulation:
at the level of absorption

18. Iron metabolism:
Deplece ceruloplasminu (Wilsonova choroba) - ukládání železa v pankreatu a mozku (DM a nerv. příznaky)

19. Recommended dietary allowance 10-15 mg
Iron metabolism:
Recommended dietary allowance mg
10-50 mg in the diet (only 10-15% is normally absorbed)
Iron distribution: g %
Hemoglobin
2,5 68
Myoglobin
0,15 4
Transferrin
0,003
0,1
Ferritin, tissue
1,0 27
Ferritin, serum
0,0001
0,004
Enzymes
0,02
0,6
Total
3,7
100
Volné železo poškodí makromolekuly

20. Iron absorption from the intestine:
D (DMT 1), I (Integrin), M (Mobilferrin), Fn (Ferritin), Fp (Ferroportin), H (Hephaestin), R (Ferrireductasa)

21. Intestinal absorption of iron:
- in the duodenum
- regulation (by the synthesis of apoferritin within mucosal cells)
The heme iron (unknown mechanism)
The nonheme iron
is not readily absorbed (chelates with oxalates, phytates, etc.)
vit. C increases the uptake
Iron sources:
meat, liver, fish, eggs, green vegetables, cereals
Iron loss:
- daily loss ~ 1-2 mg (cell desquamation, ♀ menstruation, pregnancy, multiple births, lactation)
- bleeding
Recyclation of iron:
- from aged erythrocytes (~ 20 mg)
- transferrin receptors on cells

22. Iron transport:
Transferrin (Fe3+) Transferrin + Fe3+ + CO32- → Transferrin • 2(Fe3+CO32-)
- only one third saturated with iron
- unsaturated transferrin protects againsts infections (iron overload and infection)
Lactoferrin
- binds iron in milk
- antimicrobial effect (protects newborns from gastrointestinal infections)
Haptoglobin
- binds hemoglobin in the plasma
Iron storage:
Ferritin (Fe3+)
- storage of iron (hepatocytes, RES, muscles)
- in the blood → sensitive indicator of the amount of iron in the body
Hemosiderin
- when iron is in excess (amorphous iron deposition)

23. Iron-containing proteins:
1. Heme proteins
Hemoglobin
Myoglobin
Enzymes that contain heme as their prosthetic group (catalase, peroxidase, NO synthase)
2. Nonheme proteins
Transferrin
Ferritin
Enzymes that contain iron at the active site
Iron-sulphur proteins

24. Regulation of iron metabolism:
Hepcidin (a key regulator in iron metabolism)
↓ resorption of iron in the intestine → ↓ concentration of iron in plasm
mechanism: binding to ferroportin (the iron is trapped in the cell)
increased concentration in inflammation (chronic disease anemia)
reduced production → hereditary hemochromatosis

25. Iron deficiency (sideropenia):
Causes
inadequate intake, reduced resorption, increased loss
Symptoms
reduction of iron stores in liver and bone marrow
decrease in the amount of plasma ferritin
decrease in the percentage saturation of serum transferrin
decrease in the level of Hg, morphological changes of erythrocytes
microcytic hypochromic anemia (excessive menstrual flow, multiple births, GIT bleeding)
Therapy
supplementation

26. Iron overload → hemochromatosis:
Causes
genetic - iron uptake regulation (hereditary hemochromatosis)
treatment of patients with hemolytic anemias
excessive ethanol and iron ingestion
Symptoms
accumulation of iron in the liver, pancreas and heart
Therapy
bloodletting, chelating agents

27. Summary:
1. Function of iron (O2 transport, redox reactions , detoxification, cell division)
2. Iron can be toxic
3. Complicated regulation at the level of resorption
4. Iron is important for microorganisms
5. Abnormalities of iron metabolism → diseases