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Metabolism of tetrapyrrols
Pavla Balínová
Tetrapyrrols
• circular compounds binding a
metal ion (most frequently
Fe2+ and Fe3+)
• consist of 4 pyrrol rings
interconnected via methine
bridges
Examples:
• heme (Fe2+)
• chlorophyll (Mg2+)
• vitamin B12 (Co2+)
Figure was assumed from http://en.wikipedia.org/wiki/Porphyrin
Where can we find a heme??
Hemoproteins
• Hemoglobin (Hb)
• Myoglobin (Mb)
• Cytochrome c
• Catalases (decomposition
of H2O2 to H2O and O2)
Figure was assumed from http://en.wikipedia.org/wiki/Heme
Heme structure
methine bridge
pyrrol
Figure was assumed from a book T. M. Devlin et al.: Textbook of Biochemistry With Clinical
Correlations, 4th ed., Wiley-Liss, Inc., New York, 1997.
Biosynthesis of heme
• Organ location: bone marrow 85% and liver
• Subcellular location: mitochondria and cytosol
• Substrates: succinyl-CoA and glycine
• Important intermediates: δ-aminolevulinic acid
(ALA), porphobilinogen, uroporphyrinogen III,
protoporphyrin IX
• Key regulatory enzyme: ALA synthase
Heme biosynthesis
Figure was assumed from http://www.porphyrin.net/mediporph/_netbiochem/synthesis/_synthmain.html
Delta-aminolevulinic acid (ALA)
• synthesis of heme starts in mitochondria
• succinyl-CoA and glycine (Gly) undergo condensation
→ δ-aminolevulinic acid (ALA)
• reaction is catalyzed by enzyme ALA synthase
-OOC-CH
2-CH2-CO-S-CoA
+ NH3+-CH2-COO-
CO2
-OOC-CH -CH -CO-CH -NH +
2
2
2
3
Porphobilinogen (PBG)
• ALA leaves the mitochondria → cytoplasm
• 2 molecules of ALA condense to form porphobilinogen
• reaction is catalyzed by enzyme porphobilinogen
synthase
pyrrol ring
Figure was assumed from http://en.wikipedia.org/wiki/Porphobilinogen
Uroporphyrinogen III
Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical
Correlations, 4th ed., Wiley-Liss, Inc., New York, 1997.
Uroporphyrinogen → coproporphyrinogen III
• enzyme hydroxymethylbilane synthase catalyzes the
linkage of 4 PBG molecules and cleavage of 4 NH4+ to
yield uroporphyrinogen III
• 4 acetate residues are decarboxylated into methyl
groups → coproporphyrinogen III returns to the
mitochondria again
Protoporphyrinogen IX
Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical
Correlations, 4th ed., Wiley-Liss, Inc., New York, 1997.
Protoporphyrinogen IX → protoporphyrin IX
• oxidation of protoporphyrinogen IX produces the
conjugated π-electron system of protoporphyrin IX
Figure was assumed from book T. M. Devlin et al.: Textbook of Biochemistry With Clinical
Correlations, 4th ed., Wiley-Liss, Inc., New York, 1997.
Heme
• Fe2+ is incorporated into protoporhyrin IX
• reaction is catalyzed by enzyme ferrochelatase
Figure was assumed from http://www.porphyrin.net/mediporph/_netbiochem/synthesis/
ferrochelatase.html
Regulation of heme biosynthesis
ALA synthase is a key regulatory enzyme
• it is an allosteric enzyme that is inhibited by heme =
feedback inhibition
• requires pyridoxal phosphate
• certain drugs and steroid hormones can increase heme
synthesis
Porphobilinogen synthase is inhibited by lead ions Pb2+ in
case of lead poisoning.
Ferrochelatase can be also inhibited by Pb2+. Its activity
is influenced by availability of Fe2+ and ascorbic acid.
Porphyrias
• are hereditary or acquired disturbances of heme
synthesis
• in all cases there is an identifiable abnormality of the
enzymes which synthesize heme
• this leads to accumulation of intermediates of the
pathway and a deficiency of heme → excretion of heme
precursors in feces or urine, giving them a dark red
color
● accumulation of porphyrinogens in the skin can lead to
photosensitivity
• the neurological symptoms
Heme degradation
• around 100 – 200 million aged erythrocytes per hour
are broken down in the human organism
• Organ location: RES (reticuloendothelial cells) in the
spleen, liver and bone marrow
Hb is degraded to:
● globin → AAs → metabolism
● heme → bilirubin
2+ → transport with transferrin and used in the next
● Fe
heme biosynthesis
Not only Hb but other hemoproteins also contain heme
groups which are degraded by the same pathway.
Conversion of heme to bilirubin
Figure was assumed from http://web.indstate.edu/thcme/mwking/heme-porphyrin.html
Bilirubin
Bilirubin (Bil) is released from RES into the blood. BUT!
Bil is only poorly soluble in plasma, and therefore
during transport it is bound to albumin.
↓
LIVER
In the hepatocytes, Bil is conjugated by 2 molecules of
glucuronic acid → bilirubin diglucuronide (soluble in
water, „conjugated Bil“). Conjugation is catalyzed by
UDP-glucuronosyltransferase.
Bilirubin diglucuronide
Figure was assumed from http://web.indstate.edu/thcme/mwking/heme-porphyrin.html
Bile pigments
bilirubin diglucuronide
↓
BILE
↓
INTESTINE
Bil is reduced to urobilinogen and stercobilinogen by
bacteria → oxidation to urobilin and stercobilin
Bile pigments are mostly excreted in feces, but a small
proportion is resorbed (enterohepatic circulation).
Small amount of urobilinogen is excreted with urine.
Determination of bilirubin in serum
Blood tests
• Bil reacts directly when dyes are added to the blood
sample → conjugated bilirubin = direct
• free Bil does not react to the reagents until alcohol
(methanol) or caffeine is added to the solution.
Therefore, the measurement of this type of bilirubin
is indirect → unconjugated bilirubin = indirect
• Total bilirubin measures both unconjugated and
conjugated Bil (normal value up to 20 µmol/L).
Hyperbilirubinemias
• Hyperbilirubinemia = an elevated bilirubin level (> 10
mg/L) → Bil can diffuses from the blood into
peripheral tissues and gives it a yellow color (jaundice
= icterus)
Jaundice can have various causes:
• Increased erythrocyte degradation – hemolytic
jaundice
• Impaired conjugation of bilirubin in the liver –
hepatocellular jaundice
• Disturbance of bile drainage (gallstones) –
obstructive jaundice
In the urine, only conjugated bilirubin can be present.
Icterus
Icterus is the yellow coloration of skin and mucus
membranes of jaundice (hyperbilirubinemia with
various ethiology)
• Hemolytic icterus: elevated level of unconjugated Bil
in blood
• Neonatal jaundice usually appears after a few days
after birth (elevated hemolysis, decreased activity of
UDP-glucuronosyltransferase → ↑ unconjugated Bil)
In severe cases, unconjugated Bil can cross the bloodbrain barrier and lead to brain damage (kernicterus).