Download 7-Heme Degradation

Heme Degradation
Dr. Shumaila Asim
Lecture # 7
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FATE OF RED BLOOD CELLS
 Life span in blood stream is 60-120 days
 RBCs are phagocytosed and/or lysed
Normally, lysis occurs extravascularly in the
reticuloendothelial system subsequent to RBC
phagocytosis
 Lysis can also occur intravascularly (in blood stream)
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Extravascular Pathway for RBC Destruction
(Liver, Bone marrow,
& Spleen)
Phagocytosis & Lysis
Hemoglobin
Globin
Heme
Amino acids
Fe2+
Amino acid pool
Bilirubin
Excreted
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Handling of Free (Intravascular) Hemoglobin
Purposes:
1. Scavenge iron
2. Prevent major iron losses
3. Complex free heme (very toxic)
• Haptoglobin: hemoglobin-haptoglobin complex is readily metabolized
in the liver and spleen forming an iron-globin complex and bilirubin.
Prevents loss of iron in urine.
• Hemopexin: binds free heme. The heme-hemopexin complex is taken
up by the liver and the iron is stored bound to ferritin.
• Methemalbumin: complex of oxidized heme and albumin.
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Bilirubin Metabolism

Bilirubin formation

Transport of bilirubin in plasma

Hepatic bilirubin transport


Hepatic uptake

Conjugation

Biliary excretion
Excrete through intestine system
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• Bilirubin is the terminal product of heme
metabolism. Heme is present in hemoglobin and in
other oxidative compounds such as hepatic
mitochondrial and microsomal cytochromes (P450).
• Thus plasma bilirubin is part erythropoietic and
part non-erythropoietic.
• Approximately, 85 % erythropoietic and 15% nonerythropoietic.
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• The erythropoietic fraction originates from
two sources:
• The circulating normal aging red cells and
• The immature defective red cells of the
bone marrow.
• The daily production of bilirubin is 250 to
350 mg.
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• Shunt bilirubin is called that portion that
does not originate from circulating red
cells but originates from immature and
defective red cells (7%) and from nonhemoglobin heme compounds, particularly
from hepatic cytochromes and from
myoglobin
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• Bilirubin from erythropoietic heme is
produced by monocytic macrophages,
reticulo-endothelium, in every organ but
especially in the spleen, liver and bone
marrow in order of importance.
• The bilirubin from non-erythropoietic hepatic
heme is produced in the hepatocytes.
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Bilirubin formation
microsomal

cytosol
The iron-free porphyrin portion of heme is also degraded,
mainly in the reticuloendothelial cells of the liver, spleen,
and bone marrow.
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The first step
Heme oxygenase
Heme oxygenase (HO) is an enzyme that
catalyzes the degradation of heme. This produces
biliverdin, iron, and carbon monoxide.
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• The tetrapyrrolic ring of heme is broken
by an oxygenase at the alpha bridge, the
bond between the two carbons opposite to
the gamma bridge which is between the two
carbons carrying the two propionic acids.
• The tetrapyrrolic molecule from a ring is
transformed into a tetrapyrrolic chain
without iron
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Heme oxygenase
There are three known isoforms of heme oxygenase.
 Heme oxygenase 1 (HO-1) is an inducible isoform in response
to stress such as oxidative stress, hypoxia, heavy metals, cytokines,
etc. Its activity is induced by its substrate heme and by various
nonheme substances.

Heme oxygenase 2 (HO-2) is a constitutive isoform which is
expressed under homeostatic conditions. Both HO-1 and HO-2 are
ubiquitously expressed and catalytically active.
 A third heme oxygenase (HO-3) is not catalytically active, but is
thought to work in oxygen sensing.
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In mammalian cells Heme oxygenase (HO1) has two basic
functions:
1. it recycles iron supplies within the cell to maintain
homeostasis.
2. biliverdin and biliruben (its reduced form), are
powerful antioxidants believed to aid in the prevention of
oxidative cell damage.
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HOOC
M
V
M
CH2
CH2
CH
O
N
H
CH2
CH2 M
CH2
N
H
M：-CH2
V：-CH=CH2
M V
COOH
N
H
O
CH
N
H
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The building of
intermolecular hydrogen
bonds by the NH and
COOH groups is spatially
hided.
Bilirubin is lipophilic
and therefore insoluble in
aqueous solution.the
solubility in water is less.
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• HEME + Heme oxygenase = OXYHEME ( closed tetrapyrrolic ring with iron)
• OXY- HEME + heme reductase
= BILIVERDIN (open tetrapyrrolic ring without
iron)
• BILIVERDIN + biliverdin reductase
= BILIRUBIN (unconjugated)
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DEGRADATION OF HEME TO BILIRUBIN
 75% is derived from RBCs
P450 cytochrome
 In normal adults this results in a
daily load of 250-300 mg of
bilirubin
 Normal plasma concentrations
are less then 1 mg/dL
 Hydrophobic – transported by
albumin to the liver for further
metabolism prior to its excretion
“unconjugated” bilirubin
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