Heme Metabolism
•Heme biosynthesis and Porphyrias
•Heme degradation: Jaundice
Heme Biosynthesis: Porphyrias
• Cruelly referred to as a Vampire’s disease.
Thought to be a cause of the madness of
King George III.
• Can be caused by lead poisoning: The fall
of the Roman Empire!
Not a ‘vampire’s’ disease
Some symptoms of porphyrias have lead
people to believe that these diseases
provide some basis for vampire legends:
Extreme sensitivity to sunlight
Anemia
This idea has been discarded both for
scientific reasons:
Porphyrias do not cause a craving for
blood.
Drinking blood would not help a victim
of porphyria.
And for compasionate reasons:Porphyria is a rare, but
frightening condition: hard to diagnose and there is no cure.
The Madness of Inbreeding
George III : Severe abdominal pain, mental confusion, dark urine.
Mitochondria
GLYCINE + SuccinylCoA
d-aminolevulinic acid(ALA)
Porphobilinogen(PBG)
hydroxymethylbilane
uroporphyrinogen III
coprophyrinogene III
Protoporphyrinogene IX
protoporphyrin IX
Heme
PORPHYRIAS
Agent Orange
ALA synthase
3p21/Xp11.21
ALA dehydratase
ALA-dehydratase
Deficiency porphyria
PBG deaminase
Acute intermittent
porphyria
Uroporphyrinogen III
cosynthase 10q26
Congenital erythropoietic
porphyria
Uroporphyrinogen
decarboxylase
Prophyria
cutanea tarda
Coproporphyrinogen
oxidase 9
Herediatary
coproporphyria
Protoporphyrinogen
oxidase 1q14
Variegate
porphyria
Ferrochelatase
Erythropoietic
protoporphyria
9q34
11q23
1q34
18q21.3
COORDINATED REGULATION OF HEME
AND GLOBIN SYNTHESIS:
Heme:
inhibits activity of pre-existing d-ALA synthase
diminishes the transport of d-ALA synthase from cytoplasm
to mitochondria after synthesis of the enzyme.
represses the production of d-ALA synthase by regulating gene
transcription.
stimulates globin synthesis to ensure that levels of free heme
remain low in concentration.
Inhibition of the synthase and stimulation of globin synthesis are
the most important aspects in balancing hemoglobin production.
Heme Degradation
NADPH
HEME
O2
NADP+
Fe+3
(opens the porphyrin ring)
BILIVERDIN
NADPH
NADP+
BILIRUBIN
BILIRUBIN diglucuronide
BILE
Heme Catabolism
Jaundice
Hyperbilirubinemia:
Two forms:
Direct bilirubin: Conjugated with
glucoronic acid
Indirect bilirubin: unconjugated,
insoluble in water.
What’s the cause of jaundice?
1- Increased production of bilirubin by hemolysis or blood disease:
•Increase in blood indirect bilirubin
•Called pre-hepatic jaundice
•Stool color remains normal.
2- Abnormal uptake or conjugation of bilirubin:
•Leads to non-hemolytic unconjugated hyperbilirubinemia
•Increased indirect bilirubin.
•Stool color turns gray.
•Caused by liver damage or disease.
What’s the cause of jaundice?
3- Cholestasis = Problems with bile flow.
a: Intrahepatic cholestasis: hyper conjugated bilirubinemia
•Increase in blood indirect and direct bilirubin
•Caused by liver damage or disease: eg cirrhosis, hepatitis
•Can also occur in pregnancy:
b:Extrahepatic cholestasis:
•Blockage of bilirubin transport in the bilary tract.
•Increased direct bilirubin.
•Stool color turns gray.
•Caused by: Tumors or gall stones.
CLINICAL PREMISE
Newborns often have a yellowish tint to their skin. This condition is
known as jaundice and results from the infant ridding itself of "fetal"
hemoglobin which will be replaced by "adult" hemoglobin. As you will
learn in this lecture, catabolic products from hemoglobin are removed by
the liver. However, the infant's liver is often too immature to handle the
excessive breakdown products. Instead they accumulate giving the
yellowish tint. Exposure to mild UV light from the sun is usually
sufficient to destroy these compounds, although in very severe cases
blood dialysis may become necessary as these byproducts can be toxic.
Table 1- The porphyrias. You are responsible for the enzyme defects in red
Type
Enzyme
Involved
Major Symptoms
Acute intermittent
porphyria
Uroporphyrinogen
synthase
Abdominal pain
Neuropsychiatric
urinary porphobilinogen
Congenital
erythropoietic
porphyria
Uroporphyrinogen
cosynthase
Photosensitivity
urinary uroporphyrin
Porphyria cutanea
tarda
Decarboxylase
Photosensitivity
Variegate porphyria
Oxidase
Erythropoietic
protoporphyria
Laboratory tests
porphobilinogen
urinary uroporphyrin
porphobilinogen
Ferrochelatase





Photosensitivity
Abdominal pain
Neuropsychiatric
urinary uroporphyrin
fecal coproporphyrin
fecal protoporphyrin



Photosensitivity
fecal protoporphyrin
red cell protoporphyrin


BLOOD
CELLS
Stercobilin
excreted in feces
Urobilin
excreted in urine
Hemoglobin
Globin
Heme
O2
Heme oxygenase
Urobilinogen
formed by bacteria
INTESTINE
KIDNEY
reabsorbed
into blood
CO
Biliverdin IX
via bile duct to intestines
NADPH
Bilirubin diglucuronide
(water-soluble)
Biliverdin
reductase
NADP+
Bilirubin
(water-insoluble)
2 UDP-glucuronic acid
via blood
to the liver
Bilirubin
(water-insoluble)
LIVER
Figure 2. Catabolism of hemoglobin
Figure 3. Examples of hyperbilirubinemia
A. Hemolytic anemia
B. Hepatitis
C. Biliary duct stone
excess
hemolysis
 unconjugated bilirubin
(in blood)
 conjugated bilirubin
(released to bile duct)
 unconjugated bilirubin
(in blood)
 conjugated bilirubin
(in blood)
 unconjugated bilirubin
(in blood)
 conjugated bilirubin
(in blood)
Table 2- Genetic Disorders of Bilirubin Metabolism
Condition
Defect
Bilirubin
Clinical Findings
Crigler-Najjar
syndrome
severely defective
Unconjugated
UDP-glucuronyltransferase bilirubin 
Profound jaundice
Gilberts
syndrome
reduced activity of
Unconjugated
UDP-glucuronyltransferase bilirubin 
Very mild jaundice
during illnesses
DubinJohnson
syndrome
abnormal transport of
conjugated bilirubin into
the biliary system
Moderate jaundice
Conjugated
bilirubin 
Formation of
porphobilinogen:
Lead Poisoning
Cyclization to the porphyrin
Cyclization to the porphyrin