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 PORPHYRIAS
GLYCINE + SuccinylCoA Agent Orange
ALA synthase
3p21/Xp11.21
-aminolevulinic acid(ALA)
ALA-dehydratase
ALA dehydratase
9q34 Deficiency porphyria
Porphobilinogen(PBG)
Acute intermittent
PBG deaminase porphyria
11q23
hydroxymethylbilane
Uroporphyrinogen III Congenital erythropoietic
cosynthase 10q26 porphyria
uroporphyrinogen III
Uroporphyrinogen Prophyria
decarboxylase cutanea tarda
1q34
coprophyrinogene III
Coproporphyrinogen Herediatary
oxidase 9 coproporphyria
Protoporphyrinogene IX
Protoporphyrinogen Variegate
protoporphyrin IX oxidase 1q14 porphyria

Ferrochelatase Erythropoietic
Heme 18q21.3 protoporphyria
 COORDINATED REGULATION OF HEME
AND GLOBIN SYNTHESIS:
Heme:

inhibits activity of pre-existing -ALA synthase

diminishes the transport of -ALA synthase from cytoplasm
to mitochondria after synthesis of the enzyme.
represses the production of -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
Heme Catabolism
HEME
NADPH O2
(opens the porphyrin ring)
Fe+3 NADP +

BILIVERDIN
NADPH

NADP+
BILIRUBIN

BILIRUBIN diglucuronide

BILE
 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 Laboratory tests

Acute intermittent Uroporphyrinogen Abdominal pain urinary porphobilinogen 

porphyria synthase Neuropsychiatric
Congenital Uroporphyrinogen Photosensitivity urinary uroporphyrin 
erythropoietic cosynthase
porphobilinogen 
porphyria
Porphyria cutanea Decarboxylase Photosensitivity urinary uroporphyrin 
tarda
porphobilinogen 
Variegate porphyria Oxidase Photosensitivity urinary uroporphyrin 
Abdominal pain
fecal coproporphyrin 
Neuropsychiatric
fecal protoporphyrin 
Erythropoietic Ferrochelatase Photosensitivity fecal protoporphyrin 
protoporphyria
red cell protoporphyrin 
BLOOD
Stercobilin
CELLS Urobilin
excreted in feces
Hemoglobin excreted in urine

Globin
Urobilinogen
Heme
O2 formed by bacteria KIDNEY
reabsorbed
Heme oxygenase INTESTINE into blood
CO

Biliverdin IX via bile duct to intestines

NADPH
Biliverdin Bilirubin diglucuronide
reductase (water-soluble)

NADP+ 2 UDP-glucuronic acid

Bilirubin Bilirubin
(water-insoluble) LIVER
(water-insoluble) via blood
to the liver

Figure 2. Catabolism of hemoglobin

 Figure 3. Examples of hyperbilirubinemia

A. Hemolytic anemia B. Hepatitis C. Biliary duct stone

excess
hemolysis

 unconjugated bilirubin
 unconjugated bilirubin  unconjugated bilirubin
(in blood)
(in blood) (in blood)
 conjugated bilirubin
 conjugated bilirubin  conjugated bilirubin
(released to bile duct)
(in blood) (in blood)
 Table 2- Genetic Disorders of Bilirubin Metabolism

Condition Defect Bilirubin Clinical Findings

Crigler-Najjar severely defective Unconjugated Profound jaundice
syndrome UDP-glucuronyltransferase bilirubin 
Gilberts reduced activity of Unconjugated Very mild jaundice
syndrome UDP-glucuronyltransferase bilirubin  during illnesses
Dubin-Johnson abnormal transport of Conjugated Moderate jaundice
syndrome conjugated bilirubin into bilirubin 
the biliary system
 Formation of
porphobilinogen:
Lead Poisoning
Cyclization to the porphyrin
Cyclization to the porphyrin