Heme Metabolism

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Heme Metabolism

• Heme biosynthesis and Porphyrias
• Heme degradation Jaundice

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Heme Biosynthesis Porphyrias

• Cruelly referred to as a Vampires 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!

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Not a vampires 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 reasonsPorphyria is a rare,
but frightening condition hard to diagnose and
there is no cure.
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The Madness of Inbreeding
George III Severe abdominal pain, mental
confusion, dark urine.
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PORPHYRIAS
Mitochondria
GLYCINE SuccinylCoA
Agent Orange
ALA synthase
3p21/Xp11.21
d-aminolevulinic acid(ALA)
ALA-dehydratase Deficiency porphyria
ALA dehydratase
9q34
Porphobilinogen(PBG)
Acute intermittent porphyria
PBG deaminase
11q23
hydroxymethylbilane
Congenital erythropoietic porphyria
Uroporphyrinogen III cosynthase
10q26
uroporphyrinogen III
Uroporphyrinogen decarboxylase
Prophyria cutanea tarda
1q34
coprophyrinogene III
Coproporphyrinogen oxidase
Herediatary coproporphyria
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Protoporphyrinogene IX
Protoporphyrinogen oxidase
Variegate porphyria
protoporphyrin IX
1q14
Ferrochelatase
Erythropoietic protoporphyria
Heme
18q21.3
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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.
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Heme Catabolism
Heme Degradation
HEME
O2
(opens the porphyrin ring)
Fe3
BILIVERDIN
BILIRUBIN
BILIRUBIN diglucuronide
BILE
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(No Transcript)
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Jaundice
Hyperbilirubinemia Two forms Direct bilirubin
Conjugated with glucoronic acid Indirect
bilirubin unconjugated, insoluble in water.
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Whats 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.

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Whats 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
• bExtrahepatic cholestasis
• Blockage of bilirubin transport in the bilary
  tract.
• Increased direct bilirubin.
• Stool color turns gray.
• Caused by Tumors or gall stones.

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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.
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Table 1- The porphyrias. You are responsible for
the enzyme defects in red
Type Enzyme Involved Major Symptoms Laboratory tests
Acute intermittent porphyria Uroporphyrinogen synthase Abdominal painNeuropsychiatric urinary porphobilinogen ?
Congenital erythropoietic porphyria Uroporphyrinogen cosynthase Photosensitivity urinary uroporphyrin ? porphobilinogen ?
Porphyria cutanea tarda Decarboxylase Photosensitivity urinary uroporphyrin ? porphobilinogen ?
Variegate porphyria Oxidase PhotosensitivityAbdominal painNeuropsychiatric urinary uroporphyrin ? fecal coproporphyrin ? fecal protoporphyrin ?
Erythropoietic protoporphyria Ferrochelatase Photosensitivity fecal protoporphyrin ? red cell protoporphyrin ?
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BLOOD CELLS
KIDNEY
reabsorbed into blood
INTESTINE
via bile duct to intestines
LIVER
Figure 2. Catabolism of hemoglobin
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Figure 3. Examples of hyperbilirubinemia
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Table 2- Genetic Disorders of Bilirubin Metabolism
Condition Defect Bilirubin Clinical Findings
Crigler-Najjar syndrome severely defective UDP-glucuronyltransferase Unconjugated bilirubin ??? Profound jaundice
Gilberts syndrome reduced activity of UDP-glucuronyltransferase Unconjugated bilirubin ? Very mild jaundice during illnesses
Dubin-Johnson syndrome abnormal transport of conjugated bilirubin into the biliary system Conjugated bilirubin ?? Moderate jaundice
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Formation of porphobilinogenLead Poisoning
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Cyclization to the porphyrin
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Cyclization to the porphyrin