Download HEME SYNTHESIS

Pathophysiology of Heme Synthesis
Beth A. Bouchard
BIOC 212: Biochemistry of Human Disease
Spring 2005
HEME-CONTAINING PROTEINS
 Hemoglobin
 Myoglobin
 Cytochromes
 Catalase
 Some peroxidases
Iron Utilization
STRUCTURE OF HEME
• Ferrous iron (Fe2+)
• Protoporphyrin IX:
contains 4 pyrrole
rings linked together
by methenyl bridges
HEME SYNTHESIS
8
8
Succinyl CoA
Glycine**
Heme
** Amino acid (building blocks of protein) synthesized in your body
Heme
synthesis
HEME SYNTHESIS
HEME SYNTHESIS: Red blood cells
•85% of total heme synthesis
occurs in red blood cells (RBC)
•Ceases when RBC’s mature
•Heme stimulates protein
synthesis in reticulocytes
Synthesis is regulated at the
level of the enzymes
ferrochelatase* and
porphobilinogen deaminase**
*
**
HEME SYNTHESIS: Liver
•The liver is the main non-RBC source of heme
synthesis
•Heme produced in the liver is used mainly for the
synthesis of the cytochrome P450 class of enzymes
that are involved in detoxification
Regulated at level of ALA synthase: Formation of 5ALA is the rate-limiting step in heme synthesis in
the liver
Formation of 5-aminolevulinate (5-ALA)
5-ALA
 5-ALA is formed in the mitochondria and transported
to the cytoplasm
Regulation of ALA Synthase
Level of enzyme synthesis
Enzyme synthesis, as well as its transport to the
mitochondria, is inhibited by elevated levels of heme and
hemin, the Fe3+ oxidation product of heme
Enzyme synthesis is upregulated by a large number of
drugs including barbiturates, steroids with a 4,5 double
bond (e.g. testosterone) and some oral contraceptives:
These drugs are metabolized by the microsomal
cytochrome P450 mono-oxygenase system, a hemecontaining protein.
Level of enzyme activity
Heme and hemin inhibit ALA synthase activity
Requires pyridoxal phosphate (Vitamin B6) as a
coenzyme
Disorders of Heme Synthesis
• Acquired: Lead poisoning
• Congenital: Porphyrias
• Deficiency of heme has far-reaching effects
(hemoglobin, cytochromes, etc.)
LEAD TOXICITY
Symptoms
 Irritibility
 Lethargy
 Sleeplessness
 Headaches
Pathophysoiology
 Poor appetite
 Abdominal pain (with or
without vomiting)
 Constipation
 Binds to any compound with a sulfhydryl group
 Inhibits multiple enzyme reactions including those
involved in heme biosynthesis (ALA synthase &
ferrochelatase)
 One symptom of lead toxicity is increases in 5-ALA
without concomitant increases in PBG
HEME SYNTHESIS (CONT.)
Vitamin
B6
lead
PORPHYRIAS
 A group of rare disorders caused by deficiencies of enzymes of the
heme biosynthetic pathway
The majority of the porphyrias are inherited in a autosomal dominant
fashion - thus, affected individuals have 50% normal levels of the
enzymes, and can still synthesize some heme
Affected individuals have an accumulation of heme precursors
(porphyrins), which are toxic at high concentrations
Attacks of the disease are triggered by certain drugs, chemicals, and
foods, and also by exposure to sun
 Treatment involves administration of hemin, which provides negative
feedback for the heme biosynthetic pathway, and therefore, prevents
accumulation of heme precursors
Scriver et al., The Metabolic & Molecular Basis of Inherited Disease, 8th edition, 2001.
ACUTE INTERMITTENT PORPHYRIA
 Hepatic, autosomal dominant
 Caused by a deficiency in porphobilinogen
deaminase, which is involved in the conversion of
porphobilinogen (PBG) to uroporphyrinogen III
PBG, uroprophryin, and 5-ALA accumulate in the plasma
and the urine
Patients have neuropyschiatric symptoms and
abdominal pain (neurovisceral)
PORPHYRIA CUTANEA TARDA
Most common porphyria
Hepatic, autosomal dominant
Disease is caused by a deficiency in uroporphyrinogen
decarboxylase, which is involved in the conversion of
uroporphyrinogen III to coproporphyrinogen III
 Uroporphyrinogen accumulates in urine
 Patients are photosensitive (cutaneous photosensitivity)
Accumulation of porphyrinogens results in their
conversion to porphyrins by light
Porphyrins react with molecular oxygen to form
oxygen radicals
Oxygen radicals can cause severe damage to the
skin