Heme Metabolism
(synthesis)Dr. Marian Maher
Lecturer of Medical Biochemistry and Molecular Biology
Intended Learning Outcomes ILOs
1. Describe the structure of Porphyrins
2. List important heme-proteins
3. Describe steps of heme biosynthesis
4. Identify the regulation of heme synthesis
5. Define Porphyrias
6. Identify clinical manifestations of porphyrias
7. List different types of porphyrias
8. Describe the treatment of porphyrias
Structure Of Porphyrins
They are cyclic compounds formed from:
▪ 4 pyrrole rings
linked by methenyl
bridges
▪ 4 methyl , 2
propionyl and 2
vinyl groups
connected to the
pyrrole rings
▪They constitute a system of
conjugated double bonds which
absorb light
▪ Porphyrinogens are reduced
forms of porphyrins .They contain
methyl (- CH2-) rather than
methenyl bridges (-HC=).
So,
they have no conjugated double
bonds and colorless .
Porphyrins form complexes
with metal ions , that bind
to Nitrogen of pyrrole
rings.:
Iron porphyrins (Heme),
Magnesium porphyrins
(Clorophyll).
▪ Haemoglobin
▪ Myoglobin
▪ Cytochromes of electron transport chain (cyt
aa3,cyt.c)
▪ cytochrome 450
▪ Catalse and Peroxidase (degradation of H2O2), ,
▪ Tryptophan pyrrolase (Oxidation of tryptophan),
▪ Cytoplasmic guanyl cyclase (activated by NO) .
Some important heme-proteins
Biosynthesis of Heme
The principal tissues involved in hemebiosynthesis are the bone marrow
and the liver.Heme biosynthetic pathway is partly mitochondrial and partly cytosolic.
The reactions are Irreversible.
Steps:
The initial
reaction and the last three
steps in the formation of
porphyrins occur
in mitochondria, whereas the
intermediate steps of the
biosynthetic
pathway occur in the cytosol
(A pyrrol)
(tetrapyrrol)
▪ Glycine and succinyl coenzyme A that condense
to form ALA by mitochondrial ALA synthase
(ALAS) .
▪ This reaction requires pyridoxal phosphate (PLP)
▪ It is the committed and rate-limiting step in
porphyrin biosynthesis.
▪ There are two isoforms of ALAS, 1 and 2.
▪ Erythroid tissue produces only ALAS2.
TCA cycle
COASH
All true about Hemophilia except:
A.Can occur due to Factor IX deficiency
B. Inherited as an autosomal recessive
C. Can occur due to Factor VIII deficiency
D.Can occur due to Factor XI deficiency
▪ By Zn-containing ALA dehydratase
(porphobilinogen synthase)
▪ It is extremely sensitive to inhibition
by heavy metal ions e.g. lead that
replace thezinc .
▪ This inhibition cause the elevation in
ALA and the anemia seen in lead
poisoning.
(-)
(cytosolic enzyme)
The condensation of four
porphobilinogens produces the
linear tetrapyrrole,
hydroxymethylbilane,
Hydroxymethylbilane,which is
isomerized and cyclized by uroporphyrinogen III
Synthase to produce the
asymmetric uroporphyrinogen III.
This cyclic tetrapyrrole undergoes decarboxylation of its acetate groups, generating coproporphyrinogen III.
Thesereactions occur in the cytosol.
CH2 CH
(IX)
(IX)
enters the mitochondrion,
2 CO2
inhibited bylead
zinc
CO2
Fe
▪ ALA synthase is the rate
limiting regulatory enzyme
▪ Excess heme in bone marrow
is converted to hemin by
oxidation of Fe2+to Fe3+.
Hemin acts as an
aporepressor which
decreases its synthesis .
Regulation of Heme Synthesis
▪ hypoxia and availability of intra-
cellular iron increases the
activity of ALA synthase due to
increase erythropoietin hormone
▪ Substances metabolized by
cytochrome P450 increases the
activity of ALA synthase e.g.
barbiturates , alcohol and
carcinogens.
Drugs that metabolized by cytochrome P450 monooxygenase in the liver .
Synthesis of cytochrome P450,
Consumption of hemea component of cytochrome P450
proteins.
The concentration of heme in liverCells.
The synthesis of ALAS1 (derepression),
▪ ALA dehydratase and
ferrochelatase inhibited by
Lead poisoning
A group of diseases
collectively called
porphyrias are associated
with abnormalities in
biosynthesis of heme.
They are characterized by
accumulation and excretion
of porphyrins or porphyrin
precursors.
Disorders of Heme Synthesis ( Porphyrias)
“Porphyria” refers to the purple color caused by
pigment-like porphyrins in the urine of some patients
with defects in heme synthesis.
The porphyrias are classified as erythropoietic or
hepatic (chronic or acute)
depending on whether the enzyme deficiency occurs in
the erythropoietic cells of the bone marrow or in the
liver.
The exact prevalence of porphyria is unknown, but
it probably ranges from 1 in 500 to 1 in 50,000
people worldwide.
For some forms of porphyria, the prevalence is
unknown because many people with a genetic
mutation associated with the disease never
experience signs or symptoms.
▪ Most of porphyrias are inherited as autosomal
dominant manner except congenital erythropoietic
porphyria (recessive).
▪ However acquired porphyrias can result from lead
poisoning. The toxic effect of lead is due to inhibition
of ferrochelatase.
• Low levels of ALA synthase cause no porphyria (only anemia).
Overall, porphyria cutanea tarda is the most common type of porphyria.
❑ Enzyme deficiency early in pathway before formation of cyclic
tetrapyroles :
only abdominal pains and neuro-psychiatric symptoms are present as
in acute intermittent porphyria which is characterized by deficiency
of the enzyme porphobilinogen deaminase
❑ Enzyme deficiency late in pathway after formation of porphyrinogen :
Porphyrinogens are oxidized to their corresponding porphyrins which react with molecular oxygen to form reactive oxygen
species that cause oxidative damage of cells.
photosensitivity (skin inflammation damage with ultimate disfigurement and scaring.) in response
to visible light
Porphyria cutanea tarda which is the (most common type).
Due to low levels of Uroporphyrinogen decarboxylase
❑ Individuals with an enzyme defect prior to the
synthesis of the tetrapyrroles manifest
abdominal and neuropsychiatric signs.
Clinical manifestations:
❑ Whereas those with enzyme defects leading to
the accumulation of tetrapyrrole intermediates show
photosensitivity that is, their skin itches and burns
(pruritus) when exposed to visible light.
❑ The accumulation of these toxic intermediates is
the major pathophysiology of the porphyrias.
❑ Drugs that cause induction of cytochrome P450 e.g.
steroids , alcohol, Phenobarbital ,are
contraindicated for porphyria patients because they
precipitate attacks.
❑ The severity of symptoms of porphyrias can be
diminished by intravenous injection of hemin which
decreases synthesis (represses) ALA synthase.
❑ Avoidance of sunlight and ingestion of B-carotenes
(anti-oxidant), are helpful in photosensitivity.
❑ A high-carbohydrate diet is typically recommended;
in severe attacks, a glucose 10% infusion is
commenced, which may aid in recovery
Treatment