PowerPoint PresentationIntended Learning Outcomes ILOs
2. List important heme-proteins
4. Identify the regulation of heme synthesis
5. Define Porphyrias
Structure Of Porphyrins
4 pyrrole rings
linked by methenyl
conjugated double bonds which
methyl (- CH2-) rather than
bonds and colorless .
Porphyrins form complexes
to Nitrogen of pyrrole
aa3,cyt.c)
Tryptophan pyrrolase (Oxidation of tryptophan),
Cytoplasmic guanyl cyclase (activated by NO) .
Some important heme-proteins
Biosynthesis of Heme
The principal tissues involved in heme biosynthesis are the bone
marrow
and the liver. Heme biosynthetic pathway is partly mitochondrial
and partly cytosolic.
The reactions are Irreversible.
porphyrins occur
(A pyrrol)
(ALAS) .
It is the committed and rate-limiting step in
porphyrin biosynthesis.
Erythroid tissue produces only ALAS2.
TCA cycle
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
by heavy metal ions e.g. lead that
replace thezinc .
ALA and the anemia seen in lead
poisoning.
Synthase to produce the
These reactions occur in the cytosol.
CH2 CH
limiting regulatory enzyme
Hemin acts as an
cellular iron increases the
increase erythropoietin hormone
Substances metabolized by
barbiturates , alcohol and
Drugs that metabolized by cytochrome P450 monooxygenase in the
liver .
Synthesis of cytochrome P450 ,
proteins.
The synthesis of ALAS1 (derepression),
ALA dehydratase and
ferrochelatase inhibited by
“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)
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.
unknown because many people with a genetic
mutation associated with the disease never
experience signs or symptoms.
dominant manner except congenital erythropoietic
porphyria (recessive).
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 :
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
Due to low levels of Uroporphyrinogen decarboxylase
Individuals with an enzyme defect prior to the
synthesis of the tetrapyrroles manifest
abdominal and neuropsychiatric signs.
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
precipitate attacks.
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
