• Hemoglobin structure & synthesis

Hemoglobin
•MITOCHONDRIA & CYTOSOL
MITOCHONDRIA
STARTING MATERIAL
B6
RATE LIMITING ENZYME
 ALA Synthase the Key Regulatory
Hepatic Biosynthesis of Heme
• It occurs
– hepatic (ALAS1)
– erythroid (ALAS2)
• Heme, probably acting through an aporepressor molecule,
acts as a negative regulator of the synthesis of ALAS1.
the rate of synthesis of ALAS1 increases greatly in the absence
of heme and is diminished in its presence.
Heme also affects translation of the enzyme and its transfer
from the cytosol to the mitochondrion.
• Drugs marked increase in ALAS1
 erythroid form of ALAS (ALAS2)
• differs from that of ALAS1.
not induced by the drugs that affect ALAS1,
and it
does not undergo feedback regulation by
heme.
• Cytosol
two molecules of ALA are condenses
ALA dehydratase is a zinc-containing enzyme
is sensitive to inhibition by lead ( lead poisoning.)
 COO

COO CH2

CH2 CH2
Porphobilinogen
(PBG) is the first
H2C
N
pathway N
+ H
H intermediate that NH3
pyrrole includes a pyrrole Porphobilinogen (PBG)
ring.
The porphyrin ring is formed by condensation of 4
molecules of porphobilinogen. 
Porphobilinogen Deaminase catalyzes
successive PBG condensations, initiated in each
case by elimination of the amino group.
 PORPHYRIAS
Greek “porphyros” (purple urine)
I. Enzymes Inhibitors/ deficient
II. Genetic porphyrias
autosomal dominant manner, with the exception of
congenital erythropoietic porphyria, which is inherited in a
recessive mode
May be classified on the basis of organs or cell mostly affected
either erythropoietic or hepatic
On the basis of clinical features acute or cutaneous

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 porphyrias
• abnormalities in biosynthesis of heme;
• genetic or acquired.
• not prevalent, but important to consider in
differential diagnosis of
• abdominal pain ,
• a variety of neuropsychiatric findings
• photosensitivity (favoring nocturnal activities) and
• severe disfigurement (congenital erythropoietic
porphyria)
• Six major types,
resulting from depressions in
the activities of enzymes 3 –
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• Individuals with low activities
of enzyme 1 (ALAS2) develop
anemia, not porphyria.
• ALAD deficiency(lead)
porphyria (excrete ALA not
PBG, symptoms like
(neurological).
3) Acute intermittent porphyria
( phosphobilinogenin deaminase deficiency, the most common hepatic porphyria).
1. Symptoms - excrete PBG and ALA, high plasma PBG/AL
severe abdominal pain, nausea, vomiting, hypertension(cardiovascular)
then CNS - anxiety, insomnia, confusion, hallucination, then
peripheral neuropathy - fatal respiratory paralysis
2. a. PBG deaminase deficiency), autosomal dominant
b. Genetic and precipitated by phenytoin, phenobarbital drugs,
alcohol, fasting, tryptophan kynuramine
hormones estrogen, stress, infection heme
c. lead poisoning deficiency

3. Biochemistry of neurotoxicity serotonin

a. heme deficiency   P450 drug metabolism
  tryptophan dioxygenase  brain tryptophan
 brain serotonin
 mitochondrial cytochromes i.e. a
mitochondrial disease
b.  ALA  , mitochondrial damage, DNA damage
4. Therapy - heme arginate on admission (taken up by liver not b.m.)
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Major findings in the porphyrias
Skin eruptions in a patient with porphyria cutanea
tarda.