Overview of Heme Synthesis and Porphyrias
Heme
synthesis
and
porphyrias
•
Hemoglobin
.
•
Myoglobin
.
•
Cytochromes
.
•
Peroxidase
.
•
Catalase
.
•
Tryptophan
pyrrolase
.
•
Nitric
oxide
synthase.
Heme
is
present
in:
Hemoglobin
contain
four
Heme
groups
.
Each
Heme
holds
one
iron
atom
,
each
iron
atom
holds
one
molecule
of
oxygen.
Four
oxygen
molecules.
.
250
million
molecules
of
hemoglobin
per
cell.
Each
red
blood
cell
carries
one
billion
molecules
of
oxygen
.
Organs
mainly
involved
in
Heme
synthesis
?
variable
constant
Which
part
of
the
cell
does
the
Heme
synthesis
take
place?
cytosol
mitochondria
Heme
Bile
pigments
+
iron
Heme
deg
r
ad
a
tion
Heme
synthesis
How
is
the
structure
of
porphyrin
?
•
Porphyrins are
cyclic
compounds
formed
by
the
linkage
of
four
pyrrole
rings
through
methyne
(=HC
—)
bridges
•
A
characteristic
property
of
porphyrins
is
the
formation
of
complexes
with
metal
ions
bound
to
the
nitrogen
atom
of
the
pyrrole
rings
Structure
of
Heme
He
m
e
synthesis
Step-1
(mitochondria
(
Succinyl-CoA
Glycine
F
r
o
m
c
i
t
r
i
c
a
c
i
d
c
y
c
l
e
N
o
n
e
s
s
e
n
t
i
a
l
a
m
i
n
o
a
c
i
d
(
P
y
r
i
d
o
x
a
l
p
h
o
s
p
h
a
t
e
a
c
t
i
v
a
t
e
s
)
α-amino-β-ketoadipic
acid
c
o
n
d
e
n
s
a
t
i
o
n
r
e
a
c
t
i
o
n
ALA
s
y
n
t
h
ase
CoA-SH
Step-2
(mitochondria)
α-amino-β-ketoadipic
acid
δ-aminolevulinate
(ALA)
d
e
c
a
r
b
o
x
y
l
a
t
i
o
n
r
e
a
c
t
i
o
n
ALA
synthase
(
r
a
t
e
c
o
n
t
r
o
l
l
i
n
g
e
n
z
y
m
e
-
p
o
r
p
h
y
r
i
n
b
i
o
s
y
n
t
h
e
s
i
s
–
l
i
v
e
r
)
Step-3
(cytosol
(
(
2molecules
)
δ-aminolevulinate
(ALA)
ALA
dehydratase
(1)
porphobilinogen
(PBG
(
zinc-containing
enzyme
and
is
sensitive
to
inhibition
by
lead
.
2
H
2
0
First
precursor
of
pyrrole
(4molecules)
porphobilinogen
(PBG)
Step-4
(cytosol
(
Hydroxy
methyl
bilane
HMB
linear
tetr
a
pyrrole
uroporphyrinogen
I
synthase
4N
H
3
condenses
PBG
deaminase
HMB
synthase
AIP
Step-5
(cytosol
(
Hydroxymethylbilane
(HMB
(
U
roporphyrinogen
III
U
roporphyrinogen
I
H
M
B
c
y
c
l
i
z
e
s
s
p
o
n
t
a
n
e
o
u
s
l
y
uroporphyrinogen
III
synthase
F
o
r
m
s
u
n
d
e
r
n
o
r
m
a
l
c
o
n
d
i
t
i
o
n
s
CEP
uroporphyrinogen
I
uroporphyrinogen
III
coproporphyrinogen
I
coproporphyrinogen
III
light
6H
Uroporphyrin
I
6H
light
Coproporphyrin
I
U
roporp
h
yrino
g
en
decarboxylase
6H
Uroporphyrin
III
6H
Coproporphyrin
III
light
light
Step-6
(mitochondria
(
P
C
T
coproporphyrinogen
III
Protoporphyrinogen
III
Step-7
(mitochondria
(
Coproporphyrinogen
oxidase
HCP
Protoporphyrinogen
III
Protoporphyrin
III
P
r
o
t
oporp
h
yrino
g
en
oxidase
Step-8
(mitochondria
(
Por.variegata
Step-9
(mitochondria
(
Protoporphyrin
IX
Ferrochetalase
Heme
H.protoporphyria
Heme
synthase
Regulation
of
Heme
Synthesis
•
Heme
inhibits
the
synthesis
of
ALA
synthase
r
e
p
r
e
s
s
i
o
n
m
e
c
h
a
n
i
s
m
ALA
synthase
is also
allosterically
inhibited
by
h
e
m
a
t
i
n
.
•
T
h
e
c
o
m
p
a
r
t
m
e
n
t
a
l
i
z
a
t
i
o
n
o
f
t
h
e
e
n
z
y
m
e
s
,
m
a
k
e
s
t
h
e
r
e
g
u
l
a
t
i
o
n
e
a
s
i
e
r
.
•
T
h
e
s
t
e
p
s
c
a
t
a
l
y
z
e
d
b
y
f
e
r
r
o
c
h
e
l
a
t
a
s
e
a
n
d
A
L
A
d
e
h
y
d
r
a
t
a
s
e
a
r
e
i
n
h
i
b
i
t
e
d
b
y
l
e
a
d
.
•
D
r
u
g
s
l
i
k
e
b
a
r
b
i
t
u
r
a
t
e
s
i
n
d
u
c
e
h
e
m
e
s
y
n
t
h
e
s
i
s
.
B
a
r
b
i
t
u
r
a
t
e
s
r
e
q
u
i
r
e
t
h
e
h
e
m
e
c
o
n
t
a
i
n
i
n
g
c
y
t
o
c
h
r
o
m
e
P
4
5
0
f
o
r
t
h
e
i
r
m
e
t
a
b
o
l
i
s
m
.
•
Out
of
the
total
heme
synthesized,
two
thirds
are
used
for
cytochrome
P450
production
.
•
I
N
H
(
I
s
o
n
i
c
o
t
i
n
i
c
a
c
i
d
h
y
d
r
a
z
i
d
e
)
t
h
a
t
d
e
c
r
e
a
s
e
s
t
h
e
a
v
a
i
l
a
b
i
l
i
t
y
o
f
p
y
r
i
d
o
x
a
l
p
h
o
s
p
h
a
t
e
m
a
y
a
l
s
o
a
f
f
e
c
t
h
e
m
e
s
y
n
t
h
e
s
i
s
.
Regulation
of
Heme
Synthesis
•
H
i
g
h
c
e
l
l
u
l
a
r
c
o
n
c
e
n
t
r
a
t
i
o
n
o
f
g
l
u
c
o
s
e
p
r
e
v
e
n
t
s
i
n
d
u
c
t
i
o
n
o
f
A
L
A
s
y
n
t
h
a
s
e
.
•
This
is
the
basis
of
administration
of
glucose
to
relieve
the
acute
attack
of
porphyrias.
•
R
e
g
u
l
a
t
i
o
n
i
n
t
h
e
e
r
y
t
h
r
o
i
d
c
e
l
l
s
:
The
enzyme
ALA
synthase
does
not
appear
to
control
the
heme
synthesis
in
the
erythroid
cells.
U
r
o
p
o
r
p
h
y
r
i
n
o
g
e
n
s
y
n
t
h
a
s
e
a
n
d
f
e
r
r
o
c
h
e
l
a
t
s
e
m
o
s
t
l
y
r
e
g
u
l
a
t
e
h
e
m
e
f
o
r
m
a
t
i
o
n
i
n
t
h
e
s
e
c
e
l
l
s
.
Regulation
of
Heme
Synthesis
What
are
porphyrias
?
•
Porphyria
refers
to
a
growing
collection
of
disorders
in
which
there
are
abnormalities
in
the
enzymes
involved
in
Heme
synthesis
.
•
Although
porphyrias
are
not
very
prevalent,
physicians
must
be aware
of
them.
What
are the
causes
of
porphyrias?
•
There
are
at
least
eight
steps
in
the
production
of
Heme,
and
at
least
eight
different
types
of
porphyria
can
result
when
an
enzyme
malfunctions
and
levels
of
intermediate
substances
rise
to
beyond
what
the
body
is
needed.
Porphyrias
classification
•
This
classification
is
based
on
the
major
site
,
where
the
enzyme
deficiency
is
manifested.
•
The
porphyrias
are
classified
as
erythropoietic
or
hepatic
,
depending
on
whether
the
enzyme
deficiency
occurs
in
the
erythropoietic
cells
of
the
bone
marrow
or
in the
liver.
•
Hepatic
porphyrias
can
be
further
classified
as
chronic
or
acute
.
•
In
general,
individuals
with
an
enzyme
defect
prior
to
the
synthesis
of
the tetrapyrroles
manifest
abdominal
and
neuropsychiatric
signs
.
•
W
hereas
those
with
enzyme
defects
leading
to
the
accumulation
of
tetrapyrrole
intermediates
show
photosensitivity
.
•
T
hat
is,
their
skin
itches
and
burns
when
exposed
to
visible
light
.
Porphyrias
classification
4
molecules
porphobilinogen
(
PBG
(
Acute
intermittent
porphyria
Hydroxymethylbilane
HMB
(linear
tetrapyrrole
)
Uroporphyrinogen
I
synthase
condenses
This
disorder
occurs
due
to
the
deficiency
of
the
enzyme
uroporphyrinogen
I
synthase.
Characterized
by
increased
excretion
of
porphobilinogen
and
6-aminolevulinate.
The
urine
gets
darkened
on
exposure
to
air
due
to
the
conversion
of
porphobilinogen
to
porphobilin
and
porphyria
.
Other
characteristic
features
of
AIP
•
Usually
expressed
after
puberty
in
humans
.
•
The
symptoms
include
abdominal pain
,
vomiting
and
cardiovascular
abnormalities
.
•
The
neuropsychiatric
disturbances
observed.
•
The
symptoms
are
more
severe
after
administration
of
D
rugs
:
e.g.
B
arbiturates
.
•
These
patients
are
not
photosensitive
since
the
enzyme
defect
occurs
prior
to
the
formation
of
uroporphyrinogen.
Hydroxymethylbilane
uroporphyrinogen
III
Congenital
erythropoietic
porphyria
uroporphyrinogen
III
synthase
c
h
a
r
a
c
t
e
r
i
s
t
i
c
f
e
a
t
u
r
e
s
Rare
congenital
disorder
A
u
t
o
s
o
m
a
l
r
e
c
e
s
s
i
v
e
Confined
to
erythropoietic
tissues.
T
h
e
i
n
d
i
v
i
d
u
a
l
s
e
x
c
r
e
t
e
u
r
o
p
o
r
p
h
y
r
i
n
o
g
e
n
I
a
n
d
c
o
p
r
o
p
o
r
p
h
y
r
i
n
o
g
e
n
I
w
h
i
c
h
o
x
i
d
i
z
e
r
e
s
p
e
c
t
i
v
e
l
y
t
o
u
r
o
p
o
r
p
h
y
r
i
n
I
a
n
d
c
o
p
r
o
p
o
r
p
h
y
r
i
n
|
.
r
e
d
p
i
g
m
e
n
t
s
.
T
h
e
p
a
t
i
e
n
t
s
a
r
e
p
h
o
t
o
s
e
n
s
i
t
i
v
e
.
I
n
c
r
e
a
s
e
d
h
e
m
o
l
y
s
i
s
.
uroporphyrinogen
I
uroporphyrinogen
III
P
orphyria
cutanea
tarda
U
roporp
h
yrino
g
en
decarboxylase
coproporphyrinogen
I
coproporphyrinogen
III
T
h
i
s
i
s
a
l
s
o
k
n
o
w
n
a
s
c
u
t
a
n
e
o
u
s
h
e
p
a
t
i
c
p
o
r
p
h
y
r
i
a
.
T
h
e
m
o
s
t
c
o
m
m
o
n
p
o
r
p
h
y
r
i
a
.
Usually
associated
with
liver
damage
caused
by
alcohol
overconsumption
or
iron
overload.
The
partial
deficiency
of
the
enzyme
uroporphyrinogen
decarboxylase
appears
to
be
responsible
for
the
occurrence
of
porphyria
cutanea
tarda
.
T
h
e
o
t
h
e
r
c
h
a
r
a
c
t
e
r
i
s
t
i
c
f
e
a
t
u
r
e
s
i
n
c
l
u
d
e
:
•
Increased
excretion
of
uroporphyrins
l
and
lll
and
rarely
porphobilinogen.
•
Cutaneous
photosensitivity
is
the
most
important
clinical
manifestation
of
these
Patients.
•
Liver
exhibits
fluorescence
due
to
high
concentration
of
accumulated
porphyrins.
P
orphyria
cutanea
tarda
coproporphyrinogen
III
Hereditary
cutaenia
tarda
Cop
r
oporp
h
yri
n
o
g
en
oxidase
Protoporphyrinogen
III
C
o
p
r
o
p
o
r
p
h
y
r
i
n
o
g
e
n
l
l
l
a
n
d
o
t
h
e
r
i
n
t
e
r
m
e
d
i
a
t
e
s
(
A
L
A
a
n
d
P
B
C
)
excreted
in
urine
and
feces
.
The
patients
of
hereditary
coproporphyria
are
photosensitive.
They
exhibit
the
clinical
manifestations
observed
in the
patients
of
acute
intermittent
porphyria.
Infusion
of
hematin
is
used
to
control
this
disorder.
H
e
m
a
t
i
n
i
n
h
i
b
i
t
s
A
L
A
s
y
n
t
h
a
s
e
a
n
d
t
h
u
s
r
e
d
u
c
e
s
t
h
e
accumulation
of
various
intermediates.
Protoporphyrinogen
III
Protoporphyrinogen
oxidase
Variegate
porphyria
Protoporphyrin
IX
T
h
e
e
n
z
y
m
e
p
r
o
t
o
p
o
r
p
h
y
r
i
n
o
g
e
n
o
x
i
d
a
s
e
i
s
d
e
f
e
c
t
i
v
e
i
n
t
h
i
s
d
i
s
o
r
d
e
r
.
D
u
e
t
o
t
h
i
s
b
l
o
c
k
a
d
e
,
p
r
o
t
o
p
o
r
p
h
y
r
i
n
l
X
r
e
q
u
i
r
e
d
f
o
r
t
h
e
u
l
t
i
m
a
t
e
s
y
n
t
h
e
s
i
s
o
f
H
e
m
e
i
s
n
o
t
p
r
o
d
u
c
e
d
.
Almost
all
the
intermediates
(porphobilinogen,
coproporphyrin,
uroporphyrin,
protoporphyrin
etc.)
of
Heme
synthesis
accumulate
i
n
t
h
e
b
o
d
y
a
n
d
a
r
e
e
x
c
r
e
t
e
d
i
n
u
r
i
n
e
a
n
d
f
e
c
e
s
.
T
h
e
u
r
i
n
e
o
f
t
h
e
s
e
p
a
t
i
e
n
t
s
i
s
c
o
l
o
u
r
e
d
a
n
d
t
h
e
y
e
x
h
i
b
i
t
p
h
o
t
o
s
e
n
s
i
t
i
v
i
t
y
.
P
rotoporphyria
Protoporphyrin
IX
Ferrochetalase
Heme
Heme
synthase
T
h
i
s
d
i
s
o
r
d
e
r
,
a
l
s
o
k
n
o
w
n
a
s
e
r
y
t
h
r
o
p
o
i
e
t
i
c
p
r
o
t
o
p
o
r
p
h
y
r
i
a
D
e
f
i
c
i
e
n
c
y
o
f
t
h
e
e
n
z
y
m
e
f
e
r
r
o
c
h
e
l
a
t
a
s
e
.
P
r
o
t
o
p
o
r
p
h
y
r
i
n
l
X
a
c
c
u
m
u
l
a
t
e
s
i
n
t
h
e
t
i
s
s
u
e
s
a
n
d
i
s
e
x
c
r
e
t
e
d
i
n
t
o
u
r
i
n
e
a
n
d
f
e
c
e
s
.
R
e
t
i
c
u
l
o
c
y
t
e
s
(
y
o
u
n
g
R
B
C
)
a
n
d
s
k
i
n
b
i
o
p
s
y
e
x
h
i
b
i
t
r
e
d
fl
uo
rescence
.
Acquired
porphyrias
(toxic
(
•
T
h
e
p
o
r
p
h
y
r
i
a
s
,
t
h
o
u
g
h
n
o
t
i
n
h
e
r
i
t
e
d
,
m
a
y
b
e
a
c
q
u
i
r
e
d
d
u
e
t
o
t
h
e
t
o
x
i
c
i
t
y
o
f
s
e
v
e
r
a
l
c
o
m
p
o
u
n
d
s
.
•
Exposure
of
the
body
to
:
Heavy
metals
e.g.
lead,
Toxic
compounds
e.g
hexachlorobenzene
.
Drugs
.
E.g.
G
riseofulvin
inhibits
many
enzymes
in
heme
synthesis
.
These
include
:
ALA
dehydratase
.
Uroporphyrin
I
synthase
.
F
errochetalase
.
•
The
best
time
to
attempt
diagnosis
is
when
the
symptoms
are
active
.
•
Porphyria
sufferers
are
affected
by
anything
that
can
alter
the
functioning
of
the
deficient
enzymes.
•
Disease
can
occur
to
different
degrees
.
•
Some
people
are
affected
so
slightly
that
the
diagnosis is
never
considered.
•
Herbs,
drugs,
alcohol
and
even
hormones
can
produce
acute
attacks
by
interfering
with
enzyme
function.
Diagnosis
•
Lab
tests
are required
to
make
a
definitive
diagnosis
of
porphyria
and
to
determine
which
form
of
the
disease
you
have
.
•
If
your
doctor
suspects
porphyria,
he
or
she
may
recommend these
tests:
•
Urine
,
blood
and
stool
:
E
xamination
for
various
porphyrins.
•
Spectrophotometry
:
Is
Used
to
Test
for
Porphyrins
&
Their
Precursors
Coproporphyrins
and
uroporphyrins
.
Diagnosis
•
Urine
test:
I
f
y
o
u
h
a
v
e
a
f
o
r
m
o
f
a
c
u
t
e
p
o
r
p
h
y
r
i
a
,
a
u
r
i
n
e
t
e
s
t
m
a
y
r
e
v
e
a
l
e
l
e
v
a
t
e
d
l
e
v
e
l
s
o
f
t
w
o
s
u
b
s
t
a
n
c
e
s
:
porphobilinogen
and
delta-
aminolevulinic
acids
,
as
well
as
other
porphyrins.
•
Blood
test
:
If
you
have
a
form
of
cutaneous
porphyria,
a
blood
test
may
show
an
elevation
in
the
level
of
porphyrins
in
your
blood
plasma.
•
Stool
sample
test
:
Analysis
of
a
stool
sample
may
reveal
elevated
levels
of
some
porphyrins
that
may
not
be
detected
in
urine
samples
.
This
test
may
help
your
doctor
determine
your
specific
type
of
porphyria
.
•
T
o
d
e
m
o
n
s
t
r
a
t
e
p
o
r
p
h
y
r
i
n
s
,
U
V
f
l
u
o
r
e
s
c
e
n
c
e
i
s
t
h
e
b
e
s
t
t
e
c
h
n
i
q
u
e
.
•
T
h
e
p
r
e
s
e
n
c
e
o
f
p
o
r
p
h
y
r
i
n
p
r
e
c
u
r
s
o
r
i
n
u
r
i
n
e
i
s
d
e
t
e
c
t
e
d
b
y
E
h
r
l
i
c
h
’
s
r
e
a
g
e
n
t
.
•
W
h
e
n
u
r
i
n
e
i
s
o
b
s
e
r
v
e
d
u
n
d
e
r
u
l
t
r
a
v
i
o
l
e
t
l
i
g
h
t
p
o
r
p
h
y
r
i
n
s
i
f
p
r
e
s
e
n
t
,
w
i
l
l
e
m
i
t
s
t
r
o
n
g
r
e
d
f
l
u
o
r
e
s
c
e
n
c
e
.
•
S
p
e
c
t
r
o
p
h
o
t
o
m
e
t
r
y
:
I
s
U
s
e
d
t
o
T
e
s
t
f
o
r
P
o
r
p
h
y
r
i
n
s
&
T
h
e
i
r
P
r
e
c
u
r
s
o
r
s
C
o
p
r
o
p
o
r
p
h
y
r
i
n
s
a
n
d
u
r
o
p
o
r
p
h
y
r
i
n
s
.
•
U
s
e
o
f
a
p
p
r
o
p
r
i
a
t
e
g
e
n
e
p
r
o
b
e
s
h
a
s
m
a
d
e
p
o
s
s
i
b
l
e
t
h
e
p
r
e
n
a
t
a
l
d
i
a
g
n
o
s
i
s
o
f
s
o
m
e
o
f
t
h
e
p
o
r
p
h
y
r
i
a
s
.
Thank
you
Heme is a crucial component present in various essential proteins in the body, such as hemoglobin, myoglobin, and cytochromes. The synthesis of heme takes place in multiple steps involving different organelles and enzymes in the cell. Porphyrias are a group of disorders related to heme synthesis, characterized by an abnormal accumulation of porphyrins. Understanding the structure and synthesis of heme is vital for comprehending the implications of porphyrias on human health.
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Presentation Transcript
Heme is presentin: Hemoglobin. Myoglobin. Cytochromes. Peroxidase. Catalase. Tryptophanpyrrolase. Nitric oxidesynthase.
Hemoglobin contain four Hemegroups. Each Heme holds one iron atom, each iron atom holds one molecule of oxygen. Four oxygen molecules. .250 million molecules of hemoglobin per cell. Each red blood cell carries one billion molecules of oxygen.
Organs mainly involved in H e m esynthesis? variable constant
cytosol mitochondria
Heme Heme degradation Hemesynthesis Bilepigments+ iron
How is the structure of porphyrin? Porphyrins are cyclic compounds formedby the linkage of four pyrrole rings through methyne (=HC ) bridges A characteristic property of porphyrins isthe formation of complexes with metal ions bound to the nitrogen atom of the pyrrole rings
Step-1(mitochondria( From citricacidcycle Non essential aminoacid Succinyl-CoA Glycine ( Pyridoxal phosphate activates) condensation reaction ALA synthase CoA-SH -amino- -ketoadipic acid
Step-2(mitochondria) -amino- -ketoadipic acid decarboxylationreaction ALAsynthase (rate controlling enzyme - porphyrin biosynthesis liver) -aminolevulinate (ALA)
Step-3(cytosol( ( 2molecules) -aminolevulinate(ALA) ALAdehydratase 2H20 zinc-containing enzyme andis sensitive to inhibition bylead. (1) porphobilinogen (PBG( First precursor of pyrrole
Step-4 (cytosol( (4molecules) porphobilinogen (PBG) AIP condenses uroporphyrinogenI synthase 4NH3 HydroxymethylbilaneHMB lineartetra pyrrole PBGdeaminase HMB synthase
Step-5(cytosol( Hydroxymethylbilane (HMB( uroporphyrinogenIII synthase UroporphyrinogenI HMB cyclizesspontaneously UroporphyrinogenIII CEP Forms under normalconditions
Step-6(mitochondria( uroporphyrinogenI uroporphyrinogenIII 6H 6H light Uroporphyrinogen decarboxylase light UroporphyrinIII UroporphyrinI coproporphyrinogenI coproporphyrinogenIII 6H 6H light light PCT CoproporphyrinIII CoproporphyrinI
Step-7(mitochondria( coproporphyrinogenIII Coproporphyrinogen oxidase HCP ProtoporphyrinogenIII
Step-8(mitochondria( ProtoporphyrinogenIII Protoporphyrinogen oxidase Por.variegata ProtoporphyrinIII
Step-9(mitochondria ( ProtoporphyrinIX Hemesynthase Ferrochetalase H.protoporphyria Heme
Regulation of HemeSynthesis Heme inhibits the synthesis of ALAsynthase repression mechanism ALA synthaseis also allosterically inhibitedby hematin. Thecompartmentalizationof theenzymes, makes the regulationeasier. The steps catalyzed by ferrochelatase andALA dehydratase are inhibited bylead.
Regulation of HemeSynthesis Drugs like barbituratesinduce hemesynthesis. Barbiturates require the hemecontaining cytochrome P450for their metabolism. Out of the totalhemesynthesized, two thirds are used for cytochrome P450production. INH (Isonicotinic acid hydrazide) that decreases the availability of pyridoxal phosphate may also affect hemesynthesis.
Regulation of HemeSynthesis High cellular concentration of glucose prevents induction of ALA synthase. This isthe basis of administration of glucose to relieve the acute attack ofporphyrias. Regulation in the erythroid cells: The enzyme ALA synthase does not appear to control the hemesynthesis in the erythroid cells. Uroporphyrinogen synthaseand ferrochelatse mostly regulate hemeformation in thesecells.
What are porphyrias? Porphyria refers to a growing collection of disorders in which there are abnormalities in the enzymes involved in Hemesynthesis. Although porphyrias are not veryprevalent, physicians must be aware ofthem.
What are the causesof porphyrias? There are at least eight steps in the production of Heme, and at least eight different types of porphyria can result when an enzyme malfunctions and levels of intermediate substances rise tobeyond what the body is needed.
Porphyriasclassification This classification is based on the majorsite, where the enzyme deficiency ismanifested. The porphyrias are classified as erythropoietic or hepatic, depending on whether the enzyme deficiency occurs inthe erythropoietic cells of the bone marrow or in theliver. Hepatic porphyrias can be further classified as chronic or acute.
Porphyriasclassification In general, individuals with an enzyme defect prior to the synthesis of the tetrapyrroles manifest abdominal and neuropsychiatricsigns. Whereas those with enzyme defects leading to the accumulation of tetrapyrrole intermediates photosensitivity. That is, their skin itches and burns when exposed to visiblelight. show
Acute intermittentporphyria 4molecules porphobilinogen (PBG( This disorder occurs due to the deficiencyof the enzyme uroporphyrinogen Isynthase. condenses Characterized by increased excretionof porphobilinogen and6-aminolevulinate. Uroporphyrinogen I synthase Theurine getsdarkenedon exposuretoair due to the conversion of porphobilinogen to porphobilinandporphyria. Hydroxymethylbilane HMB(lineartetrapyrrole)
Other characteristic features ofAIP Usually expressed after puberty inhumans. The symptoms include abdominal pain, vomitingand cardiovascularabnormalities. The neuropsychiatric disturbancesobserved. The symptoms are more severe after administrationof Drugs: e.g.Barbiturates. These patients are not photosensitive sincethe enzyme defect occurs prior to the formation of uroporphyrinogen.
Congenital erythropoieticporphyria characteristicfeatures Rare congenital disorder Autosomalrecessive Confined to erythropoietic tissues. The individuals excrete uroporphyrinogen I and coproporphyrinogen I which oxidize respectively touroporphyrin I and coproporphyrin | . red pigments. Hydroxymethylbilane uroporphyrinogenIII synthase uroporphyrinogenIII The patients arephotosensitive. Increasedhemolysis.
Porphyriacutaneatarda uroporphyrinogenI uroporphyrinogenIII Uroporphyrinogen decarboxylase coproporphyrinogenI coproporphyrinogenIII This is also known ascutaneous hepatic porphyria. Themost common porphyria . Usually associated with liver damage caused byalcohol overconsumption or ironoverload. The partial deficiency of the enzyme uroporphyrinogen decarboxylase appears to be responsible for theoccurrence of porphyria cutaneatarda.
Porphyria cutaneatarda The other characteristic features include: Increased excretion of uroporphyrins l andlll and rarelyporphobilinogen. Cutaneous photosensitivity is the mostimportant clinical manifestation of thesePatients. Liver exhibits fluorescence due to high concentration of accumulatedporphyrins.
Hereditary cutaeniatarda coproporphyrinogenIII Coproporphyrinogen oxidase ProtoporphyrinogenIII Coproporphyrinogen lll and other intermediates (ALA andPBC) excreted in urine andfeces. The patients of hereditary coproporphyria arephotosensitive. Theyexhibit the clinical manifestations observed in the patients of acute intermittentporphyria. Infusionof hematinis usedto control this disorder. Hematin inhibits ALA synthaseand thus reduces the accumulation of variousintermediates.
Variegateporphyria ProtoporphyrinogenIII Protoporphyrinogen oxidase ProtoporphyrinIX The enzyme protoporphyrinogen oxidase is defective in this disorder. Due to this blockade, protoporphyrin lX required for theultimate synthesis of Heme is notproduced. Almost all theintermediates(porphobilinogen,coproporphyrin, uroporphyrin,protoporphyrin etc.)of Hemesynthesisaccumulate in the body andareexcretedin urine andfeces. Theurineof thesepatients iscolouredandtheyexhibit photosensitivity.
Protoporphyria ProtoporphyrinIX Hemesynthase Ferrochetalase Heme This disorder, also known aserythropoieticprotoporphyria Deficiency of the enzymeferrochelatase. Protoporphyrin lXaccumulates in the tissues and is excreted into urine andfeces. Reticulocytes (young RBC) and skin biopsyexhibit red fluorescence.
Acquired porphyrias(toxic( The porphyrias, though not inherited, may beacquired due to the toxicity ofseveral compounds. Exposure of the body to: Heavy metals e.g.lead, Toxic compounds e.ghexachlorobenzene. Drugs. E.g.Griseofulvin inhibits many enzymes inheme synthesis. Theseinclude: ALAdehydratase. Uroporphyrin Isynthase. Ferrochetalase.
Diagnosis The best time to attempt diagnosis is whenthe symptoms areactive. Porphyria sufferers are affected by anythingthat can alter the functioning of the deficient enzymes. Disease can occur to different degrees. Some people are affected so slightly that the diagnosis is neverconsidered. Herbs, drugs, alcohol and even hormones can produce acute attacks by interfering withenzyme function.
Diagnosis Lab tests are required to make adefinitive diagnosis of porphyria and to determine which form of the disease youhave. If your doctor suspects porphyria, he orshe may recommend thesetests: Urine , blood and stool: Examinationfor variousporphyrins. Spectrophotometry: Is Used to Testfor Porphyrins & Their Precursors Coproporphyrins anduroporphyrins.
Urinetest: If you have a form of acute porphyria, a urinetest may reveal elevated levels of two substances: porphobilinogen and delta-aminolevulinicacids, as well as other porphyrins. Blood test: If you have a form of cutaneous porphyria, a blood test may show an elevation in the level ofporphyrins in your bloodplasma. Stool sampletest: Analysis of a stool sample may reveal elevatedlevels of someporphyrinsthatmaynotbedetectedinurine samples. This test may help your doctor determine your specific type ofporphyria.
T o demonstrate porphyrins, UV fluorescence is the besttechnique. The presence of porphyrin precursor in urineis detected by Ehrlich sreagent. When urine is observed under ultravioletlight porphyrins if present, will emit strong red fluorescence. Spectrophotometry :Is Used to Test for Porphyrins & Their PrecursorsCoproporphyrins and uroporphyrins. Use of appropriate gene probes has made possible the prenatal diagnosis of some ofthe porphyrias.
