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HAEM SYNTHESIS
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| A molecule
of ALA is formed by the condensation of
glycine and succinyl-coA (not shown). This
is catalysed by the enzymeALA synthase,
which is vitally important as its activity
controls the rate at which porphyrins and
haem are synthesised. It is the controlling
enzyme of the pathway. |
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5-aminolaevulinic
acid (ALA) |
| Two molecules
of ALA combine to form a monopyrrole—the
five-sided ring in the centre of PBG. This
is catalysed by the enzyme ALA dehydratase,
which is defective in ALA dehydratase
porphyria. |
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Porphobilinogen
(PBG) |
| Four molecules
of PBG combine to form a linear tetrapyrrole—four
monopyrroles strung together end to end.
This step is catalysed by the enzyme hydroxymethylbilane
synthase (also known as PBG deaminase),
which is defective in acute intermittent
porphyria (AIP). |
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Hydroxymethylbilane |
| The open
section on the left of the structure above
- where two pyrrole rings lie adjacent to
each other but not joined—is then closed,
producing a tetrapyrrole ring. This produces
the first porphyrin on the pathway, uroporphyrinogen.
This step is catalysed by uroporphyrinogen
lll cosynthase, which also tweaks the
ring into a particular orientation called
the lll isomer. This enzyme is defective
in congenital erythropoietic protoporphyria. |
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Uroporphyrinogen
lll |
| Four of
the carboxylic acid side chains (COOH) are
successively knocked off by the enzyme uroporphyrinogen
decarboxylase (UROD), producing the
heptacarboxylic, hexacarboxylic and pentacarboxylic
porphyrinogen intermediates (not shown),
ending in coproporphyrinogen lll. This enzyme
is defective in porphyria cutanea tarda
(PCT). |
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Coproporphyrinogen
lll |
| A further
two carboxylic acid side chains are knocked
off by the enzyme coproporphyrinogen
oxidase, which is defective in hereditary
coproporphyria (HCP). |
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Protoporphyrinogen
lX |
| This molecule
is then oxidised from protoporphyrinogen
lX to protoporphyrin lX by the enzyme protoporphyrinogen
oxidase, which is defective in variegate
porphyria. |
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Protoporphyrin
lX |
| An iron
atom (Fe2+) is inserted into the centre
of the tetrapyrrole ring to form haem. This
is catalysed by the enzyme ferrochelatase,
which is defective in erythropoietic
protoporphyria. |
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Haem |
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HAEM BREAKDOWN
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| The tetrapyrrole
ring is broken open (See the gap between
the O atoms at the top of the structure
below). This step is catalysed by the enzyme
haem oxygenase. |
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Biliverdin |
| This is
further reduced to bilirubin by the enzyme
biliverdin reductase |
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Bilirubin |
| Bilirubin
is the form in which the breakdown products
of haem are excreted from the body: in the
bowel, it is further broken down to urobilinogen
and stercobilinogen by bacteria. |
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