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chapter 29
Metabolism of Iron and Heme
Protoporphyrinogen IX
Protoporphyrin IX
H em e
F IG U R E 2 9 -8
Formation of heme. In the reaction catalyzed by protoporphyrinogen oxidase, six hydrogens are removed and the
primary electron acceptor is not known, but oxygen is required for enzyme activity. In the terminal step of heme
synthesis, only Fe2+ is incorporated into protoporphyrin.
manifestations are mild to severe photosensitivity and
liver disease. Most affected individuals have increased
hepatic iron stores, which can be successfully decreased
by phlebotomy. Acute episodes can be precipitated by
overindulgence of alcohol or, less frequently, by therapy
with estrogen.
Hereditary coproporphyria
and
variegate porphyria
are inherited as autosomal dominant traits. They are caused
by deficiency of coproporphyrinogen oxidase and proto-
porphyrinogen oxidase, respectively.
In most of these disorders, increased hepatic ALA
synthase activity is due to decreased heme synthesis.
There are also increased amounts of ALA and por-
phobilinogen in liver, plasma, and urine and specific
metabolites produced before the metabolic block. ALA
synthase is regulated by the heme by a feedback pro-
cess and by gene repression. Hematin has been used to
treat acute attacks with marked success. Although of-
ten inadequate, carbohydrate feeding has been associ-
ated with improvement in acute intermittent porphyria.
This “glucose effect” may depend on repression of
the gene for ALA synthase, but the mechanism is not
known.
Erythropoietic Porphyrias
A defect in synthesis of type III isomers from hydroxy-
methylbilane, due to deficiency of uroporphyrinogen III
Glycine + Succinyl-CoA
ALAsynthase
------------ |
ALAdehydratase
Porphobilinogen
deaminase
Uroporphyrinogen III
synthase
Uroporphyrinogen
decarboxylase
Coproporphyrinogen
oxidase
5-aminolevuIinic acid (ALA)
------
1
-----
Porphobilinogen
------ I ------------
[Hydroxymethylbilane]
------ I ------------
Uroporphyrinogen III
------ I ----------
Coproporphyrinogen III
------ I ------------
Protoporphyrinogen
oxidase
Ferrochelatase
Protoporphyrinogen IX
---------
1
------------
Protoporphyrin IX
Fe
2 + 1
Heme
Inheritance & Clinical
Manifestations
ALAdhydratase deficiency
porphyria
A R , N eurovisceral.
acute episodes
Acute intermittent porphyria
AD , N eurovisceral.
acute episodes
Congenital erythropoietic
porphyria
AR, Photosensitivity and
skin lesions
Porphyria cutanea tarda
AD , Photosensitivity and
skin lesions
Hereditary coproporphyria
AD , N eurovisceral. skin lesions
in som e, acute episodes
Variegate porphyria
AD , N eurovisceral. skin lesions
in som e, acute episodes
Erythropoietic protoporphyria
A D , Photosensitivity
F IG U R E 2 9 -9
Heme biosynthetic pathway and the enzyme defects in various porphyrias. AD, autosomal dominant; AR, autosomal
recessive.
