section 29.2
Heme Biosynthesis
F IG U R E 2 9 -6
Formation of coproporphyrinogen III from uroporphyrinogen III. Acetic
acid side chains (Ac) are decarboxylated to methyl groups (M),
sequentially, starting clockwise from ring D. P, -CH
(an abnormally excessive growth of hair). Four por-
phyrias can manifest as acute disorders: 8
ALA dehy-
dratase deficiency porphyria, acute intermittent porphyria,
hereditary coproporphyria, and variegate porphyria.
Porphyria maybe classified as hepatic or erythropoi-
etic. However, enzyme defects are sometimes common
to both tissues. Porphyrias can be induced by alcohol,
stress, infection, starvation, hormonal changes (e.g., men-
struation), and certain drugs. These drugs presumably
precipitate acute manifestations in susceptible subjects
since they are inducers of cytochrome P-450 and in-
crease the need for synthesis of heme as they deplete
the mitochondrial pool of free heme. Major hepatic
porphyrias include
acute intermittent porphyria, varie-
gate porphyria, hereditary coproporphyria,
cutanea tarda.
The principal erythropoietic porphyrias
hereditary erythropoietic porphyria
Hepatic Porphyrias
Acute intermittent porphyria
is associated with exces-
sive urinary excretion of ALA and porphobilinogen. The
lack of polymerization of porphobilinogen is due to de-
ficiency of porphobilinogen deaminase in several cell
types (e.g., hepatocytes, erythrocytes, fibroblasts, lympho-
cytes). Acute clinical manifestations include neuropsychi-
atric disorders and abdominal pain. The cause of these
manifestations is not clear, but accumulation of porphyrin
precursors (ALA and porphobilinogen) in pharmacologi-
cal amounts has been implicated. Since afflicted subjects
cannot make porphyrins to any great extent, they are not
photosensitive. This disorder is inherited as an autosomal
dominant trait.
Porphyria cutanea tarda
is the most common form. It is
inherited as an autosomal dominant trait and is due to de-
ficiency of uroporphyrinogen III decarboxylase. Clinical
Coproporphyrinogen 111
Protoporphyrinogen IX
F IG U R E 2 9 -7
Formation of protoporphyrinogen IX from coproporphyrinogen III by coproporphyrinogen oxidase. Sequential
oxidative decarboxylation of the propionic acid (P) sidechains of rings A and B produces vinyl (V) groups (V =
>. The reaction proceeds via the stereospecific loss of one hydrogen atom and decarboxylation of the
propionic acid group. Molecular oxygen is the oxidant, and /S-hydroxypropionate is a probable intermediate. M, CH
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