section 29.2

Heme Biosynthesis

687

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

2

CH

2

COOH.

(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,

and

porphyria

cutanea tarda.

The principal erythropoietic porphyrias

are

hereditary erythropoietic porphyria

and

erythropoietic

protoporphyria.

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

Harderoporphyrinogen

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 =

-CH=CH

2

>. 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

3

.