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C H A P T E R 38

HEME BIOSYNTHESIS AND ITS DISORDERS:
PORPHYRIAS AND SIDEROBLASTIC ANEMIAS

Stephen J. Fuller and James S. Wiley

The porphyrias and the sideroblastic anemias are metabolic disorders porphyrias and in porphyria cutanea tarda (PCT), the liver is the main
that involve defects in heme biosynthesis. Most forms of porphyria are source of overproduction; in congenital erythropoietic porphyria
inherited in a mendelian autosomal dominant pattern, but some types (EPP), the marrow is the main source; and in erythropoietic protopor-
are recessive and others are acquired through exposure to porphyrino- phyria, porphyrins are overproduced by the liver and marrow.
genic drugs and chemicals. A linked group of diseases, the porphyrin- Control of hepatic heme biosynthesis is regulated by the rate of
urias, are not porphyrias but have in common alterations of heme the initial enzymatic step, ALAS, nonspecific, mitochondrial (now
biosynthesis. Porphyrins are tetrapyrroles, which are ubiquitous in designated ALAS1), which is under negative-feedback control by
nature and exhibit characteristic red fluorescence on exposure to ultra- heme. This occurs by more than one mechanism. Heme represses
violet light. The iron-porphyrin complex, called heme, is central to all transcription of the ALAS1 gene and increases the rate of degradation
biologic oxidation reactions. In plants, the porphyrin molecule is of the messenger ribonucleic acid (mRNA) (Fig. 38.2A). At the
combined with magnesium to form chlorophyll. Porphyrin biosynthesis posttranslational level, heme blocks the translocation of pre-ALAS1
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is one of the most essential biochemical processes in most life forms. into the mitochondrion. In the mitochondrion, the molecular mass
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In humans, mutations affecting the first enzyme of the heme of ALAS1 is smaller than that of the cytosolic pre-ALAS1 because
biosynthetic pathway produce sideroblastic anemia. Inborn errors of the removal of the mitochondrial targeting sequence. Finally, heme
that occur at subsequent sites in this pathway usually result in meta- regulates levels of mature ALAS1 by activation of a mitochondrial
bolic disorders known as the porphyrias (Fig. 38.1). It has been proteolysis system. 16
hypothesized that Vincent van Gogh suffered from acute porphyria The erythroid bone marrow is the major heme-forming tissue in
and historical analyses have suggested the presence of a hereditary the body, producing 85% of the daily heme requirement. Heme
1–4
porphyria, variegate porphyria, in the British royal family. However, synthesis in erythroid cells varies from that in hepatocytes; it is linked
a critical review of the characteristics of inheritance and clinical fea- to tissue differentiation, and the half-life of the same end product of
tures in affected members make this diagnosis less likely. 4,5 the two is quite different. Heme complexed with globin is preserved
in circulating red blood cells for approximately 120 days, whereas
heme produced in liver for cytochromes and enzymes, such as catalase,
HEME BIOSYNTHESIS is subject to much more rapid turnover, measurable in hours. Regula-
tion in the liver is exquisitely sensitive to fluctuations in intracellular
Biosynthetic Pathways heme levels and responds rapidly to the requirements for synthesis,
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as described in Fig. 38.2A. However, heme synthesis in the bone
Heme biosynthesis is an essential pathway and occurs in all metaboli- marrow shows a more leisurely response. This fundamental difference
cally active cells that contain mitochondria. It is most active in is explained by the finding of two different tissue-specific isoenzymes
erythropoietic tissue, where it is required for hemoglobin synthesis, and two different cDNAs for human liver or “housekeeping” ALAS1
and in hepatic tissue, where the heme forms the basis of various and ALAS, erythroid-specific, mitochondrial (ALAS-E or ALAS2),
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heme-containing enzymes such as the cytochromes P450, catalase, which is expressed exclusively in erythroid cells. The gene for ALAS2
cytochrome oxidase, and tryptophan pyrrolase. The synthetic pathway has been mapped to the X chromosome and that for the hepatic
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starts with the condensation of glycine and succinyl CoA to form enzyme to chromosome 3. The ALAS2 gene has 11 exons; exons 5
5-aminolevulinate (ALA) under the control of the mitochondrial to 11 encode the catalytic domain of the enzyme and include a lysine
enzyme 5-aminolevulinate synthase (ALAS). This enzyme requires residue that forms a Schiff base with the pyridoxal phosphate cofactor.
pyridoxal phosphate as a cofactor. A series of enzymes then controls Exon 1 contributes to the 5′ untranslated region (UTR) whose
the conversion of ALA first to the monopyrrole porphobilinogen structure allows iron to regulate ALAS2 mRNA translation, whereas
(PBG) and then to the various porphyrins. Iron is inserted into exons 1 and 2 contribute the sequence that targets the enzyme to the
protoporphyrin by the enzyme ferrochelatase to form heme (see Fig. mitochondria and is cleaved after import. Succinyl CoA synthetase
38.1). During the past 30 years, complementary deoxyribonucleic associates specifically with ALAS2 within the mitochondrion, which
acid (cDNA) clones have been obtained for all of the enzymes of helps promote the first step of heme synthesis. 19
heme biosynthesis, and the structures of the corresponding genes Enzyme levels of ubiquitous and erythroid isoenzymes of ALAS
have been determined. These advances are certain to improve under- are controlled by different mechanisms. Ubiquitous ALAS1 levels in
standing of the pathogenesis of the porphyrias and methods for liver are regulated by negative feedback by heme that inhibits gene
identification of carriers. The enzymes of the biosynthetic pathway transcription and import of pre-ALAS1 (see Fig. 38.2A). More
have all been mapped to specific chromosomes (Table 38.1). Heme recently ALAS1 has been shown to be upregulated by peroxisome
synthesis and its disorders have been the subject of reviews, 7–12 and proliferator-activated receptor-gamma, coactivator 1, alpha (PPAR-γ
advances in our knowledge of mitochondrial iron trafficking and coactivator 1-α), which regulates mitochondrial biogenesis and oxi-
metabolism have recently been reviewed. 13,14 dative metabolism. Transcription of this coactivator 1-α is controlled
by glucose availability. Coactivator 1-α production increases when
glucose levels are low, leading to increased levels of ALAS1 and heme.
Control of Heme Biosynthesis These conditions are conducive to an acute attack of porphyria.
However, the relative contribution of heme and PPAR-γ coactivator
The overproduction of porphyrins and their precursors in the different 1-α in regulating ALAS1 expression remains to be resolved. 20,21 In
porphyrias is mainly hepatic or erythropoietic in origin. In the acute contrast, heme does not affect transcription of the ALAS2 gene,

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