Disorders of Heme Biosynthesis
المؤلف:
Peter J. Kennelly, Kathleen M. Botham, Owen P. McGuinness, Victor W. Rodwell, P. Anthony Weil
المصدر:
Harpers Illustrated Biochemistry
الجزء والصفحة:
32nd edition.p319-321
2025-08-26
360
Disorders of heme biosynthesis may be genetic or acquired. An example of an acquired defect is lead poisoning. Lead can inactivate ferrochelatase and ALA dehydratase by complexing with essential thiol groups. Signs include elevated levels of protoporphyrin in erythrocytes and elevated urinary levels of ALA and coproporphyrin.
Genetic disorders of heme metabolism and of bilirubin metabolism share the following features with metabolic disorders of urea biosynthesis:
1. Similar or identical clinical signs and symptoms can arise from different mutations in genes that encode either a given enzyme or an enzyme that catalyzes a successive reaction.
2. Rational therapy requires an understanding of the bio chemistry of the enzyme-catalyzed reactions in both nor mal and impaired individuals.
3. Identification of the intermediates and side products that accumulate prior to a metabolic block can provide the basis for metabolic screening tests that can implicate the impaired reaction.
4. Definitive diagnosis involves quantitative assay of the activity of the enzyme(s) suspected to be defective. To this might be added consideration of the as yet incompletely identified factors that facilitate translocation of enzymes and inter mediates between cellular compartments.
5. Comparison of the DNA sequence of the gene that encodes a given mutant enzyme to that of the wild-type gene can identify the specific mutation(s) that cause the disease.
The Porphyrias
The signs and symptoms of porphyria result either from a deficiency of intermediates beyond the enzymatic block, or from the accumulation of metabolites prior to the block. Table 1 lists six major types of porphyria that reflect low or absent activity of enzymes that catalyze reactions 2 through 8 of Figure 1. Possibly due to potential lethality, there is no known defect of ALAS1. Individuals with low ALAS2 activity develop anemia, not porphyria (Table 1). Porphyria consequent to low activity of ALA dehydratase, termed ALA dehydratase-deficient porphyria, is extremely rare.
Table1. Summary of Major Findings in the Porphyriasa
Fig1. Intermediates, enzymes, and regulation of heme synthesis. The numbers of the enzymes that catalyze the indicated reactions are those used in the accompanying text and in column 1 of Table 1. Enzymes 1, 6, 7, and 8 are mitochondrial, but enzymes 2 to 5 are cytosolic. Regulation of hepatic heme synthesis occurs at ALA synthase (ALAS1) by a repression– derepression mechanism mediated by heme and a hypothetical aporepressor (not shown). Mutations in the gene encoding enzyme 1 cause X-linked sideroblastic anemia. Mutations in the genes encoding enzymes 2 to 8 give rise to the porphyrias.
Congenital Erythropoietic Porphyria
While most porphyrias are inherited in anautosomal dominant manner, congenital erythropoietic porphyria is inherited in a recessive mode. The defective enzyme in congenital erythropoietic porphyria is uroporphyrinogen III synthase (Figure 2, bottom). The photosensitivity and severe disfigurement exhibited by some victims of congenital erythropoietic porphyria has suggested them as prototypes of so-called werewolves.
Fig2. Synthesis of hydroxymethylbilane and its subsequent cyclization to porphobilinogen III. Cytosolic hydroxy methylbilane synthase (ALA dehydratase) forms a linear tetrapyrrole, which cytosolic uroporphyrinogen synthase cyclizes to form uroporphyrinogen III. Notice the asymmetry of the substituents on ring 4, so that the highlighted acetate and propionate substituents are reversed in uroporphyrinogens I and III. (A, acetate [—CH2 COO–]; P, propionate [—CH2CH2 COO–].)
Acute Intermittent Porphyria
The defective enzyme in acute intermittent porphyria is hydroxymethylbilane synthase (Figure 2, bottom). ALA and porphobilinogen accumulate in body tissues and fluids (Figure 3).
Fig3. Biochemical basis of the major signs and symptoms of the porphyrias.
Subsequent Metabolic Blocks
Blocks later in the pathway result in the accumulation of the porphyrinogens indicated in Figures 1 and 3.
Their oxidation to the corresponding porphyrin derivatives cause photosensitivity to visible light of about 400-nm wavelength. Possibly as a result of their excitation and reaction with molecular oxygen, the resulting oxygen radicals injure lysosomes and other subcellular organelles, releasing proteolytic enzymes that cause variable degrees of skin damage, including scarring.
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