Heme biosynthesis disorders

Anderson KE et al Disorders of heme biosynthesis X-linked sideroblastic anemia and the porphyrias. In The Metabolic and Molecular Bases of Inherited Disease, 8th ed. Scriver CR et al (editors). McGraw-Hill, 2001. 

Heme biosynthesis takes place primarily in immature erythrocytes (85% of the body s heme groups), with the remainder occurring in the liver. Several genetic defects in heme biosynthesis have been identified that give rise to the disorders called porphyrias. 

Within the past few years, there has been considerable progress in understanding the role played by the mitochondria in the cellular homeostasis of iron. Thus, erythroid cells devoid of mitochondria do not accumulate iron (7, 8), and inhibitors of the mitochondrial respiratory chain completely inhibit iron uptake (8) and heme biosynthesis (9) by reticulocytes. Furthermore, the enzyme ferrochelatase (protoheme ferro-lyase, EC 4.99.1.1) which catalyzes the insertion of Fe(II) into porphyrins, appears to be mainly a mitochondrial enzyme (10,11,12,13, 14) confined to the inner membrane (15, 16, 17). Finally, the importance of mitochondria in the intracellular metabolism of iron is also evident from the fact that in disorders with deranged heme biosynthesis, the mitochondria are heavily loaded with iron (see Mitochondrial Iron Pool, below). It would therefore be expected that mitochondria, of all mammalian cells, should be able to accumulate iron from the cytosol. From the permeability characteristics of the mitochondrial inner membrane (18) a specialized transport system analogous to that of the other multivalent cations (for review, see Ref. 19) may be expected. The relatively slow development of this field of study, however, mainly reflects the difficulties in studying the chemistry of iron. 

The porphyrias are a heterogeneous group of diseases, all of which involve disorders of heme biosynthesis, which result in accumulation and increased excretion of porphyrins or porphyrin precursors. The porphyrias can be divided into two kinds the hereditary porphyrias, some of which can be exacerbated by exposure to certain chemicals, and the toxic porphyrias, which can be produced by exposure to certain chemicals alone. The pattern of excretion of porphyrins and porphyrin precursors is characteristic for each type. Clinical symptoms consist mainly of cutaneous photosensitivity and/or neurological disturbances. Hexachlorobenzene is a chemical inducer of porphyria. 

The porphyrias are a group of disorders caused by abnormalities in heme biosynthesis. They are inherited and acquired disorders characterized by excessive accumulation and excretion of porphyrins or their precursors. Defects in any one of the eight enzymes involved in heme biosynthesis may cause inherited porphyrin-related disorders (Figure 29-9). Porphyrins have a deep red or purple color (Greek porphyra = purple). Porphyrins are... 

Porphyria—A group of disorders involving heme biosynthesis, characterized by excessive excretion of porphyrins or their precursors may be inherited or may be acquired, as from the effects of certain chemical agents. 

Porphyrias clinical conditions resulting from genetic defects in heme biosynthesis. For the pathway of heme biosynthesis, see Porphyrins. Inborn errors have been described for 7 of the 8 enzymes in this pathway. Although no major genetic defect has been described for the first enzyme of the pathway, S-aminolevulinate synthase (EC 2.3.1.37), low activity has been reported in a case of congenital sideroblastic anemia [G. R. Buchanan et al. Blood 55 (1980) 109-115]. Heme is an essential constituent of many important enzymes and hemoproteins. Absence of heme synthesis is therefore incompatible with life, and homozygotes of inherited autosomal dominant disorders of heme synthesis are not viable, unless there is residual activity of the enzyme concerned. P. are classified as erythropoietic or hepatic, depending on whether the defect is located mainly in the erythroid cells or the liver. 

The most studied of the genetic polymorphisms for blood components in potentially lead-exposed populations and relevant to Pb toxicokinetics is that for the erythrocyte heme pathway enzyme 6-ALAD (EC 4.2.1.24). This enzyme, also known as porphobilinogen synthase (PBG-S), participates in the heme biosynthesis pathway, catalyzing the cyclodehydration of two units of 6-ALA to PBG. Inhibition by lead leads to the accumulation of 6-ALA in plasma and urine. Excess substrate is neurotoxic in animals and may play a role in manifestations of lead poisoning (Audeskirk, 1985) and, presumably, in the genetic disorder acute intermittent porphyria (Bonkowsky, 1982). It is... 

Mitochondria play a key role in iron metabolism since heme and various iron-sulfur (Fe-S)-cluster containing proteins are synthesized in them. The last step in heme biosynthesis, the insertion of Fe into protoporphyrin IX by ferrochelatase, takes place in the mitochondrial matrix. Fe-S clusters are synthesized mainly, if not entirely, in mitochondria and are combined with mitochondrial apo-proteins to form mature proteins or are exported from mitochondria for utilization by cytosolic and nuclear proteins. Table 8.2 summarizes some known proteins involved in mitochondrial iron homeostasis and utilization and their deficiency-related human disorders. 

The porphyrias are a group of disorders due to abnormalities in the pathway of biosynthesis of heme they can be genetic or acquired. They are not prevalent, but it is important to consider them in certain circumstances (eg, in the differential diagnosis of abdominal... 

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