Disordered hemes

The authors attribute the lifetimes to three different emitting species of myoglobin (Fig. 7.13). (1) Species I with normal heme as shown in the crystal structure (2) species II where heme is inverted, i.e rotated 180° around the a-y-me o-axis of the porphyrin ring and (3) species III in reversible dissociation equilibrium with heme. Species I with normal hemes have the shortest lifetimes, up to 150 ps, species II with disordered hemes have longer, Tntermediate lifetimes of a few hundred ps, species III with dissociated hemes have the longest lifetimes near 5000 ps. 

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... 

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. 

The structural picture that was envisaged to represent the temperature-dependent fluctuations of the EFG tensor [15] is based on the X-ray structure of MbOa that exhibits a geometric disorder of Fe02 with two different positions of the terminal O-atom [28]. Within this stmcture, the projection of the 0-0 bond on the heme plane is rotated by about 40° in position 2 compared to 1 (Fig. 9.10). Conventional Mossbauer studies of single crystals of Mb02 have shown that the principal component of the FFG tensor lies in the heme plane and is oriented along the projection of the 0-0 bond onto this plane [29]. If the terminal O-atom is located in position 2, the EFG should be of the same magnitude as in position 1, but its orientation is different. The EFG fluctuates between positions 1 and 2 with a rate that depends on temperature. 

Fig. 9.10 Dynamic stractural disorder of the terminal oxygen in oxymyoglobin between positions 1 and 2 which are related via a rotation by 40° about the heme normal...

Health effects that have been associated with lead exposures during infancy or childhood include, anemia (Schwartz et al. 1990) (and related disorders of heme synthesis), neurological impairment (e.g., encephalopathy), renal alterations, and colic (Chisolm 1962, 1965 Chisolm and Harrison 1956), and impaired metabolism of vitamin D (Mahaffey et al. 1982 Rosen and Chesney 1983). Death from encephalopathy may occur with PbB levels 125 pg/dL. In addition to the above effects, the following health effects have been associated with lead exposures either in utero, during infancy or during... 

These results with regard to heme disorder differ from those observed in solution by NMR spectroscopy, where one heme orientation is at least highly favored (Section 11,E,2). The difference in conditions (high salt, PEG) may be involved in the fact that different ratios of the two heme orientations are observed in the crystalline state than in solntion. The difference in heme orientation ratios of 1.5 1 and 10 1, for example, represents a AG difference of only 4.9 kJ/mol. 

The ruffled heme appears to result from llel23 and Ilel33 pushing down from the distal pocket side (3.4 and 3.5 A), and from His59, the proximal histidine, pushing up from below (3.4 and 3.5 A), Fig. 17. Despite the ultrahigh resolution of the structure, residues 31-37 are sufficiently disordered that side-chain positions cannot be modeled. 

This four-volume set has good chapters on disorders of amino acid, porphyrin, and heme metabolism. See also the chapters on inborn errors of purine and pyrimidine metabolism. 

Porphyrias are caused by inherited (or occasionally acquired) defects in heme synthesis, resulting in the accumulation and increased excretion of porphyrins or porphyrin precursors (see Summary Figure 21.7). With the exception of congenital erythropoietic porphyria, which is a genetically recessive disease, all porphyrias are inherited as autosomal dominant disorders. The mutations that cause the porphyrias are heterogenous (not all are at the same DNA locus), and nearly every affected family has its own mutation. Each porphyria results in the accumulation of a unique pattern of intermediates caused by the deficiency of an enzyme in the heme synthetic pathway. 

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. 

Acute hereditary porphyrias are disorders of heme synthesis in which overproduction of heme precursors is often accompanied by severe clinical manifestations. Most of the time these diseases remain clinically latent and only occasionally result in acute abdominal and neuropsychiatric symptoms. Occurrence of the symptoms often follows exposure to drugs, such as barbiturates, sulfonamides, estrogens and some local anesthetics (Blanloeil et al. 1989). 

Tosaik, Arpad Das, Dipak K. The role of heme oxygenase signaling in various disorders. Mo/ Cell Biochem, No. 232 149-157 2002. 

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