Porphyrins, iron-free

Under physiologic conditions in the human adult, 1—2 X 10 erythrocytes are destroyed per hour. Thus, in 1 day, a 70-kg human turns over approximately 6 g of hemoglobin. When hemoglobin is destroyed in the body, globin is degraded to its constiment amino acids, which are reused, and the iron of heme enters the iron pool, also for reuse. The iron-free porphyrin portion of heme is also degraded, mainly in the reticuloendothehal cells of the liver, spleen, and bone marrow. 

Extensive investigations on the catalytic mechanism of classical peroxidases resulted in a consensus model involving five different iron species [30, 31], These species are ferrous, ferric, Compound I, Compound II, and Compound III (Fig. 11.1). As discussed in Chap. 5, after the reaction of ground state (GS) Femporphyrin with H202, Compound I (Cl) is formed, a cationic oxob e,vpor-phyrin-based Ji-free radical. Electron paramagnetic resonance (EPR) studies established that, in peroxidases of classes I and III, the second oxidation equivalent in Cl is present as a porphyrin-based free radical [32, 33]. In peroxidases from fungal sources, electron abstraction from the protein results in the formation of a different species with the free radical based in a residue close to the porphyrin. 

In two factories, in addition to chloracne, porphria cutanea tarda (a disturbance of porphyrin metabolism characterized by chronic skin lesions ranging from slight skin fragility to severe chronic scarring, by enlarged livers and by excessive urinary excretion of uroporphyrin and coproporphyrins. Uroporphyrin and coproporphyrin are iron-free cyclic tetrapyrrole derivatives) developed in the workers, (22,25). The possibility of simultaneous exposure to hexachlorobenzene, however, cannot be excluded. Hexachlorobenzene may be a contaminant in the production of... 

In spite of the attractiveness of an iron-free porphyrin-cytochrome in demonstrating the role of the tetrapyrrole ring as a folding template,... 

Fig. 1. The structures of protohaem (A), mesohaem (B), 7-PF (13,17-hw(2-carboxyla-toethyl)-3,8-diethyl-2,12,18-trimethyl-7-trifluoro-methylporphyrinatoiron(III)) (Q, 3,7-DF (13,17-hw(2-carboxyethyl)-2,8,12,18-tetramethyl-3,7-difluoroporphyrinatoiron(III)) (D), and 2-MF (13,17-hA(2-carboxylatoethyl)-3,8-diethyl-2-fluoro-7,12,18-trimethylporphyrinatoiron (III)) (E). Iron-free porphyrins of protohaem and mesohaem are called protoporphyrin and mesoporphyrin, respectively, and those of 7-PF, 3,7-DF, and 2-MF are indicated as 7-PFP, 3,7-DFP, and 2-MFP, respectively.

Porphyrins, iron porphyrins and hemoproteins 2, 32-37, 43 Free radicals in biology 2, 45, 65, 73, 153... 

Protoporphyrin IX [222], the iron-free precursor of heme, stimulates soluble guanylate cyclase (EC 4.6.1.2) independently of NO (Ignarro et al. 1982). As protoporphyrin IX does not contain Fe, its structure resembles that of NO-heme complex in which the iron is moved out of the plane of the porphyrin ring. In both cases, i.e. in the protoporphyrin IX- and the NO-stimulated enzyme, the axial histidine is unbound. 

Due to their chelating properties hydroxamic acids are of importance in the solubilization and uptake of iron in many microorganisms. Aerobactin participates in the uptake of iron in Escherichia coli. Sideramines, e.g., ferrichrome, are involved in the Fe + uptake in fungi (C 2.2). Some iron-free sideramine-like compounds, e.g., nocardamine, are antibiotics (E 5.2) and inhibit the activity of sideramines by competition. If the Fe +.ion is reduced to Fe + the stability of the hydroxamic acid complexes is reduced and iron may be transferred, for instance from ferrichrome, to compounds with porphyrin ring system (D 10.1). 

At autopsy, few findings are striking. The body is often emaciated, and the cause of death may have been uremia, cachexia, or respiratory paralysis. The most conspicuous and consistent findings are in the liver and nervous system. The liver is congested, with central lobular necrosis and occasionally fatty degeneration. An iron-free lipochrome pigment is found in the hepatic cells of some patients. Chemical analysis of the liver demonstrates chromogen, but no porphyrins are found in spleen or bone marrow. 

Hsematoporphyrin, C3 H,gOgN4, an iron-free derivative of h m, is obtained by the action of strong acids on haemoglobin, or by dissolving haematin chloride in glacial acetic acid saturated with HBr. After four days, the mixture is diluted and the porphyrin precipitated by exact neutralisation. Haematoporphyrin is a dark violet powder, almost insoluble in water, but soluble in alcohol, alkalies, and concentrated sulphuric acid. It is a di-hydroxy derivative of Protoporphyrin, in which each vinyl side-chain, —CH CHg, has become —CHg.CHg.OH. 

Reaction of free-base porphyrin compounds with iton(II) salts in an appropriate solvent results in loss of the two N—H protons and insertion of iron into the tetradentate porphyrin dianion ligand. Five-coordinate iton(III) porphyrin complexes (hemins), which usually have the anion of the iton(II) salt for the fifth or axial ligand, ate isolated if the reaction is carried out in the presence of air. Iron(II) porphyrin complexes (hemes) can be isolated if the reaction and workup is conducted under rigorously anaerobic conditions. Typically, however, iton(II) complexes are obtained from iton(III) porphyrin complexes by reduction with dithionite, thiolate, borohydtide, chromous ion, or other reducing agents. 

It should be emphasized that virmaUy all of the above discussion is based on biomimetic chemistry, where the Fe(II) source varies from salts such FeS04 to the more reactive FeCla-THaO as well as heme mimetics (TPP) and ester hematin variants. When heme models are used, since porphyrin alkylation is a favoured process, end-product distributions of products can be very different from when a free ferrous ion source is employed. Furthermore, solvent has been shown to have a profound effect on the rate of reaction and product distributions obtained in iron-mediated endoperoxide degradation. Thus all of these studies are truly only approximate models of the actual events within the malaria parasites. Future work is needed to correlate the results of biomimetic chemistry with the actual situation within the parasite. In general, most workers do accept the role of carbon-centred radicals in mediating the antimalarial activity of the endoperoxides, but the key information defining (a) the chemical mechanism by which these species alkylate proteins and (b) the basis for the high parasite selectivity remains to be unequivocally established. 

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