Iron plays the leading role in all biological processes wherein oxygen turnover takes place. Iron(II) coordinates to a certain type of porphyrin and forms a complex labeled heme (Figure 10.8). Vertebrates utilize two such heme proteins for reversible O2 transport and storage: hemoglobin in red blood cells and myoglobin in muscle tissue. Anemia results from insufficient dioxygen supply usually due to a low hemoglobin blood level.
A significant heme enzyme is cytochrome P-450, a dioxygen activating metalloporphyrin that catalyzes a series of important biological oxidation processes. Enzymatic monooxygenation reactions, e.g., the conversion of vitamin-D or transformation of drugs like morphine are indicative of such processes. Unwanted transformations like epoxidation of benzene to produce carcinogenic derivatives or oxidation of nitrosamines to form reactive radicals are examples of a toxicological function of cytochrome P-450.
For every 30 seconds, a child in Africa dies from malaria and the commonly used antima-larial therapy has become increasingly ineffective due to chloroquine resistance. However, a new series of drugs based on tervalent metal ion coordination compounds, like the ethylenediamine-bis[propylbenzylimino]Fe(III) complex, exhibit highly selective activity, ironically, particularly against chloroquine-resistant parasites. Heme, released from hemoglobin in the parasite, is very toxic to eukaryotic cells due to lysing of the membranes. In order to prevent this destructive action, the parasite polymerizes heme, but the aforementioned imino complexes inhibit this protective process thereby destroying the parasite.
Transport and storage of iron have been studied assiduously. As Fe(II) easily becomes oxidized to Fe(III) the products formed are in general highly insoluble at pH 7, unless Fe(III) becomes sequestered to some chelate like the siderophores (Section 10.5.4; cf. Figure 10.4C). The salmonella
bacteria produce a siderophore that binds iron(III) with a stability constant of not less than 1050 M-1. Another siderophore, desferrioxamine produced by the Streptomyces fungus, is used in order to prevent iron poisoning in connection with blood transfusion. Pathogenic microorganisms rely on a constant supply of iron, and therefore the availability of iron to bacteria invading the organism plays an important role in many diseases, like cholera and tuberculosis where a decrease in iron content in the blood is invariably observed. Effective iron scavenging chelates will thus act as potent antibiotics and naturally occurring iron complexing agents are, therefore, of great interest in medicine both as antibiotics and as drug delivery agents. An example is bleomycin, an antitumor agent that is isolated from the Streptomyces fungus.
"Sodium nitroprusside," Na2[Fe(CN)5NO] (Figure 10.9) is an active hypotensive agent used in the treatment of heart infarct and in the control of blood pressure during heart surgery. The release of NO causes relaxation of the muscles surrounding the blood vessels, probably by the coordination of nitric oxide to an iron porphyrin receptor within the guanylate cyclase enzyme, which converts guanine triphosphate to cyclic guanine monophosphate. NO is also synthesized in the human body in a process where an iron containing (heme) enzyme catalyzes oxidation of the amino acid, argi-nine to nitric oxide.
The role of cobalt as essential trace element is confined to only one function, namely, as the redox active metal ion in coenzyme-Bj2 (Figure 10.10), which contains a Co-C (adenosyl) bond. As early as in the 1920s, it was well established that pernicious anemia (a state of anemia due to vitamin B12 deficiency) could be cured with injections of extracts from liver samples, and trace element analysis demonstrated later that the extracts contained cobalt. One of the axial cobalt ligands can be an alkyl residue: C„H2n+1. This is the only known example of a naturally occurring beneficial metal-carbon bond. The rate of alkylation may be accelerated enzymatically up to 1010 times.
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