Iron, cytochrome

The above sequence mimics the proposed biosynthesis of Ervatamia alkaloids and in this context Thai and Mansuy (190) set out to determine whether an enzyme preparation would be able to promote the same transformation. By incubation of dregamine hydrochloride with a suspension of liver microsomes from a rat pretreated with phenobarbital (as a good inducer of P-450 cytochromes) in the presence of NADPH and 02, 20-epiervatamine (45) was formed together with the major metabolite Nl -demethyldregamine. It is well known that microsomal reaction on tertiary amines results in Af-oxide formation or N-deal-kylation. Thus it is likely that 45 was derived either from a rearrangement of dregamine JV4-oxide, catalyzed by the iron cytochrome P-450 or from one-electron oxidation of 30. 

Because of their structural and spectroscopic analogies with the hemo-chromes Fe(P)L2, e.g. the protoporphyrin derivative 3 (L, L = Py or 1-Meim), the corresponding 4d and 5d homologs are named ruthenochromes or osmo-chromes . The hemochromes derive their name from the cytochromes, the widespread electron-carrying heme proteins. Cytochrome b (coordination type F, M = Fe) has two imidazole donors from histidine side chains at the central iron, cytochrome c (coordination type G, M = Fe) an imidazole and a methyl-thioether function from a methionine. F is an axially symmetrical, G an axially unsymmetrical system. 

Stal P, Johansson I, Ingelman Sundberg M, et al. Hepatotoxicity induced by iron overload and alcohol. Studies on the role of chelatable iron, cytochrome P450 2E1 and lipid peroxidation. J Hepatol 1996 25(4) 538 46. 

Cytochromes a and a3 contain heme A, in which two of the side chains are modified (Figure 15.6b). Cytochromes a and a3 evidently represent two identical heme A moieties, attached to the same polypeptide chain. They are within different environments in the inner membrane, however, so they have different reduction potentials. Each of the hemes in cytochromes a and a3 is associated with a copper ion, located close to the heme iron. Cytochromes undergo oxidoreduction through the complexed metal, which cycles between +2 and +3 states for the heme iron and +1 and +2 states for the copper in cytochromes a and a3. Thus, the cytochromes are one-electron carriers. Cytochromes a and a3 form part of mitochondrial complex IV (Figures 15.2 and 15.3). 

Electron spin resonance spectrometry is one of the main methods to study transition metal containing metalloproteins, i.e., copper (cytochrome oxidase, superoxide dismutase), molybdenum (xanthine oxidase), and iron (cytochromes, ferredoxln, haemoglobin, etc.)... 

Figure C3.2.5. Strongest tunnelling patliways between surface histidines and tire iron atom in cytochrome c. Steps in patliways are denoted by solid lines (covalent bonds), dashed lines (hydrogen bonds), and tlirough-space contacts (dotted lines). Electron transfer distance to His 72 is 5 A shorter tlian in His 66, yet tire two rates are approximately...

Organosulfur Compounds. These compounds, Hsted in Table 8, are used in a variety of appHcations, including cooling water, paint, and metalworking. Methylenebisthiocyanate hydroly2es rapidly at a pH above 8 to cyanate ion which complexes with ferric iron to poison the cytochrome systems (36). 

N—Fe(IV)Por complexes. Oxo iron(IV) porphyrin cation radical complexes, [O—Fe(IV)Por ], are important intermediates in oxygen atom transfer reactions. Compound I of the enzymes catalase and peroxidase have this formulation, as does the active intermediate in the catalytic cycle of cytochrome P Q. Similar intermediates are invoked in the extensively investigated hydroxylations and epoxidations of hydrocarbon substrates cataly2ed by iron porphyrins in the presence of such oxidizing agents as iodosylbenzene, NaOCl, peroxides, and air. 

The abihty of iron to exist in two stable oxidation states, ie, the ferrous, Fe ", and ferric, Fe ", states in aqueous solutions, is important to the role of iron as a biocatalyst (79) (see Iron compounds). Although the cytochromes of the electron-transport chain contain porphyrins like hemoglobin and myoglobin, the iron ions therein are involved in oxidation—reduction reactions (78). Catalase is a tetramer containing four atoms of iron peroxidase is a monomer having one atom of iron. The iron in these enzymes also undergoes oxidation and reduction (80). 

The most conspicuous use of iron in biological systems is in our blood, where the erythrocytes are filled with the oxygen-binding protein hemoglobin. The red color of blood is due to the iron atom bound to the heme group in hemoglobin. Similar heme-bound iron atoms are present in a number of proteins involved in electron-transfer reactions, notably cytochromes. A chemically more sophisticated use of iron is found in an enzyme, ribo nucleotide reductase, that catalyzes the conversion of ribonucleotides to deoxyribonucleotides, an important step in the synthesis of the building blocks of DNA. 

All these intermediates except for cytochrome c are membrane-associated (either in the mitochondrial inner membrane of eukaryotes or in the plasma membrane of prokaryotes). All three types of proteins involved in this chain— flavoproteins, cytochromes, and iron-sulfur proteins—possess electron-transferring prosthetic groups. 

In the third complex of the electron transport chain, reduced coenzyme Q (UQHg) passes its electrons to cytochrome c via a unique redox pathway known as the Q cycle. UQ cytochrome c reductase (UQ-cyt c reductase), as this complex is known, involves three different cytochromes and an Fe-S protein. In the cytochromes of these and similar complexes, the iron atom at the center of the porphyrin ring cycles between the reduced Fe (ferrous) and oxidized Fe (ferric) states. 

Cytochromes were first named and classified on the basis of their absorption spectra (Figure 21.9), which depend upon the structure and environment of their heme groups. The b cytochromes contain iron—protoporphyrin IX (Figure 21.10), the same heme found in hemoglobin and myoglobin. The c cytochromes contain heme c, derived from iron-protoporphyrin IX by the covalent attachment of cysteine residues from the associated protein. UQ-cyt c... 

FIGURE 21.13 The structure of mitochou-dtial cytochrome c. The heme is shown at the center of the structure, covalently linked to the protein via its two sulfur atoms (yellow). A third sulfur from a methionine residue coordinates the iron. 

Electrons from cytochrome c are transferred to Cu sites and then passed to the heme iron of cytochrome a. Cu is liganded by two cysteines and two histidines (Figure 21.18). The heme of cytochrome a is liganded by imidazole rings of histidine residues (Figure 21.18). The Cu and the Fe of cytochrome a are within 1.5 nm of each other. 

Cub and the iron atom of cytochrome Og are also situated close to each other and are thought to share a ligand, which may be a cysteine sulfur (Figure 21.19). This closely associated pair of metal ions is referred to as a buiuclear center. 

FIGURE 21.18 (a) The Cn site of cytochrome oxidase. Copper ligands inclnde two histidine imidazole groups and two cysteine side chains from the protein, (b) The coordination of histidine imidazole ligands to the iron atom in the heme a center of cytochrome oxidase. 

This impressive reaction is catalyzed by stearoyl-CoA desaturase, a 53-kD enzyme containing a nonheme iron center. NADH and oxygen (Og) are required, as are two other proteins cytochrome 65 reductase (a 43-kD flavo-protein) and cytochrome 65 (16.7 kD). All three proteins are associated with the endoplasmic reticulum membrane. Cytochrome reductase transfers a pair of electrons from NADH through FAD to cytochrome (Figure 25.14). Oxidation of reduced cytochrome be, is coupled to reduction of nonheme Fe to Fe in the desaturase. The Fe accepts a pair of electrons (one at a time in a cycle) from cytochrome b and creates a cis double bond at the 9,10-posi-tion of the stearoyl-CoA substrate. Og is the terminal electron acceptor in this fatty acyl desaturation cycle. Note that two water molecules are made, which means that four electrons are transferred overall. Two of these come through the reaction sequence from NADH, and two come from the fatty acyl substrate that is being dehydrogenated. 

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