Oxygen transfer from cytochrome

Oxometalloporphyrins were taken as models of intermediates in the catalytic cycle of cytochrome P-450 and peroxidases. The oxygen transfer from iodosyl aromatics to sulfides with metalloporphyrins Fe(III) or Mn(III) as catalysts is very clean, giving sulfoxides, The first examples of asymmetric oxidation of sulfides to sulfoxides with significant enantioselectivity were published in 1990 by Naruta et al, who used chiral twin coronet iron porphyrin 27 as the catalyst (Figure 6C.2) [79], This C2 symmetric complex efficiently catalyzed the oxidation... 

Cytochrome c transfers electrons to the cytochrome aa3 complex, which transfers the electrons to molecular oxygen, and the oxygen is reduced to water. Cytochromes a and a3 contain heme a and two different proteins containing copper. The energy released by the transfer of electrons from cytochrome c to oxygen is used to pump protons across the inner mitochondrial membrane. Every two electrons that are transferred from cytochrome c to oxygen produce one ATP. 

J. M. Garrison, T. C. Bruice, Intermediates in the epoxidation of alkenes by cytochrome P-450 models. 3. Meclranism of oxygen transfer from substituted oxochromium(V) porphyrins to olefinic substrates, f. Am. Chem. Soc. Ill (1989) 191. 

A FIGURE 8-20 Schematic depiction of the cytochrome c oxidase complex showing the pathway of electron flow from reduced cytochrome c to O2. Heme groups are denoted by red diamonds. Blue arrows indicate electron flow. Four electrons, sequentially released from four molecules of reduced cytochrome c, together with four protons from the matrix, combine with one O2 molecule to form two water molecules. Additionally, for each electron transferred from cytochrome c to oxygen, one proton is transported from the matrix to the intermembrane space, or a total of four for each O2 molecule reduced to two H2O molecules. 

Cyanide is a respiratory inhibitor that blocks electron transfer from cytochrome oxidase (Complex IV) to oxygen in the electron transport system (Figure 15.9). 

The l l l l-electron mechanisms of oxygen reduction by cytochrome oxidase are the most frequently discussed in biochemistry. The reaction implies that the Gibbs free energy of the first electron transfer from cytochrome oxidase to O2 is positive (Fig. 2). As a result,... 

Although this oxidation state has yet to be characterized for the cytochromes P450, most of their reactions and those of the biomimetic analogs can be accounted for by oxygen transfer from I to a variety of substrates to give characteristic reactions, such as hydrox-ylation, epoxidation, and heteroatom oxidationJ Other products resulting from hydroxyl and hydroperoxyl radicals have also been detected. The metabolic processes in vivo contribute in substantial measure to the efficacy, side effects, and toxicity of a pharmaceutical entity. These factors are responsible for the success or failure of a clinical candidate. Metabolic processes of drugs are always the subject of intense scrutiny in pharmaceutical companies. 

The respiratory chain. Boxes indicate the composition of complexes I to IV. Electron flow is shown by arows. Sites of action of some inhibitors are labeled 1, 2 and 3, and indicated by horizontal bars. Sites 2 and 3 are also coupled with ATP synthesis, i.e. according to the chemiosmotic theory, each of these stages of electron transfer (from cytochrome b to cytochrome c, and from cytochrome to oxygen) provides enough energy to generate a proton gradient for the synthesis of one molecule of ATP. The first site of ATP synthesis may not be identical with inhibition site 1 as shown here, but it is known to exist on the ubiquinone side (rather than the substrate side) of complex I. 

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. 

P. Mitchell (Nobel Prize for Chemistry, 1978) explained these facts by his chemiosmotic theory. This theory is based on the ordering of successive oxidation processes into reaction sequences called loops. Each loop consists of two basic processes, one of which is oriented in the direction away from the matrix surface of the internal membrane into the intracristal space and connected with the transfer of electrons together with protons. The second process is oriented in the opposite direction and is connected with the transfer of electrons alone. Figure 6.27 depicts the first Mitchell loop, whose first step involves reduction of NAD+ (the oxidized form of nicotinamide adenosine dinucleotide) by the carbonaceous substrate, SH2. In this process, two electrons and two protons are transferred from the matrix space. The protons are accumulated in the intracristal space, while electrons are transferred in the opposite direction by the reduction of the oxidized form of the Fe-S protein. This reduces a further component of the electron transport chain on the matrix side of the membrane and the process is repeated. The final process is the reduction of molecular oxygen with the reduced form of cytochrome oxidase. It would appear that this reaction sequence includes not only loops but also a proton pump, i.e. an enzymatic system that can employ the energy of the redox step in the electron transfer chain for translocation of protons from the matrix space into the intracristal space. 

We propose that the first step in the formation of quinones, as shown in Scheme 3 for BP, involves an electron transfer from the hydrocarbon to the activated cytochrome P-450-iron-oxygen complex. The generate nucleophilic oxygen atom of this complex would react at C-6 of BP in which the positive charge is appreciably localized. The 6-oxy-BP radical formed would then dissociate to leave the iron of cytochrome P-450 in the normal ferric state. Autoxidation of the 6-oxy-BP radical in which the spin density is localized mainly on the oxygen, C-l, C-3 and C-12 (19,20) would produce the three BP diones. 

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