BIOCHEMISTRY - Textbook - Ostapchenko L. I. - 2012

Chapter 16. ENERGY METABOLISM

16.5. Generation of Reactive Oxygen Species in the ETC

The ETC consumes about 90 % of the O₂ entering The Cell. The remaining portion of O₂ is utilized in other redox reactions. Enzymes involved in oxygen-dependent redox reactions are divided into two groups: oxidases and oxygenases. Oxidases use molecular oxygen exclusively as an electron acceptor, reducing it to H₂O or H₂O₂. Oxygenases incorporate either one (Monooxygenases) or two (Dioxygenases) oxygen atoms into the resulting reaction product.

Although these reactions are not accompanied by ATP synthesis, they are essential for many specific pathways involving Amino acid METABOLISM, Bile acid and steroid synthesis, and the detoxification of xenobiotics in the Liver.

In most reactions involving molecular oxygen, reduction proceeds stepwise with The transfer of a single electron at each step. This univalent electron transfer leads to The formation of highly reactive intermediate oxygen species.

In its unexcited state, molecular oxygen is non-toxic. The formation of its toxic derivatives is related to the peculiarities of its molecular Structure. O₂ contains two unpaired electrons with parallel spins that cannot form a thermodynamically stable pair and are located in different orbitals. Each of these orbitals can accept one more electron.

Complete reduction of O₂ occurs through four consecutive one-electron transitions:

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Superoxide, peroxide, and the hydroxyl radical are potent oxidizing agents that pose a serious threat to many Structural components of the cell (Fig. 16.18).

Reactive oxygen species (ROS) can Abstract electrons from numerous compounds, converting them into new free radicals and initiating chain oxidation reactions. A significant portion of ROS is generated during electron transport in the ETC, primarily through the functioning of the QH₂-dehydrogenase complex. This occurs As a result of the non-enzymatic transfer ("leakage") of electrons from QH₂ to oxygen (Fig. 16.19).

Unlike the mechanism observed during electron transfer mediated by cytochrome c oxidase (Complex IV), electron "leakage" is prevented here due to the presence of specialized active centers in the enzyme containing Fe and Cu, which reduce O₂ without releasing intermediate free radicals.

In phagocytic leukocytes (granulocytes, macrophages, and eosinophils), phagocytosis is accompanied by enhanced oxygen uptake and the generation of active radicals. Reactive oxygen species are produced via the activation of NADPH oxidase, which is predominantly localized on the outer surface of The Plasma Membrane, triggering the so-called "respiratory burst" with the formation of ROS.

Fig. 16.18. Damaging effects of free radicals on cellular components:

1 - protein degradation; 2 - Endoplasmic reticulum damage;

3 - destruction of the nuclear membrane and DNA damage;

4 - mitochondrial membrane damage; 5 - Lipid Peroxidation (LPO) of The cell membrane;

6, 7, 8 - influx of Water and ions into the cell

Fig. 16.19. Superoxide generation in the ETC:

Electron "leakage" in the ETC can occur during coenzyme Q-mediated electron transfer. Upon reduction, ubiquinone is converted into a semiquinone radical anion. This radical non-enzymatically interacts with O₂ to yield the superoxide radical. Complex II is not shown in the figure

Cellular defense against the Toxic effects of ROS relies on the presence of highly specific enzymes in all Cells—superoxide dismutase, catalase, and Glutathione peroxidase—as well as the action of antioxidants.