BIOCHEMISTRY: A TEXTBOOK FOR MEDICAL UNIVERSITIES - E.S. Severin - 2004

SECTION 6. ENERGY METABOLISM

IV. Formation of Toxic Oxygen Species in the ETC

About 90% of the O₂ entering Cells is consumed in the ETC. The remainder of O₂ is utilized in other oxidation-reduction reactions. Enzymes involved in redox reactions utilizing oxygen are divided into two groups: oxidases and oxygenases.

Oxidases use molecular oxygen solely as an electron acceptor, reducing it to H₂O or H₂O₂.

Oxygenases incorporate one (Monooxygenases) or two (Dioxygenases) oxygen atoms into the resulting reaction product.

Although these reactions are not coupled with ATP synthesis, they are essential for many specific reactions in Amino acid METABOLISM (see Section 9), the synthesis of Bile acids and Steroids (see Sections 8, 11), and xenobiotic detoxification reactions in the Liver (see Section 12).

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

In its unexcited state, oxygen is non-toxic. The formation of toxic oxygen species is related to the Specific features of its molecular Structure. O₂ contains two unpaired electrons with parallel spins, which cannot form a thermodynamically stable pair and occupy different orbitals. Each of these orbitals can accept one more electron.

Complete reduction of O₂ occurs As a result of four single-electron transfers:

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Superoxide, peroxide, and the hydroxyl radical are potent oxidizing agents, posing a serious threat to many Structural components of The Cell (Fig. 6-30).

Fig. 6-30. Damaging effect of free radicals on cellular components. 1 — protein destruction; 2 — ER damage; 3 — destruction of the nuclear membrane and DNA damage; 4 — destruction of mitochondrial membranes; 5 — Lipid Peroxidation (LPO) of The cell membrane; 6, 7, 8 — influx of Water and ions into the cell.

Reactive oxygen species can Abstract electrons from many compounds, converting them into new free radicals and initiating chain oxidation reactions (see Section 8).

Most reactive oxygen species are generated during electron transfer in the ETC, primarily through the functioning of the QH₂-dehydrogenase complex. This occurs as a result of non-enzymatic electron transfer (“leakage”) from QH₂ to oxygen (Fig. 6-31).

Fig. 6-31. Superoxide formation in the ETC. Electron "leakage" in the ETC can occur during electron transfer involving coenzyme Q. Upon reduction, ubiquinone is converted into the semiquinone radical anion. This radical non-enzymatically interacts with O₂ to form the superoxide radical. Complex II is not shown in the figure.

Unlike the mechanism discussed above, electron "leakage" does not occur during electron transfer mediated by cytochrome c oxidase (Complex IV) 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), oxygen consumption and the generation of active radicals increase during phagocytosis. Reactive oxygen species are produced as a result of NADPH oxidase activation, predominantly localized on the outer surface of The Plasma Membrane, initiating the so-called "respiratory burst" with the formation of reactive oxygen species (see Section 14).

The body's defense against the Toxic effects of reactive oxygen species relies on the presence of highly specific enzymes in all cells—superoxide dismutase, catalase, and Glutathione peroxidase—as well as the action of antioxidants (see Section 8).