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учебное пособие биохимия английский вариант.doc
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Inhibition of oxidative phosphorylation.

Various substances are known to inhibit formation of ATP without interrupting transport of hydrogen or electrons through the respiratory chain. This phenomenon is known as “uncoupling” of oxidative phosphorylation. The important examples of such uncouples are dinitrophenol, dicoumaral, v.K antagonists, a glycoside (atractyloside), thyroxine.

Normally the process of oxidation and phosphorylation are coupled in such a way, that about 42% of the energy released in oxidation-reduction is trapped as useful energy in the form of ATP. Some energy is used by the mitochondria themselves for doing osmotic work and for mechanical work, contraction.the remaining energy appears as heat and is used to warm the body at colder temperature. There are many substances like dinitrophenol, some antibiotics, thyroxine, arsenate, bilirubin, salicylates and v.K-antogonists, which can uncouple this process. These substances, called uncoupling agents, cause a decreased formation of ATP and relatively greater loss of energy as body heat.

The types of oxidation

The concept about oxidase’s type

80% of O2 is used for this type. It is also named biologic oxidation. It is a 1-st type of oxidation that is 1 molecule of O2 is reduced by 4 electrons. This type serves as source of energy which need for synthesis of ATP

Oxygenase’s type of oxidation

20% of O2 is used for other types of oxidation. This type occurs in 2 pathways – mono- and dioxygenetic. In the monooxygenase’s pathway the substrate is oxidized by 1 atom of oxygen, other atom is used for the formation of water. This pathway occurs in mitochondrions and microsomes. The formation of metabolic-active forms of vitamin D, cholesterol, bile acids and corticosteroids occurs in mitochondrions. The oxidation in microsomes is named microsomic. It can occur as hydroxylation (in participation of NADPH2). In this case the oxidated product containing OH group, water and NADP are formed. Microsomic oxidation occurs in microsomes of liver. In this kind of oxidation the multienzymatic membrane’s system including NADPH2, FP and CytP450 participate. This type of oxidation is a preventive reaction of the body because the oxidation of different xenobiotics occurs. In dioxygenase’s pathwway the including of whole molecule of O2 in substrate occurs. Usually it occurs with substances having unsaturated bonds, for example, PUFA. The including of O2 occurs in site of rupture of double bond: S + O2 --> SO2.

Peroxide’s type of oxidation or free radical or lipid peroxidation (LPO)

It occurs in 1 electron reduction of O2. PUFA undergo to this type too. LPO is iniciated under action of active forms of O2 (AFO) such as superoxideanion, peroxide radical, hydroxy radical, radical of NO, hypochlorite anion etc. AFO are formed in the interaction of O2 with metals of variable valency: O2 + Fe++ ·O2 + Fe+++

Superoxide anion

2H+ + ·O2 + ·O2 ----- H2O2 + O2 (SOD)

H2O2 2H2O + O2 (catalase)

H2O2 + ·O2 -- ·OH + OH + O2 (Haber-Weis reaction)

H2O2 + HCl H2O + HOCl (myeloperoxidase)

2GSH + ROOH GSSG + H2O +ROH (GPO)

GSSG 2GSH (with NADPH2 and GR)

Hydrogen peroxide (H2O2) interacting with ·O2 can form ·OH. AFO are dangerous for cells in a large amount. ·O2 can cause the depolymerization of GAG, oxidation of epinephrine and thiols. Hydrogen peroxide is toxic too. Its excess causes the oxidation of thiogroups of proteins and can lead to formation of ·OH. The main danger of AFO is their ability to initiate LPO.

LPO has a chain character. In normal conditions LPO occurs in a small scale and is necessary for: 1) formation of prostanoids; 2) utilization of PUFA. Proteins and nucleic acids undergo to LPO too. It causes a derangement of their functions. A high velocity of LPO is able to cause the damage of membrane and death of cells. But in small scale LPO is necessary for renew of cells membranes. The velocity of LPO is controlled by antioxidant system (AOS). It is divided into enzymatic and nonenzymatic. To enzymatic AOS are referred: 1) SOD which translates ·O2 to H2O2: 2·O2 + 2H+  H2O2 + O2; 2) catalase which breaks H2O2 to water and O2; 3) glutathione peroxidase (GPO) which reduces the hydroperoxides of lipids to oxiacids. in the result of reaction the oxidated glutathione (GSSG) and water are formed; 4) glutathione reductase (GR) reducing the oxidated glutathione. The cells of animals usually contain a large quantity of reduced and less quantity of oxidated glutathione. There are also present mix disulfides of reduced glutathione with proteins in the cells.

Fat soluble vitamins, vitamin C, P, B2, carnosine (which neutralizes ·OH), ferritin (binds Fe++ ), ceruloplasmin (binds Cu++ ), metalothineins (bind some metals), taurine (neutralizes OHCl) are referred to nonenzymatic AOS.