Metabolism oxidative phosphorylation

The active form is undissociated acid (pJC = 4.19 at 25 °C), which is about 100 times more effective than its anion. The antimicrobial effect is probably due to inhibition of amino acid utility by microorganisms, inhibition of transport of substrates and inhibition of enzymes involved in the acetic acid metabolism, oxidative phosphorylation and the citric acid cycle. 

ATP is derived primarily from oxidative metabolism (oxidative phosphorylation in the respiratory chain). 

The combustion of the acetyl groups of acetyl-CoA by the citric acid cycle and oxidative phosphorylation to produce COg and HgO represents stage 3 of catabolism. The end products of the citric acid cycle, COg and HgO, are the ultimate waste products of aerobic catabolism. As we shall see in Chapter 20, the oxidation of acetyl-CoA during stage 3 metabolism generates most of the energy produced by the cell. 

Although the interior of a prokaryotic cell is not subdivided into compartments by internal membranes, the cell still shows some segregation of metabolism. For example, certain metabolic pathways, such as phospholipid synthesis and oxidative phosphorylation, are localized in the plasma membrane. Also, protein biosynthesis is carried out on ribosomes. 

The processes of electron transport and oxidative phosphorylation are membrane-associated. Bacteria are the simplest life form, and bacterial cells typically consist of a single cellular compartment surrounded by a plasma membrane and a more rigid cell wall. In such a system, the conversion of energy from NADH and [FADHg] to the energy of ATP via electron transport and oxidative phosphorylation is carried out at (and across) the plasma membrane. In eukaryotic cells, electron transport and oxidative phosphorylation are localized in mitochondria, which are also the sites of TCA cycle activity and (as we shall see in Chapter 24) fatty acid oxidation. Mammalian cells contain from 800 to 2500 mitochondria other types of cells may have as few as one or two or as many as half a million mitochondria. Human erythrocytes, whose purpose is simply to transport oxygen to tissues, contain no mitochondria at all. The typical mitochondrion is about 0.5 0.3 microns in diameter and from 0.5 micron to several microns long its overall shape is sensitive to metabolic conditions in the cell. 

Mechanistic studies have shown that TBT and certain other forms of trialkyltin have two distinct modes of toxic action in vertebrates. On the one hand they act as inhibitors of oxidative phosphorylation in mitochondria (Aldridge and Street 1964). Inhibition is associated with repression of ATP synthesis, disturbance of ion transport across the mitochondrial membrane, and swelling of the membrane. Oxidative phosphorylation is a vital process in animals and plants, and so trialkyltin compounds act as wide-ranging biocides. Another mode of action involves the inhibition of forms of cytochrome P450, which was referred to earlier in connection with metabolism. This has been demonstrated in mammals, aquatic invertebrates and fish (Morcillo et al. 2004, Oberdorster 2002). TBTO has been shown to inhibit P450 activity in cells from various tissues of mammals, including liver, kidney, and small intestine mucosa, both in vivo and in vitro (Rosenberg and Drummond 1983, Environmental Health Criteria 116). 

Glucose is metabolized to pyruvate by the pathway of glycolysis, which can occur anaerobically (in the absence of oxygen), when the end product is lactate. Aerobic tissues metabolize pyruvate to acetyl-CoA, which can enter the citric acid cycle for complete oxidation to CO2 and HjO, linked to the formation of ATP in the process of oxidative phosphorylation (Figure 16-2). Glucose is the major fuel of most tissues. 

Pathways are compartmentalized within the cell. Glycolysis, glycogenesis, glycogenolysis, the pentose phosphate pathway, and fipogenesis occur in the cytosol. The mitochondrion contains the enzymes of the citric acid cycle, P-oxidation of fatty acids, and of oxidative phosphorylation. The endoplasmic reticulum also contains the enzymes for many other processes, including protein synthesis, glycerofipid formation, and dmg metabolism. 

The major biochemical features of neutrophils are summarized in Table 52-8. Prominent feamres are active aerobic glycolysis, active pentose phosphate pathway, moderately active oxidative phosphorylation (because mitochondria are relatively sparse), and a high content of lysosomal enzymes. Many of the enzymes listed in Table 52-4 are also of importance in the oxidative metabolism of neutrophils (see below). Table 52-9 summarizes the functions of some proteins that are relatively unique to neutrophils. 

The first is cell injury (cytotoxicity), which can be severe enough to result in cell death. There are many mechanisms by which xenobiotics injure cells. The one considered here is covalent binding to cell macromol-ecules of reactive species of xenobiotics produced by metabolism. These macromolecular targets include DNA, RNA, and protein. If the macromolecule to which the reactive xenobiotic binds is essential for short-term cell survival, eg, a protein or enzyme involved in some critical cellular function such as oxidative phosphorylation or regulation of the permeability of the plasma membrane, then severe effects on cellular function could become evident quite rapidly. 

This potential, or protonmotive force as it is also called, in turn drives a number of energy-requiring functions which include the synthesis of ATP, the coupling of oxidative processes to phosphorylation, a metabohc sequence called oxidative phosphorylation and the transport and concentration in the cell of metabolites such as sugars and amino acids. This, in a few simple words, is the basis of the chemiosmotic theory linking metabolism to energy-requiring processes. 

The mechanism for the production of O2" in ischaemic tissue appears to involve changes in purine metabolism within ischaemic cells. Sublethal hypoxia decelerates mitochondrial oxidative phosphorylation, rendering the production of ATP dependent upon the... 

It is misleading to consider that ROS are always deleterious, and that to prevent release or action of ail ROS will be of therapeutic value. One could reason that some ROS are released without control or purpose, as by-products of the normal metabolism of eicosanoids, or during oxidative phosphorylation in the mitochondria. However, during normal function, inflammatory ceUs appropriately release ROS both intracellularly into vacuoles and extracellularly in order to kill foreign organisms in host defence. Also, nitric oxide is a radical species whose principal role in the lung appears to be the control of pulmonary vascular tone and platelet function. Nevertheless, there are clear examples where fhistrated phagocytosis could explain an excessive release of ROS in... 

During the recovery period from exercise, ATP (newly produced by way of oxidative phosphorylation) is needed to replace the creatine phosphate reserves — a process that may be completed within a few minutes. Next, the lactic acid produced during glycolysis must be metabolized. In the muscle, lactic acid is converted into pyruvic acid, some of which is then used as a substrate in the oxidative phosphorylation pathway to produce ATP. The remainder of the pyruvic acid is converted into glucose in the liver that is then stored in the form of glycogen in the liver and skeletal muscles. These later metabolic processes require several hours for completion. 

All the ATP comes from oxidative phosphorylation coupled to the metabolism of acetyl-CoA by the TCA cycle. No oxygen, no p oxidation. 

Cells that do not have mitochondria (such as red blood cells) must use glucose for energy since they have no TCA cycle or oxidative phosphorylation. Without a constant glucose supply, these cells would die. The brain relies heavily on glucose metabolism for energy however, the brain can adapt to use alternative energy sources if glucose is not available. 

The biochemical classification of mitochondrial DNA is based on the five major steps of mitochondrial metabolism. These steps are illustrated in Figure 42-3 and divide mitochondrial diseases into five groups defects of mitochondrial transport, defects of substrate utilization, defects of the Krebs cycle, defects of the respiratory chain and defects of oxidation-phosphorylation coupling. 

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