Cells, Krebs cycle

Physiological Role of Citric Acid. Citric acid occurs ia the terminal oxidative metabolic system of virtually all organisms. This oxidative metabohc system (Fig. 2), variously called the Krebs cycle (for its discoverer, H. A. Krebs), the tricarboxyUc acid cycle, or the citric acid cycle, is a metaboHc cycle involving the conversion of carbohydrates, fats, or proteins to carbon dioxide and water. This cycle releases energy necessary for an organism s growth, movement, luminescence, chemosynthesis, and reproduction. The cycle also provides the carbon-containing materials from which cells synthesize amino acids and fats. Many yeasts, molds, and bacteria conduct the citric acid cycle, and can be selected for thek abiUty to maximize citric acid production in the process. This is the basis for the efficient commercial fermentation processes used today to produce citric acid. 

In the liver, the ketone bodies suffer no transformation, and are excreted into the blood. The normal contents of ketone bodies (as acetoacetate or P-hydroxy-butyrate) amount to mere 0.1-0.6 mmol/ litre). Other tissues and organs (heart, lung, kidney, muscle, and nervous tissue), as distinct from the liver, utilize the ketone bodies as energy substrates. In the cells of these tissues, acetoacetate and 1-hydroxybutyrate enter ultimately the Krebs cycle and burn down to C02 and H,0 to release energy. 

The surface metabolism hypothesis can also be used to deal with questions on the formation of the first cell structures for example, molecules required for the construction of cell membranes could have been formed via the so-called reductive Krebs cycle (citric acid cycle). 

Wachtcrshauser s prime candidate for a carbon-fixing process driven by pyrite formation is the reductive citrate cycle (RCC) mentioned above. Expressed simply, the RCC is the reversal of the normal Krebs cycle (tricarboxylic acid cycle TCA cycle), which is referred to as the turntable of metabolism because of its vital importance for metabolism in living cells. The Krebs cycle, in simplified form, can be summarized as follows ... 

Fig. 7.6 A greatly simplified representation of the normal Krebs cycle (a) which occurs in today s living cells and the corresponding reductive process (b), which was possibly important in the metabolism of evolving systems...

Fig. 4.7. A scheme for the organic pathways in the cytoplasm of all cells illustrating their interconnected nature (after Kauffman see Further Reading), (a) Glycolytic (b) Krebs cycle pathways.

Figure 6.1 Pathways involved in glucose oxidation by plant cells (a) glycolysis, (b) Krebs cycle, (c) mitochondrial cytochrome chain. Under anoxic conditions. Reactions 1, 2 and 3 of glycolysis are catalysed by lactate dehydrogenase, pyruvate decarboxylase and alcohol dehydrogenase, respectively. ATP and ADP, adenosine tri- and diphosphate NAD and NADHa, oxidized and reduced forms of nicotinamide adenine dinucleotide PGA, phosphoglyceraldehyde PEP, phosphoenolpyruvate Acetyl-CoA, acetyl coenzyme A FP, flavoprotein cyt, cytochrome e, electron. (Modified from Fitter and Hay, 2002). Reprinted with permission from Elsevier...

The flux through the Krebs cycle can be estimated from the oxygen consumption of a cell or tissue. This has been done in a single human muscle during maximum physical... 

In any cell that depends on aerobic metabolism, if the rate of ATP utilisation increases, the rate of the Krebs cycle, electron transfer and oxidative phosphorylation must also increase. The mechanism of regulation discussed here is for mammalian skeletal muscle since, to provide sufficient ATP to maintain the maximal power output, at least a 50-fold increase in flux through the cycle is required so that the mechanism is easier to study (Figure 9.22). 

The results for several organs are presented in Chapter 2. It is also possible from these data to calculate the actual flux through the Krebs cycle, since one turn of the cycle consumes one third of the total oxygen uptake by a cell, tissue or organ, if glucose is the only fuel. It is somewhat less if fat is the fuel. 

Figure 17.38 A simple diagram illustrating the two roles of glutamine (i) generation of ATP, via glutaminolysis, (ii) formation of purine and pyrimidine nucleotides, for the synthesis of nucleic acids in proliferating cells (Chapter 20). ( represents the carbon atoms of glutamine, one of which is released as CO2 and the others are converted to aspartate, via part of the Krebs cycle (Chapter 9). (N) represents the amide nitrogen of glutamine.

Critical for predictivity in a recent comprehensive study was the number and choice of parameters measured [4]. Early, sublethal effects on cell proliferation, cell morphology and mitochondria occurred consistently and ubiquitously with toxicity and when used collectively were most diagnostic. It is noteworthy that the toxicity of many drugs is attributable to various mitochondrial targets, including oxidative phosphorylation, fatty acid oxidation, Krebs cycling, membrane transport, permeability transition pore, proliferation and oxidative stress (Table 14.4). 

Fluoro amino acids have been incorporated into peptides, in order to ease the transport or reduce the systemic toxicity. Thus, trifluoroalanine, a powerful inhibitor of alanine racemase, is an essential enzyme for the biosynthesis of the cell wall of bacteria. It has a low antibiotic activity because of its very poor transport. In order to facilitate this transport, the amino acid has been incorporated into a peptide. This delivery allows a reduction of the doses, and thus the toxicity of the treatment is lowered.3-FIuorophenylaIanine (3-F-Phe) is a substrate of phenylalanine hydroxylase, which transforms it into 3-F-Tyr. 3-F-Tyr has a high toxicity for animals, due to its ultimate metabolization into fluorocitrate, a powerful inhibitor of the Krebs cycle (cf. Chapter 7). 3-F-Phe has a low toxicicity toward fungus cells, but when delivered as a tripeptide 3-F-Phe becomes an efficient inhibitor of the growth of Candida albicans. This tripeptide goes into the cell by means of the active transport system of peptides, where the peptidases set free the 3-F-Phe. ... 

Malaisse WJ, Zhang T-M, Verbruggen I, Willem R (1996) Enzyme to enzyme channeling of Krebs cycle metabolic intermediates in Caco-2 cells exposed to [2-13C]propionate. Biochem J 317 861-863... 

TCA CYCLE, (tricarboxylic acid cycle Krebs cycle or citric acid cycle). A series of enzymatic reactions occurring in living cells of aerobic... 

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