Metabolism Krebs cycle

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... 

There have been attempts to unravel the mechanism of fluorouracil-induced hyperammonemia, lactic acidosis, and encephalopathy, a rare adverse effect associated with high-dose therapy. The cause is not known, although Krebs cycle metabolism is almost certainly involved (415,416). 

Compound 1080 is absorbed from the gastrointestinal tract, respiratory tract, mucous membranes, and wounds (Holstege et al, 2007). Different routes of exposure do not have a remarkable effect on toxicity. The mechanism of action for SMFA is blockage of the Krebs cycle. Metabolic activation by the formation of fluorocitrate is required a process known as lethal synthesis. Fluoroacetate is converted to fluoroacetyl-CoA and then converted by the enzyme... 

Glutamic acid is formed m most organisms from ammonia and a ketoglutaric acid a Ketoglutaric acid is one of the intermediates m the tricarboxylic acid cycle (also called the Krebs cycle) and arises via metabolic breakdown of food sources carbohy drates fats and proteins... 

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. 

NADH, which enters the Krebs cycle. However, during cerebral ischaemia, metabolism becomes anaerobic, which results in a precipitous decrease in tissue pH to below 6.2 (Smith etal., 1986 Vonhanweh etal., 1986). Tissue acidosis can now promote iron-catalysed free-radical reactions via the decompartmentalization of protein-bound iron (Rehncrona etal., 1989). Superoxide anion radical also has the ability to increase the low molecular weight iron pool by releasing iron from ferritin reductively (Thomas etal., 1985). Low molecular weight iron species have been detected in the brain in response to cardiac arrest. The increase in iron coincided with an increase in malondialdehyde (MDA) and conjugated dienes during the recirculation period (Krause et al., 1985 Nayini et al., 1985). 

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...

G. Wachtershauser formulated his suggestions on the initial metabolic processes on the primeval Earth (as described above) in the form of six postulates and eleven theses (Wachtershauser, 1990b). Laboratory experiments planned to check, and perhaps confirm, these theories have already been attempted. The reductive Krebs cycle (rTCA cycle) has recently been the subject of much discussion. Smith and Morowitz consider that the rTCA cycle is a universal, possibly primordial, core process which could have provided substances for the synthesis of biomolecules on the young Earth (Smith and Morowitz, 2004). 

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. 

De Meirleir,L. Defects of pyruvate metabolism and the Krebs cycle. /. Child Neurol. 17(Suppl. 3) S26-S33,2002. 

We will now draw attention to the Krebs cycle otherwise called the tricarboxylic acid cycle (fig. 17). It is now known that carbohydrate metabolism and fatty acid metabolism as well as acetate proceed via changes indicated in the cycle. The essential... 

The Krebs cycle will only operate when the hydrogen atoms and electrons produced in the cycle enter the electron transfer chain, ultimately to react with oxygen that is, the two processes must take place simultaneously. A metabolic pathway is defined as a sequence of reactions that is initiated by a flux-generating step. In the cycle, citrate synthase catalyses the flux-generating reaction (Table 9.2) but there is no such reaction in the electron-transfer chain. Consequently, the cycle can be considered to be the first part of a longer pathway, which includes the electron transfer chain (Figure 9.3). 

Figure 9.6 Sequence of electron carriers in the electron transfer chain. The positions of entry into the chain from metabolism of glucose, glutamine, fatty acyl-CoA, glycerol 3-phosphate and others that are oxidised by the Krebs cycle are shown. The chain is usually considered to start with NADH and finish with cytochrome oxidase. FMN is flavin mononucleotide FAD is flavin adenine dinucleotide.

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). 

Fructose is converted to fructose 6-phosphate by hexo-kinase, which phosphorylates both glucose and fructose. It then is converted to pyruvate via glycolysis, which is converted to acetyl-coenzyme-A in the mitochondria for oxidation by the Krebs cycle. The enzyme that is specific for fructose metabolism, fructokinase, has not been found in... 

Citric acid has three prochiral centres The Krebs cycle is a process involved in the metabolic degradation of carbohydrate (see Section 15.3). It is also called the ciU ic acid cycle, because citric acid was one of the first intermediates identified. Once formed, citric acid is modified by the enzyme aconitase through the intermediate... 

As we look at some of the reactions of intermediary metabolism, we shall rationahze them in terms of the chemistry that is taking place. In general, we shall not consider here the involvement of the enzyme itself, the binding of substrates to the enzyme, or the role played by the enzyme s amino acid side-chains. In Chapter 13 we looked at specific examples where we know just how an enzyme is able to catalyse a reaction. Examples such as aldolase and those phosphate isomerase, enzymes of the glycolytic pathway, and citrate synthase from the Krebs cycle were considered in some detail. It may... 

Acetyl-CoA (see Box 10.8) is a thioester of acetic acid with coenzyme A. It is a remarkably common intermediate in many metabolic degradative and synthetic pathways, for which the reactivity of the thioester fnnction plays a critical role. There are two major sonrces of the acetyl-CoA entering the Krebs cycle glycolysis via the oxidative... 

There follows cleavage of acetyl-CoA from the end of the chain via a reverse Claisen reaction (see Box 10.15). This requires use of a molecule of coenzyme A as nucleophile, with the loss of the enolate anion of acetyl-CoA as leaving group. The net result is production of a new fatty acyl-CoA that is two carbons shorter than the original, and a molecule of acetyl-CoA that can be metabolized via the Krebs cycle. 

This is undoubtedly why low-carbohydrate diets have proved so effective for rapid weight loss. As soon as the reserves of carbohydrate are used up, the body resorts to metabolizing fat for its energy needs. This continues whenever carbohydrate intake is limited. It should also be appreciated that although carbohydrate can readily be converted into fat (via acetyl-CoA see Section 15.5), fat is not readily converted into carbohydrate in animals. Fat metabolism produces acetyl-CoA, which is then usually metabolized completely via the Krebs cycle. 

---