Citric acid metabolism

More than a dozen biocompatible and biodegradable polymers have been described and studied for their potential use as carriers for therapeutic proteins (Table 13.5). However, some of the monomer building blocks such as acrylamide and its derivatives are neurotoxic. Incomplete polymerization or breakdown of the polymer may result in toxic monomer. Among the biopolymers, poly-lactide cofabricated with glycolide (PLG) is one of the most well studied and has been demonstrated to be both biocompatible and biodegradable [12]. PLG polymers are hydrolyzed in vivo and revert to the monomeric forms of glycolic and lactic acids, which are intermediates in the citric acid metabolic pathway. 

To obtain citric acid as the metabolic product again requires interference with the normal Krebs tricarboxylic acid cycle in such a way that citric acid metabolism is blocked. Usually this is achieved by careful regulation of concentrations of trace metals available as coenzymes to the various enzyme pathways used by A. niger, so that some of these are rendered ineffective (are blocked). 

Extensive work has been done on modifications of citric acid metabolism, which appear especially interesting because of the interrelationship between citrate and calcium in blood and urine, and of the numerous factors which are known to affect the citrate level in normal subjects. 

MIO. M rtenson, J., On the citric acid metabolism in mammals. Acta Physiol. Scand. 1, Suppl. 2, 1 (1940). 

Despite the postulated connection between parathyroid hormone activity and citric acid metabolism, plasma citrate concentration is normal in cases of hyperparathyroidism unless there is active bone disease present, in which case it may be raised (Wl). Plasma alkaline phosphatase is also raised only in the presence of active osteitis fibrosa. 

The citric acid metabolism products are therefore very diverse. Whatever the conditions, more than a molecule of acetic acid is surely formed from a substrate molecule. The production of others is largely determined by factors influenced by growth conditions. In limited glucose concentration conditions, a low pH and the presence of growth inhibitors, citric acid preferentially leads to the formation of acetoinic substances. In fact, due to conditions, pyruvate is orientated neither... 

Wine lactic acid bacteria can degrade tartaric acid, but this metabolism differs from malic and citric acid metabolisms. It is a veritable bacterial spoilage. Pasteur described it in the last century and named it tourne disease. It is dangerous since the disappearance of tartaric acid, an essential acid in wine, lowers the fixed acidity and is accompanied by an increase in the volatile acidity. The degradation can be total or partial, depending on the level of bacterial development, but it always lowers wine quality. 

The conversion of pyruvate to acetyl CoA catalyzed by pyruvate dehydrogenase complex serves as a link between glycolysis and the tricarboxylic acid (Krebs or citric acid) metabolic cycle [3-5]. The pivotal role of the PDHc is shown in Scheme 1.1 [6]. 

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. 

Citric acid, a tricarboxylic acid important in intermediary metabolism, can be symbolized as H3A. Its dissociation reactions are... 

FIGURE 18.2 The metabolic map as a set of dots and lines. The heavy dots and lines trace the central energy-releasing pathways known as glycolysis and the citric acid cycle. 

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. 

Certain of the central pathways of intermediary metabolism, such as the citric acid cycle, and many metabolites of other pathways have dual purposes—they serve in both catabolism and anabolism. This dual nature is reflected in the designation of such pathways as amphibolic rather than solely catabolic or anabolic. In any event, in contrast to catabolism—which converges to the common intermediate, acetyl-CoA—the pathways of anabolism diverge from a small group of simple metabolic intermediates to yield a spectacular variety of cellular constituents. 

The following model is a representation of citric acid, the key substance in the so-called citric acid cycle by which food molecules are metabolized in the body. Only the connections between atoms are shown multiple bonds are not indicated. Complete the structure by indicating the positions of multiple bonds and lone-pair electrons (gray = C, red = O, ivory = H). 

Compounds called carboxylic acids, which contain the -C02H grouping, occur abundantly in all living organisms and are involved in almost all metabolic pathways. Acetic acid, pyruvic acid, and citric acid are examples. 

Vlaleic acid has a dipole moment, but the closely related fumaric acid, a substance involved in the citric acid cycle by which food molecules are metabolized, does not. Explain. 

Problem 5.9 Predict the products of the following polar reaction, a step in the citric acid cycle for food metabolism, by interpreting the flow of elections indicated by Uie curved arrows ... 

Acid-catalyzed hydration of isolated double bonds is also uncommon in biological pathways. More frequently, biological hydrations require that the double bond be adjacent to a carbonyl group for reaction to proceed. Fumarate, for instance, is hydrated to give malate as one step in the citric acid cycle of food metabolism. Note that the requirement for an adjacent carbonyl group in the addition of water is the same as that we saw in Section 7.1 for the elimination of water. We ll see the reason for the requirement in Section 19.13, but might note for now that the reaction is not an electrophilic addition but instead occurs... 

In contrast to laboratory reactions, enzyme-catalyzed reactions often give a single enantiomer of a chiral product, even when the substrate is achiral. One step in the citric acid cycle of food metabolism, for instance, is the aconitase-catalyzed addition of water to (Z)-aconitate (usually called ris-aconitate) to give isocitrate. 

A large number of biological reactions involve prochiral compounds. One of the steps in the citric acid cycle by which food is metabolized, for instance, is... 

Water can add reversibly to o ,/3-unsalurated aldehydes and ketones to yield /3-hydroxy aldehydes and ketones, although the position of the equilibrium generally favors unsaturated reactant rather than saturated adduct. A related addition to an c /S-unsaturated carboxylic acid occurs in numerous biological pathways, such as the citric acid cycle of food metabolism where ds-aconitate is converted into isocitrate by conjugate addition of water to a double bond. 

Isocitric acid, an intermediate in the citric acid cycle of food metabolism, has the systematic name (2/ ,3S)-3-carboxy-2-hydroxypentanedioic acid. Draw the structure. 

Enzymes work by bringing reactant molecules together, holding them, in the orientation necessary for reaction, and providing any necessary acidic or basic sites to catalyze specific steps. As an example, let s look at citrate synthase, an enzyme that catalyzes the aldol-like addition of acetyl CoA to oxaloacetate to give citrate. The reaction is the first step in the citric acid cycle, in which acetyl groups produced by degradation of food molecules are metabolized to yield C02 and H20. We ll look at the details of the citric acid cycle in Section 29.7. 

The primary fate of acetyl CoA under normal metabolic conditions is degradation in the citric acid cycle to yield C02. When the body is stressed by prolonged starvation, however, acetyl CoA is converted into compounds called ketone bodies, which can be used by the brain as a temporary fuel. Fill in the missing information indicated by the four question marks in the following biochemical pathway for the synthesis of ketone bodies from acetyl CoA ... 

Citric acid cycle (Section 29.7) The metabolic pathway by which acetyl CoA is degraded to CO2. 

Ethanol is oxidized by alcohol dehydrogenase (in the presence of nicotinamide adenine dinucleotide [NAD]) or the microsomal ethanol oxidizing system (MEOS) (in the presence of reduced nicotinamide adenine dinucleotide phosphate [NADPH]). Acetaldehyde, the first product in ethanol oxidation, is metabolized to acetic acid by aldehyde dehydrogenase in the presence of NAD. Acetic acid is broken down through the citric acid cycle to carbon dioxide (CO2) and water (H2O). Impairment of the metabolism of acetaldehyde to acetic acid is the major mechanism of action of disulfiram for the treatment of alcoholism. 

Generally, NAD-linked dehydrogenases catalyze ox-idoreduction reactions in the oxidative pathways of metabolism, particularly in glycolysis, in the citric acid cycle, and in the respiratory chain of mitochondria. NADP-linked dehydrogenases are found characteristically in reductive syntheses, as in the extramitochon-drial pathway of fatty acid synthesis and steroid synthesis—and also in the pentose phosphate pathway. 

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. 

The amino acids are required for protein synthesis. Some must be supplied in the diet (the essential amino acids) since they cannot be synthesized in the body. The remainder are nonessential amino acids that are supplied in the diet but can be formed from metabolic intermediates by transamination, using the amino nitrogen from other amino acids. After deamination, amino nitrogen is excreted as urea, and the carbon skeletons that remain after transamination (1) are oxidized to CO2 via the citric acid cycle, (2) form glucose (gluconeogenesis), or (3) form ketone bodies. 

Nearly all products of digestion of carbohydrate, fat, and protein are metabolized to a common metabolite, acetyl-CoA, before final oxidation to CO2 in the citric acid cycle. 

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. 

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