Metabolism, intermediary

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 

At physiological pH values, these groups will be ionized as shown, but in schemes where stmctures are given in full, the non-ionized acids are 

Essentials of Organic Chemistry Paul M De wick 2006 John WUey Sons, Ltd 

Ionized and non-ionized forms of many compounds are regarded as synonymous in the text, thus citrate/citric acid, acetate/acetic acid or others may be used according to the author s whim and context, and should not be considered as having any especial relevance. 

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

The net reaction catalyzed by this enzyme depends upon coupling between the two reactions shown in Equations (3.26) and (3.27) to produce the net reaction shown in Equation (3.28) with a net negative AG°. Many other examples of coupled reactions are considered in our discussions of intermediary metabolism (Part III). In addition, many of the complex biochemical systems discussed in the later chapters of this text involve reactions and processes with positive AG° values that are driven forward by coupling to reactions with a negative AG°. ... 

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. 

University of Illinois, isolated Just 30 mg of lipoic acid from approximately 10 tons of liver No evidence exists of a dietary lipoic acid requirement by humans stricdy speaking, it is not considered a vitamin. Nevertheless, it is an essential component of several enzymes of intermediary metabolism and is present in body tissues in small amounts. 

Dihydropteroic acid (85) is an intermediate to the formation of the folic acid necessary for intermediary metabolism in both bacteria and man. In bacteria this intermediate is produced by enzymatic condensation of the pteridine, 86, with para-amino-benzoic acid (87). It has been shown convincingly that sulfanilamide and its various derivatives act as a false substrate in place of the enzymatic reaction that is, the sulfonamide blocks the reaction by occupying the site intended for the benzoic acid. The lack of folic acid then results in the death of the microorganism. Mammals, on the other hand, cannot synthesize folic acid instead, this compound must be ingested preformed in the form of a vitamin. Inhibition of the reaction to form folic acid Ls thus without effect on these higher organisms. 

Biotin is involved in carboxylation and decarboxylation reactions. It is covalently bound to its enzyme. In the carboxylase reaction, C02 is first attached to biotin at the ureido nitrogen, opposite the side chain in an ATP-dependent reaction. The activated C02 is then transferred from carboxybiotin to the substrate. The four enzymes of the intermediary metabolism requiring biotin as a prosthetic group are pyruvate carboxylase (pyruvate oxaloacetate), propionyl-CoA-carboxylase (propionyl-CoA methylmalonyl-CoA), 3-methylcroto-nyl-CoA-carboxylase (metabolism of leucine), and actyl-CoA-carboxylase (acetyl-CoA malonyl-CoA) [1]. 

Several enzymes of the intermediary metabolism require thiaminpyrophosphate (TPP, Fig. 1) as coenzyme, e.g., enzymes of the pyruvate dehydrogenase complex, a-ketoglutarate dehydrogenase complex, or pentose phosphate pathway. 

Agius, L., Sherratt, H.S.A. (eds.) (1996). Channelling and intermediary metabolism. Portland Press, London. 

The importance of phosphates in intermediary metabolism became evident with the discovery of the role of ATP, adenosine diphosphate (ADP), and inorganic phosphate (Pj) in glycolysis (Chapter 17). 

Mayes PA Intermediary metabolism of fructose. Am J Clin Nutr... 

This system displays a two-enzyme kinetic model in which bioconversion is controlled by the interaction between the two reactions and the mass transfer. This situation offers a more realistic model for the conditions occurring in vivo, in which some pathways of intermediary metabolism consist of linear sequences of reactions. These pathways take place in highly organized compartments. 

In the overall metabolism of the living organism distinguished are exogenous metabolism, which comprises extracellular transformations of materials on the way to their uptake and excretion by the cells, and intermediary metabolism, which occurs in the cells. The intermediary metabolism is conceived as the sum total of chemical reactions that occur in the living cell. 

Barrett, J. (1976) Intermediary metabolism in Ascaris eggs. In Van den Bossche, H. (ed.) Biochemistry of Parasites and Host-Parasite Relationships. Elsevier, Amsterdam, pp. 117-123. 

The end product of the intermediary metabolism of fatty acids with an uneven number of carbons differs sharply from those formed after the breakdown of the even-chain fatty acids. Whereas glycogen is produced from the fatty acids having an uneven number of carbon atoms, those fatty acids with an even number of carbon atoms have no glycogenic activity, but, with the possible exception of acetic acid, they are all ketogenic and possess no ketolytic activity. 

Gut I, Nerudova J, Frantik E, et al. 1984. Acrylonitrile inhalation in rats I. Effect on intermediary metabolism. J Hyg Epidemiol Microbiol Immunol 28 369-376. 

Fraser PD, Enfissi EMA, Halket JM, Truesdale MR, Yu D, Gerrish C, Bramley PM. 2007. Manipulation of phytoene levels in tomato fruit effects on isoprenoids, plastids, and intermediary metabolism. Plant Cell 19 3194-3211. 

I 10. The answer is a. (Hardman, p 1302J Cyclophosphamide is classified as a poly functional alkylating drug that transfers its alkyl groups to cellular components. The cytotoxic effect of this agent is directly associated with the alkylation of components of DNA. Methotrexate and 5-FU are classified as anti metabolites that block intermediary metabolism to inhibit cell proliferation. Tamoxifen is an antiestrogen compound. Doxorubicin is classified as an antibiotic chemotherapeutic agent. 

Since the tragic human exposure to diethyltin salts for the therapy of an infectious skin disease by Staphylococcus in France in the 1950s, the toxic and biochemical effects of many of these derivatives have been explored. Di- and tri-ethyltin salts have been demonstrated to have pronounced effects on intermediary metabolism in brain and liver. These effects have been suggested to be due to inhibition of the mitochondrial functions9,27. 

Not included are other protein kinases present in diverse tissues, including brain, that play a role in generalized cellular processes, such as intermediary metabolism, and that may not play a role in neuron-specific phenomena. CAK, CDK-activating kinase ... 

This list is not intended to be comprehensive but to indicate the wide array of neuronal proteins regulated by phosphorylation. Some of the proteins are specific to neurons but most are present in many cell types in addition to neurons and are included because their multiple functions in the nervous system include the regulation of neuron-specific phenomena. Not included are the many phosphoproteins present in diverse tissues, including brain, that play a role in generalized cellular processes, such as intermediary metabolism, and that do not appear to play a role in neuron-specific phenomena. NMDA, N-methyl-D-aspartate CREB, cAMP response element-binding proteins STAT, signal-transducing activators of transcription ... 

FIGURE 28-5 Schematic illustration of the movement of cytoskeletal elements in slow axonal transport. Slow axonal transport represents the movement of cytoplasmic constituents including cytoskeletal elements and soluble enzymes of intermediary metabolism at rates of 0.2-2 mm/day which are at least two orders of magnitude slower than those observed in fast axonal transport. As proposed in the structural hypothesis and supported by experimental evidence, cytoskeletal components are believed to be transported down the axon in their polymeric forms, not as individual subunit polypeptides. Cytoskeletal polypeptides are translated on cytoplasmic polysomes and then are assembled into polymers prior to transport down the axon in the anterograde direction. In contrast to fast axonal transport, no constituents of slow transport appear to be transported in the retrograde direction. Although the polypeptide composition of slow axonal transport has been extensively characterized, the motor molecule(s) responsible for the movement of these cytoplasmic constituents has not yet been identified. 

Cytoplasmic and cytoskeletal elements move coherently at slow transport rates. Two major rate components have been described for slow axonal transport, representing movement of cytoplasmic constituents including cytoskeletal elements and soluble enzymes of intermediary metabolism [3]. Cytoplasmic and cytoskeletal elements in axonal transport move with rates at least two orders of magnitude slower than fast transport. 

Padmaja, G. and K.R. Panikkar. 1989. Intermediary metabolic changes in rabbits administered hnamarin or potassium cyanide. Indian Jour. Exper. Biol. 27 635-639. 

The introduction of the invertase from yeast alone was not sufficient. Invertase cleaves sucrose to release the two component sugars, glucose and fructose. While fructose can be readily metabolized by fructokinase in potato tubers, there is insufficient hexokinase activity in developing potato tubers to bring the glucose into intermediary metabolism. Therefore, it was necessary to introduce a second transgene, a bacterial glucokinase, in order to ensure that the hexoses became available for subsequent metabolism.25... 

Corticosteroids synthesized by the adrenal gland are mineralocorticoids and GC. Min-eralocorticoids regulate fluid and electrolyte balance by affecting ion transport in the kidney. Cortisol, the primary circulating GC in most species (including humans), has many activities, including resistance to stress, regulation of intermediary metabolism, and immunosuppressive and anti-inflammatory effects. GC synthesis and secretion is... 

While the enzymes involved in detoxication processes are nonspecific in the classical sense of intermediary metabolism, they often have distinct specificities both for organic functional groups and for the electronic, steric, and stereochemical environments where these functional groups are located. Enzyme specificity based on organic functional groups and their environments leads to a wide diversity in the alkaloid substrates possible and therefore the products obtained from biotransformation. This section of the chapter will concentrate principally on the enzymes themselves, including general concepts of substrate specificity and mechanism. 

Excretion. Some -hexane is exhaled following cessation of exposure. This could amount to approximately 10% of that absorbed (Mutti et al. 1984 Veulemans et al. 1982). Excretion is rapid and biphasic with half-lives of 0.2 hours and 1.7 hours. Most -hexane is excreted in the urine as metabolites. Radiolabeled 14C02 in exhaled air has been detected after animal exposure to l4C] -hexane (Bus et al. 1982), indicating that intermediary metabolism of some metabolites takes place. 2,5-Hexanedione and 4,5-dihydroxy-2-hexanone are the major urinary metabolites of -hexane in humans. Half-lives of excretion have been estimated to be 13-14 hours (Perbellini et al. 1981, 1986). 

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