Nucleotide coenzymes metabolism

Veech R (1987) Pyridine nucleotides and control of metabolic processes. In Dolphin D, Avromovic O, Poulson R (eds) Pyridine nucleotide coenzymes. Wiley, New York, p 79... 

Fig. 2.8. Factors controlling the production of free radicals in cells and tissues (Rice-Gvans, 1990a). Free radicals may be generated in cells and tissues through increased radical input mediated by the disruption of internal processes or by external influences, or as a consequence of decreased protective capacity. Increased radical input may arise through excessive leukocyte activation, disrupted mitochondrial electron transport or altered arachidonic acid metabolism. Delocalization or redistribution of transition metal ion complexes may also induce oxidative stress, for example, microbleeding in the brain, in the eye, in the rheumatoid joint. In addition, reduced activities or levels of protectant enzymes, destruction or suppressed production of nucleotide coenzymes, reduced levels of antioxidants, abnormal glutathione metabolism, or leakage of antioxidants through damaged membranes, can all contribute to oxidative stress.

The metabolic function of the flavin coenzymes is as electron carriers in a wide variety of oxidation and reduction reactions central to aU metabolic processes, including the mitochondrial electron transport chain. Unlike the nicotinamide nucleotide coenzymes (Section 8.4.1), which act as cosubstrates, leaving the catalytic site of the enzyme at the end of the reaction, the flavin coenzymes remain bound to the enzyme throughout the catalytic cycle. 

It is not strictly correct to regard niacin as a vitamin. Its metabolic role is as the precursor of the nicotinamide moiety of the nicotinamide nucleotide coenzymes, nicotinamide adenine dinucleotide (NAD) and NADP, and this can also be synthesized in vivo from the essential amino acid tryptophan. At least in developed countries, average intakes of protein provide more than enough tryptophan to meet requirements for NAD synthesis without any need for preformed niacin. It is only when tryptophan metabolism is disturbed, or intake of the amino acid is inadequate, that niacin becomes a dietary essential. 

Apart from the relatively small amounts that are required for synthesis of the neurotransmitter serotonin (5-hydroxytryptamine), and for net new protein synthesis, essentially the whole of the dietary intake of tryptophan is metabolized by way of the oxidative pathway shown in Figures 8.4 and 9.4, which provides both a mechanism for total catabolism by way of acetyl coenzyme A and a pathway for synthesis of the nicotinamide nucleotide coenzymes (Section 8.3). 

Structures of the D-ribofuranose-5-phosphate nucleotide coenzymes that are important in biochemical metabolism... 

In the metabolism of the aromatic amino acid tryptophan in mammals, two pathways for the formation of pyridine nucleotide coenzyme and in-doleamines are initiated by two well-known oxygenases, tryptophan 2,3-dioxygenase and tryptophan-5-hydroxylase (monooxygenase) (Fig. 2). Kotake and Ito (5) found in 1937 that rabbits fed D-tryptophan excreted D-kynurenine in the urine. Although the tryptophan-cleaving activity in... 

Hydrogen tranter see Hydrogen metabolism. Pyridine nucleotide coenzymes Hydrolases see Enzymes, Table 1. 

The phosphates of the four ribonucleosides represented in RNA are found in virtually all cells, with erythrocytes being exceptional in that not all four ribonucleosides are represented in some nonnucleated cells. Nucleotide coenzymes and conjugated nucleotides are present in patterns which are characteristic of the tissue sample. These compounds are all nucleoside 5 -phosphate esters and the triphosphates are the most abundant species under conditions adequate for the mainteiiance of cellular energy metabolism. The nucleotide composition of a variety of animal tissues is discussed by Mandel (22) we will consider only several. 

Singer, T. P. Kearney, E. K. (1954). Chemistry, metabolism and scope of action of the pyridine nucleotide coenzymes. Advances in Enzymology 15, 79-139. 

The fact that nuclei do contain enzymes likely to be involved in nucleoside metabolism (nucleoside phosphorylase, adenosine deaminase, and guanase), together with the fact that nucleoside phosphorylase catalyzes the formation of nicotinamide ribosides, leads the authors to point out the possible role of the nucleus in controlling the formation of di- and triphos-phopyridine nucleotide coenzymes. 

In some metabolic oxidation and reduction reactions the hydrogen acceptor or donor is a prosthetic group, e.g. haem (section 2.4.1.1) or riboflavin (section 2.4.1.2). In other cases, the hydrogen acceptor or donor acts as a substrate of the enzyme (e.g. the nicotinamide nucleotide coenzymes section 2.4.1.3). 

As shown in Figure 11.13, the nicotinamide nucleotide coenzymes can be synthesized from either of the niacin vitamers, and from quinolinic acid, an intermediate in the metabolism of tryptophan. In the liver, the oxidation of tryptophan results in a considerably greater synthesis of NAD than is required, and this is catabolized to release nicotinic acid and nicotinamide, which are taken up and used by other tissues for synthesis of the coenzymes. 

The third reaction, the oxidation of cysteine sulfinate, proceeds differently in Proteus vulgaris and in animal tissues. As shown by Singer and Kearney 18,20) the Proteus enzyme system oxidizes it directly to cysteate. This oxidation requires a pyridine nucleotide coenzyme which appears to be closely related to DPN+ 23). On the other hand, in rat liver mitochondria a soluble enzyme system oxidizes L-cysteine sulfinate in the presence of DPN+ to j8-sulfinylpyruvate and NH3 20). This reaction is analogous to that catalyzed by glutamic dehydrogenase [see Eq. (7)]. There is some indication that kidney n-amino acid oxidase can also oxidize cysteine sulfinate 24). Among these pathways of cysteine sulfinate metabolism the transaminative one is of the greatest importance. 

Transport of niacin between the liver and the intestine can occur in vivo, as indicated by radioactive probes in animals, and the liver appears to be a major site of conversion of niacin to its ultimate functional products the nicotinamide nucleotide coenzymes. Nicotinamide can pass readily between the cerebrospinal fluid and the plasma, thus ensuring a supply also to the brain and spinal cord. Liver contains greater niacin coenzyme concentrations than most other tissues, but all metabolically active tissues contain these essential... 

For most of the metabolic reactions in which fatty acids take part, whether they be anabolic (synthetic) or catabolic (degradative), thermodynamic considerations dictate that the acids be activated . For these reactions thiol esters are generally utilized. The active form is usually the thiol ester of the fatty acid with the complex nucleotide, coenzyme A (CoA) or the small protein known as acyl carrier protein (ACP) (Figure 3.5). These molecules contain a thiol ester and, at the same time, render the acyl chains water soluble. 

Xanthobacter sp. strain Py2 may be grown with propene or propene oxide. On the basis of amino acid sequences, the monooxygenase that produces the epoxide was related to those that catalyzes the monooxygenation of benzene and toluene (Zhou et al. 1999). The metabolism of the epoxide is initiated by nucleophilic reaction with coenzyme M followed by dehydrogenation (Eigure 7.13a). There are alternative reactions, both of which are dependent on a pyridine nucleotide-disulfide oxidoreductase (Swaving et al. 1996 Nocek et al. 2002) ... 

This is a complex molecule, made up of an adenine nucleotide (ADP-3 -phosphate), pantothenic acid (vitamin B5), and cysteamine (2-mercaptoethylamine), but for mechanism purposes can be thought of as a simple thiol, HSCoA. Pre-eminent amongst the biochemical thioesters is the thioester of acetic acid, acetyl-coenzyme A (acetyl-CoA). This compound plays a key role in the biosynthesis and metabolism of fatty acids (see Sections 15.4 and 15.5), as well as being a building block for the biosynthesis of a wide range of natural products, such as phenols and macrolide antibiotics (see Box 10.4). 

Coenzyme A (see also p. 106) is a nucleotide with a complex structure (see p. 80). It serves to activate residues of carboxylic acids (acyl residues). Bonding of the carboxy group of the carboxylic acid with the thiol group of the coenzyme creates a thioester bond (-S-CO-R see p. 10) in which the acyl residue has a high chemical potential. It can therefore be transferred to other molecules in exergonic reactions. This fact plays an important role in lipid metabolism in particular (see pp. 162ff), as well as in two reactions of the tricarboxylic acid cycle (see p. 136). 

ATP and the other nucleoside triphosphate coenzymes not only transfer phosphate residues, but also provide the nucleotide components for this type of activation reaction. On this page, we discuss metabolites or groups that are activated in the metabolism by bonding with nucleosides or nucleotides. Intermediates of this type are mainly found in the metabolism of complex carbohydrates and lipids. 

Folate, the anion of folic acid, is made up of three different components—a pteridine derivative, 4-aminobenzoate, and one or more glutamate residues. After reduction to tetrahydrofolate (THF), folate serves as a coenzyme in the Q metabolism (see p. 418). Folate deficiency is relatively common, and leads to disturbances in nucleotide biosynthesis and thus cell proliferation. As the precursors for blood cells divide particularly rapidly, disturbances of the blood picture can occur, with increased amounts of abnormal precursors for megalocytes megaloblastic anemia). Later, general damage ensues as phospholipid... 

The hydrogenosomal membrane displays selective permeability, thereby presenting an effective barrier to pyridine nucleotides and coenzyme A (Cerkasovov et al. 1978 Lindmark and Muller 1973 Muller 1973 Steinbiichel and Muller 1986). Transport of metabolic substrates and products across the hydrogenosomal membrane remains to be studied, but isolated T. foetus hydrogenosomes were shown to readily accumulate both radiolabeled pyruvate and malate (our unpublished data). 

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