Adenosine metabolites

FIGURE 1 7-3 Adenosine metabolites. Adenosine is converted to inosine by adenosine deaminase. Removal of the ribose by nucleoside phos phorylase produces hypoxanthine, which is sequentially oxidized to xanthine and uric acid by xanthine oxidase. 

Factors controlling calcium homeostasis are calcitonin, parathyroid hormone(PTH), and a vitamin D metabolite. Calcitonin, a polypeptide of 32 amino acid residues, mol wt - SGOO, is synthesized by the thyroid gland. Release is stimulated by small increases in blood Ca " concentration. The sites of action of calcitonin are the bones and kidneys. Calcitonin increases bone calcification, thereby inhibiting resorption. In the kidney, it inhibits Ca " reabsorption and increases Ca " excretion in urine. Calcitonin operates via a cyclic adenosine monophosphate (cAMP) mechanism. 

HPLC coupled to MS was used for the determination of dimethyl xanthine metabolites in plasma.82 There have also been a number of methods published on the use of HPLC with a PDA detector. In 1996, Mei published a method for the determination of adenosine, inosine, hypoxanthine, xanthine, and uric acid in microdialysis samples using microbore column HPLC with a PDA detector.63 In this method, samples were directly injected onto the HPLC without the need for any additional sample treatment. 

Ballarin, M., Fredholm, B. B., Ambrosio, S. Mahy, N. (1991). Extracellular levels of adenosine and its metabolites in the striatum of awake rats inhibition of uptake and metabolism. Acta Physiol. Scand. 142 (1), 97-103. 

Transfer of a methyl group from S-adenosylmethionine yields S-adenosylhomocysteine, which potently inhibits several methyltransferases this may partially explain the pathology of homocystinuria. Tissue levels of S-adenosylhomocysteine ordinarily are very low, since this metabolite is rapidly cleaved by a specific hydrolase to homocysteine and adenosine (Fig. 40-4 reaction 3). 

In the past decade, a large number of studies emphasized the heterogeneous scale-free degree distribution of metabolic networks Most substrates participate in only a few reactions, whereas a small number of metabolites ( hubs ) participate in a very large number of reactions [19,45,52]. Not surprisingly, the list of highly connected metabolites is headed by the ubiquitous cofactors, such as adenosine triphosphate (ATP), adenosine diphosphate (ADP), and nicotinamide adenine dinucleotide (NAD) in its various forms, as well as by intermediates of glycolysis and the tricarboxylic acid (TCA) cycle. 

Other nuclei, such as 13C or 31P, may be used to study other metabolite pools, or they can complement H-NMR to create more sophisticated NMR spectra. 13C-NMR provides a greater spectral range ( 200 ppm) than H-NMR ( 15 ppm). Although lower natural abundance of 13C (1.1%) yields lower sensitivity, it also provides an opportunity to use isotopic enrichment to trace specific metabolic pathways with enhanced sensitivity.4 31P can observe high-energy phosphate metabolites such as adenosine triphosphate. 

MTX also has several effects on the purine synthetic pathway. MTXPGs inhibit the enzyme aminoimidazole carboxamide ribonucleotide (AlCAR) transformylase, which in turn causes intracellular accumulation of AICAR. AICAR and its metabolites can then inhibit two enzymes in the adenosine pathway adenosine deaminase and adenosine monophosphate (AMP) deaminase, which leads to intracellnlar accumulation of adenosine and adenine nucleotides. Subsequent dephosphorylation of these nucleotides results in increased extracellular concentrations of adenosine, which is a powerful anti-inflammatory agent (11). 

The cell stores chemical energy in the form of energy-rich metabolites. The most important metabolite of this type is adenosine triphosphate (ATP), which drives a large number of energy-dependent reactions via energetic coupling (see p. 16). 

The sirtuins (silent information regulator 2-related proteins class III HDACs) form a specific class of histone deacetylases. First, they do not share any sequence or structural homology with the other HDACs. Second, they do not require zinc for activity, but rather use the oxidized form of nicotinamide adenine dinucleotide (NAD ) as cofactor. The reaction catalyzed by these enzymes is the conversion of histones acetylated at specific lysine residues into deacetylated histones, the other products of the reaction being nicotinamide and the metabolite 2 -0-acetyl-adenosine diphosphate ribose (OAADPR) [51, 52]. As HATs and other HDACs, sirtuins not only use acetylated histones as substrates but can also deacetylate other proteins. Intriguingly, some sirtuins do not display any deacetylase activity but act as ADP-ribosyl transferases. 

Theophylline, a dimethylxanthine, causes broncho-dilation, possibly by inhibiting the enzyme phosphodiesterase in smooth muscle of the bronchioli. An other proposed mechanism of action is that of adenosine receptor antagonism. It has positive chronotropic and inotropic, CNS stimulant and weak diuretic properties. In obstructive lung disease sustained release tablets are to be preferred. Theophy-line has a narrow therapeutic index. Therapeutic plasma concentrations are between 7-15 mg/1. Theophylline undergoes N-demethylation via CYPl A2 in the liver and is eliminated in the urine as metabolites... 

Mechanism of Action Aproton pump inhibitor that is converted to active metabolites that irreversibly bind to and inhibit hydrogen-potassium adenosine triphosphates, an enzyme on the surface of gastricparietal cells. Inhibits hydrogen ion transport into gastric lumen. Therapeutic Effect Increases gastricpH, reducing gastric acid production. 

Adenosine deaminase (ADA) was the first therapeutic enzyme coupled to PEG with the aim of reducing clearance and thereby overcoming the short half-life of ADA. Patients deficient in ADA are unable to regulate purine metabolism. As a result purine metabolites (e.g., adenosine monophosphate) accumulate to cytotoxic levels in B-lymphocytes and lead to severe B-cell depletion that presents clinically as severe combined immunodeficiency syndrome (SCIDS). While intramuscular injection of unmodified ADA provides some relief, antibodies develop rapidly against the protein and prevent it from being useful as replacement therapy. Even in the absence of antibodies, unmodified ADA s plasma half-life is only a few minutes. 

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