Deaminase and

DiaZepin Nucleosides. Four naturally occurring dia2epin nucleosides, coformycin (58), 2 -deoxycoformycin (59), adechlorin or 2 -chloro-2 -deoxycoformycin (60), and adecypenol (61), have been isolated (1—4,174,175). The biosynthesis of (59) and (60) have been reported to proceed from adenosine and C-1 of D-ribose (30,176,177). They are strong inhibitors of adenosine deaminase and AMP deaminase (178). Compound (58) protects adenosine and formycin (12) from deamination by adenosine deaminase. Advanced hairy cell leukemia has shown rapid response to (59) with or without a-or P-interferon treatment (179—187). In addition, (59) affects interleukin-2 production, receptor expression on human T-ceUs, DNA repair synthesis, immunosuppression, natural killer cell activity, and cytokine production (188—194). 

C]-FlAC was synthesized from [2- C]cytosine in the general manner used for unlabeled 748 (FIAC), and its metabolic fate in mice was studied. The compound (after i.v. injection) was deaminated by cytosine nucleoside deaminase and appeared as [2- C]-FIAU in plasma, as confirmed by experiments on rats having a very low level of the deaminase, and by treatment with tetrahydrouridine, a nucleoside deaminase inhibitor. This was further confirmed by the use of purified human deoxycytidine deaminase. It was... 

Geborek, P., Mansson, B., Hellmer, G. and Saxne, T. (1992). Cytidine deaminase and lactoferrin in inflammatory synovial fluids - indicators of local polymorphonuclear cell function. Br. J. Rheumatol. 31, 235-240. 

Patel, B. T., Tudball, N., Wada, H. Watanabe T. (1986). Adenosine deaminase and histidine decarboxylase coexist in certain neurons of the rat brain. Neurosci. Lett. 63, 185-9. 

Lloyd, H. G. Fredholm, B. B. (1995). Involvement of adenosine deaminase and adenosine kinase in regulating extracellular adenosine concentration in rat hippocampal slices. Neurochem. Int. 26 (4), 387-95. 

Beside the use of a single enzyme, a cocktail of different biocatalysts can also be used in performing a domino process, provided that the enzymes do not interfere one with another. This approach was used by Scott and coworkers in the synthesis of precorrin-5 (8-61) (Scheme 8.16) [24]. Starting from 6-amino levulinic acid (ALA) 8-60, a mixture of eight different enzymes including the ALA-dehydratase to form porphobilinogen (PBG), as well as PBG deaminase and co-synthetase to furnish the tetracyclic uroporphyrinogen III (8-62) as intermediates, was employed to provide precorrin-5 (8-61) in 30% yield. 

Acute intermittent porphyria is a dominantly inherited partial deficiency of porphobilinogen deaminase, and causes axonal polyneuropathy. Acute intermittent porphyria is caused by partial deficiency of porphobilinogen deaminase, an enzyme required for heme biosynthesis. Patients may present with acute abdominal pain, rapidly progressive sensorimotor axonal polyneuropathy or psychosis, and have elevated concentrations of the heme precursor 8-amino-levulinic acid in their urine. Symptoms may be precipitated by treatment with barbiturates or other drugs and are suppressed by treatment with hematin [59]. 

Hibbs, J.B., Tiantor, R.R., and Vavrin, Z., Macrophage cytotoxicity Role for L-arginine deaminase and iminonitrogenoxidation of nitrite, Science, 235,473, 1987. 

A novel interesting approach is the use of multienzyme cocktails described by Scott et al. for the synthesis of precorrin-5159 starting from 8-amino levu-linic acid 158 (scheme 32).1871 For the process, a multienzyme cocktail of eight different enzymes including the ALA-dehydratase to form porphobilinogen as well as PBG deaminase and cosynthetase to give the tetracyclic uroporphyrinogen HI (10) was employed. 

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). 

Deficiencies of adenosine deaminase and hypoxanthine-guanine phosphoribosyltransferase or a low activity of thymi-dylate synthase are responsible for clinical disorders. 

A -Methyladenosine (XXV) (227, 239, 250], fV-methy 1-2 -deoxyadenosine (XXVI) [57], 3 -amino-V-methyl-3-deoxyadenosine [254], and 6-methoxy-purine ribonucleoside (LII) [63, 234, 241] are all good inhibitors of adenosine deaminase and fV-methyladenosine (XXV) has been used in combination with 9-/3-D-arabinofuranosyladenine (XIX) to increase its activity [255]. A number of 2-substituted A -methyladenosines [61] and 9-substituted adenines (see reference 256 and earlier papers by Schaeffer) are also inhibitors of the enzyme. 

L-Serine dehydratase [EC 4.2.1.13], also known as serine deaminase and L-hydroxyaminoacid dehydratase, catalyzes the pyridoxal-phosphate-dependent hydrolysis of L-serine to produce pyruvate, ammonia, and water. In a number of organisms, this reaction is also catalyzed by threonine dehydratase. 

This pyridoxal-phosphate-dependent enzyme [EC 4.2.1.16], also known as threonine deaminase and L-ser-... 

Cladribine, or 2-chlorodeoxyadenosine, is resistant to adenosine deaminase and after intracellular phosphorylation by deoxycytidine kinase, it is incorporated into DNA. It is considered the drug of choice in hairy cell leukemia because of high activity combined with acceptable toxicity. Cladribine shows variable oral absorbtion and is usually administered intravenously. Its concentration-time course is biphasic with plasma half-lives of 35 minutes and 6.7 hours. Excretion is primarily by the kidneys. Its most prominent dose-limiting toxicity is myelosup-pression. 

H. Corban-Wllhelm, W.E. Hull, G. Becker, U. Bauder-Wust, D. Greullch, J. Debus, Cytosine deaminase and thymidine kinase gene therapy In a dunning rat prostate... 

Mechanism of Action A blood modifier and platelet aggregation inhibitor that inhibits the activity of adenosine deaminase and phosphodiesterase, enzymes causing accumulation of adenosine and cyclic adenosine monophosphate. Therapeutic Effect Inhibits platelet aggregation may cause coronary vasodilation. 

The activity of hypoxanthine-guanine phosphoribosyltransferase, adenine phos-phoribosyltransferase, adenosine deaminase, and purine nucleoside phosphorylase can be determined in dried blood spots using an HPLC-linked assay [3]. 

Purine nucleotides are degraded by a pathway in which they lose their phosphate through the action of 5 -nucleotidase (Fig. 22-45). Adenylate yields adenosine, which is deaminated to inosine by adenosine deaminase, and inosine is hydrolyzed to hypoxanthine (its purine base) and D-ribose. Hypoxanthine is oxidized successively to xanthine and then uric acid by xanthine oxidase, a flavoenzyme with an atom of molybdenum and four iron-sulfur centers in its prosthetic group. Molecular oxygen is the electron acceptor in this complex reaction. 

The formation of uroporphyrinogen III from PBG in vivo requires the participation of two enzymes, porphobilinogen deaminase and uroporphyrinogen III cosynthetase. In the presence of the first enzyme alone, (65) is converted into uroporphyrinogen I which does not act as a substrate for the second enzyme. The formation of uroporphyrinogen I must... 

One of the major features of solid tumors and even small deposits of tumor tissue is deficiency in the level of oxygen, because of an inadequate vascular supply. The adenosine elevation in response to hypoxia is not exclusive to tumor tissues, but, in this context, the adenosine elevation is localized to the tumor microenvironment, since the surrounding tissue is normally oxygenated. Adenosine is generated mainly by two enzymatic systems intra- or extracellularly localized 5 -nucleoti-dases and cytoplasmic S-adenosylhomocysteine hydrolase. The processes of adenosine elimination in the cell involve reactions catalyzed by adenosine deaminase and adenosine kinase (Shryock and Belardinelli 1997) yielding inosine or 5 -AMP,... 

Examples of GDEPT include irinotecan (CPT-11), a prodrug of 7-ethyl- 10-hydroxy-camptothecin activated by carboxylesterase 5-fluorocytosine, a prodrug of 5-FU activated by cytosine deaminase and cyclophosphamide, a prodrug of 4-hydroxycyclophosphamide activated by cytochrome P450, which degrades into acrolein and phospho-ramide mustard.112-115... 

Brown, N. L., and Lemoine, N. R. Clinical trials with GDEPT Cytosine deaminase and 5-fluorocytosine. Methods Mol. Med. 90 451-458, 2004. 

Several other proteins show a low, but significant amino acid identity with atzA (Table 22.4). All of these, urease-alpha subunit (urea amidohydrolase), cytosine deaminase, and imidazolone-5-propionate hydrolase, catalyze hydrolytic reactions with substrates involved in the metabolism of nitrogenous compounds (Sadowsky et al 1998). A Rhizobium strain capable of atrazine dechlorination has been isolated from a soil that was previously treated with atrazine (Bouqard et al., 1997). This bacterium could not mineralize atrazine, and it accumulated hydroxyatrazine as the sole metabolite after long-term incubations. Interestingly, 22 of the 24 identified amino acids at the N-terminus of the atrazine halidohydrolase from Rhizobium were identical with atzA from Pseudomonas strain ADP. 

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