Polyamines, synthesis

Hyperbranched aromatic polyesters, synthesis of, 116-118 Hyperbranched aromatic polymers, 286 Hyperbranched polyamine, synthesis of, 519-520... 

ACS activity may be reversibly regulated by various substances associated with the methionine-recycling pathway, SAM metabolism, and polyamine synthesis, and by natural and chemical analogues of SAM or inhibitors of PLP-dependent enzymes. 

Ethambutol is a synthetic agent and not related to any of the other tuberculostatics. Its mechanism of action is not well understood but in actively dividing mycobacteria it appears to be an inhibitor of mycobacterial RNA synthesis. It also has effects on bacterial phosphate metabolism and on polyamine synthesis. It is an bacteriostatic agent and its main function in combination therapy is to delay the occurrence of resistance, mainly against isoniazid and rifampicin. It is well absorbed after oral administration. It is widely distributed, except to the CNS. Protein binding is about 20-30%. It is mainly excreted unchanged in the bile and urine with an elimination half-life of 3 h. Ethambutol is concentrated in erythrocytes and thus provides a depot for continuous release. 

McCarthy, M. A., Michalski, J. P., Sears, E. S., and McCombs, C. C. (1990). Inhibition of polyamine synthesis suppresses human lymphocyte proliferation without decreasing cytokine production or interleukin-2 receptor expression. Immunopharmacology 20,11-20. 

Homocysteine (Hey) metabolism is closely linked to that of the essential amino acid methionine and thus plays a central role in several vital biological processes. Methionine itself is needed for protein synthesis and donates methyl groups for the synthesis of a broad range of vital methylated compounds. It is also a main source of sulphur and acts as the precursor for several other sulphur-containing amino acids such as cystathionine, cysteine and taurine. In addition, it donates the carbon skeleton for polyamine synthesis [1,2]. Hey is also important in the metabolism of folate and in the breakdown of choline. Hey levels are determined by its synthesis from methionine, which involves several enzymes, its remethylation to methionine and its breakdown by trans-sulphuration. 

Elevated Hey occurs in a wide range of disease processes. This is not surprising bearing in mind the central role of this metabolite in several closely related pathways and because of its links to processes such as polyamine synthesis, methylation and redox potential. 

Ornithine decarboxylase is specifically inhibited by the enzyme-activated inhibitor a-difluoromethyl-ornithine, which can cure human infection with Trypanosoma brucei (African sleeping sickness) by interfering with polyamine synthesis.243-2443 In combination with inhibitors of spermidine synthase or S-adenosylmethionine decarboxylase,245 it can reduce polyamine levels and growth rates of cells. Another powerful inhibitor that acts on both ornithine and adenosylmethionine decarboxylases is the hydroxy-lamine derivative l-aminooxy-3-aminopropane 246... 

One of the insect neurohormones, the activation hormone, controls the secretion of the corpora allata, paired glands that synthesize the juvenile hormone (Fig. 22-4) in insect larvae. While the structure of the juvenile hormone varies somewhat with species, it is usually a polyprenyl ester. A specific binding protein provides the hormone with protection from degrada-tive enzymes. However, in the tobacco homworm an esterase, able to hydrolyze the protein-bound juvenile hormone, is produced at the start of pupal differentiation.354 The exact mechanism of action of juvenile hormones has been difficult to determine. However, it affects polyamine synthesis.355 356... 

Adenine phosphoribosyltransferase catalyzes the conversion of adenine to AMP in many tissues, by a reaction similar to that of hypoxanthine-guanine phosphoribosyltransferase, but is quite distinct from the latter. It plays a minor role in purine salvage since adenine is not a significant product of purine nucleotide catabolism (see below). The function of this enzyme seems to be to scavenge small amounts of adenine that are produced during intestinal digestion of nucleic acids or in the metabolism of 5 -deoxy-5 -methylthioadenosine, a product of polyamine synthesis. 

Further modifications using the same strain of ODC S. cerevisiae reconstituted a bacterial/plant polyamine synthesis pathway in yeast [41], The ODC strain was transformed with plasmids encoding arginine decarboxylase and ag-matine ureohydrolase, which conferred polyamine-independent growth on the recombinant microbe. A similar construction could be used to screen for inhibitors of the homologous enzymes from Apicomplexan protozoa, which synthesize poly amines through this pathway [42]. 

Bagni, N., Torrigiani, P, and Barbieri, P, Effect of various inhibitors of polyamine synthesis on the growth of Helianthus tuberosus, Med. Biol., 59, 403-409, 1981. 

Watson, M.B., Emory, K.K., Piatak, R.M., and Malmberg, R.L., Arginine decarboxylase (polyamine synthesis) mutants of Arabidopsis thaliana exhibit altered root growth, Plant J., 13, 231-239, 1998. 

Reduction of trypanothione levels in the cells may be achieved in two ways (a) by inhibition of trypanothione peroxidase/reductase activity, or (b) by interference with the polyamine biosynthesis. Interference with the polyamine synthesis will not only lead to a decreased turnover of various polyamines, but will also bring down trypanothione levels in cells, thereby, exposing the parasites to the toxic effects of peroxides and free radicals generated by the host. 

The precursor for polyamine synthesis in mammalian cells as well as in P. falciparum is arginine, which is converted by arginase to urea and ornithine (Muller et ah, 2005) the latter is subsequently decarboxylated by ODC to PU. However, there is evidence for an alternative pathway in the related apicomplexan Cryptosporidium, where arginine is decarboxylated to agmatine and subsequently converted to PU (Keithly et ah, 1997). Thereafter in mammals SPD and SM are formed by the catalytic action of SPD synthase and SM synthase. AdoMetDC and ODC are the rate-limiting enzymes for polyamine synthesis. 

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