Polyamine biosynthesis

Arginine serves as the formamidine donor for creatine biosynthesis, participates in polyamine biosynthesis, and provides the nitrogen of nitric oxide (NO). 

As an alternative to oxidative deamination, decarboxylation is involved in polyamine biosynthesis and in the protection of enteric bacteria from acidic conditions. Under these conditions, the electrons used to form the ketimine are provided by decarboxylation in place of those from the a-methine group. 

Graham DE, H Xu, RH White (2002) Methanococcus jannaschii uses a pyruvoyl-dependent arginine decarboxylase in polyamine biosynthesis. J Biol Chem 211 23500-23507. 

Biosynthesis of polyamines is essential for growth and multiplication of T. brucei, hence discovery of drug candidates that inhibit enzymes in the polyamine biosynthesis pathway represent an attractive approach to development of trypanocides. The consequences of gene knockout of ornithine decarboxylase (ODC), the target of eflornithine (3), have been further characterized and suggest that new inhibitors of this enzyme may be particularly effective [18]. 

A third enzyme in the polyamine biosynthesis pathway, trypanothione synthetase-amidase (TRYS), has been shown to be essential by both genetic and chemical methods [24]. Specifically, the indazole analog 24 has been identified in a TRYS screen (IC50 = 140 nM) and shown to inhibit growth of wild-type (IC50 = 5.1 pM) and TRYS-dKO (IC50 = 0.46 mM) T. brucei parasites in culture [25]. 

One of the most compelling targets in the polyamine biosynthesis pathway has been S-adenosylmethionine decarboxylase (SAM-DC). This target was chemically validated with the discovery of trypanocidal activity of MDL-73811 nearly two decades ago. Work to understand the unique kinetics for inhibition of this enzyme in T. brucei has shown that a catalytically... 

Sumper, M. and Lehmann, G. (2006) Silica pattern formation in diatoms Species-specific polyamine biosynthesis. ChemBioChem, 7, 1419-1427. 

Central Intermediary Metabolism Amino sugars Phosphorus compounds Polyamine biosynthesis Sulfur metabolism Nitrogen fixation Other... 

Kaur-Sawhney, R., Shih, L. M., Galston, A. W. (1982). Relation of Polyamine Biosynthesis to the Initiation of Sprouting in Potato Tubers. Plant Physiol., 69,411 15. 

Bowlin, T. L., McKown, B. J., Babcock, G. F., and Sunkara, P. S. (1987). Intracellular polyamine biosynthesis is required for interleukin-2 respt>nsiveness during lymphocyte mitogenesis. Cell. Immunol. 106, 420-427. 

RD Klein, TG Geary, AS Gibson, MA Favreau, CA Winterrowd, SJ Upton, JS Keithly, G Zhu, RL Malmberg, MP Martinez, N Yarlett. Reconstitution of a bacterial/plant polyamine biosynthesis pathway in Saccharomyces cerevisiae. Microbiology 145 301-307, 1999. 

DiTomaso, J. M. and Duke, S. O. 1991. Is polyamine biosynthesis a possible site of action of cinmethylin and artemisinin . Pestic. Biochem. Physiol. 39, 158-167... 

Ornithine decarboxylase (ODC) is the first enzyme in the polyamine biosynthesis pathway. Polyamines play essential roles in cell proliferation and differentiation and participate in macromolecular synthesis. Inhibitors of ODC block aspects of tumor promotion and induce cellular differentiation in several animal carcinogenesis models. Thus induction of ODC has been implicated as being important to carcinogenesis, and ODC activity is an intermediate biomarker of cell proliferation in studies... 

Bagni, N. and Speranza, A., Pathways of polyamine biosynthesis during the growth of Helianthus tuberosus parenchymatic tissue, in Plant Growth Regulators, Kudrev, T., Ivanova, I., and Karanov, E., Eds., Bulgarian Academy of Science, Sofia, Bulgaria, 1977, pp. 75-78. 

Torrigiani, P., Serafini-Fracassini, D., and Bagni, N., Polyamine biosynthesis and effect of dicyclohexylamine during the cell cycle of Helianthus tuberosus, Plant Physiol., 84, 148-152, 1987. 

Nitrogen Metabolism "" " i i (ammonia incorporation, amino acid biosynthesis, nitrate/nitrite reduction, proline oxidation, polyamine biosynthesis)... 

Camesecchi, S. Schneider, Y. Lazarus, S.A. Coehlo, D. Gosse, F. Raul, F. 2002. Flavanols and procyanidins of cocoa and chocolate inhibit growth and polyamine biosynthesis of human colonic cancer cells. Cancer Lett. 175 147-155. 

Bitonti AJ, McCann PP, Sjoerdsma A. Restriction of bacterial growth by inhibition of polyamine biosynthesis by using monoflu-oromethylornithine, difluoromethylarginine, and dicyclohexylam-monium sulfate. Biochem. J. 1982 208(2) 435-441. 

Polyamine biosynthesis is associated with regulation of a number of metabolic functions including growth of cells in most of the living organisms. In mammals, ornithine is the precursor of aliphatic polyamines. Putrescine, formed by decarboxylation of the former by ornithine decarboxylase, is the first amine formed in polyamine biosynthesis. Putrescine gives rise to the other two polyamines, spermine and spermidine by successive addition of 3-aminopropyl residues derived from S-adenosyl-L-methionine (SAM) in the presence of different enzymes [44] (Chart 7). 

Like helminths, some protozoans also require polyamines for their cell growth, membrane stabilization and as cofactors for macromolecular synthesis. Trypanosomes have been found to possess putrescine and spermidine, but not spermine. The precursor of the polyamine biosynthesis in protozoans is ornithine, which is de-carboxylated in the presence of ornithine decarboxylase to form putrescine. Other polyamines are formed from putrescine as discussed in chapter 2 (Sec. 5.3). 

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. 

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