Polyamine metabolism

Dasu VV, Y Nakada, M Ohnishi-Kameyama, K Kimura, Y Itoh (2006) Characterization and a role of Pseudomonas aeruginosa spermidine dehydrogenase in polyamine metabolism. Microbiology (UK) 152 2265-2272. 

Dunbar, J.R., A.J. DeLucia, R.V. Acuff, and K.E. Ferslew. 1988b. Prolonged intravenous paraquat infusion in the rat. II. Paraquat-induced alterations in lung polyamine metabolism. Toxicol. Appl. Pharmacol. 94 221-226. 

The enzymes involved in the polyamine metabolic pathway have been the subject of intensive study, and a number of specific inhibitors for these enzymes have been designed as potential antitumor or antiparasitic agents [166]. Thus, a-difluoromethylornithine, has become a clinically useful agent [167]. Most of the studies involving inhibitors of polyamine metabolism have focused on enzymes involved in the biosynthetic pathway. Recently, there has been considerable interest generated in the enzyme spermidine/spermine-hT -acetyltrans-ferase enzyme (SSAT), the rate-limiting step in the back conversion of polyamines. SSAT, in conjunction with polyamine oxidase (PAO), allows for reversal of the biosynthetic pathway and attenuation of the levels of individual polyamines. 

Sunkara PS, Baylin SB, Luk GD (1987) Inhibition of Polyamine Metabolism Biological Significance and Basis for New Therapies.(eds) McCann PP, Peg AE, Sjoerdsma A. Academic Press, New York, p 121... 

After 7 days, lungs of high-dose group had elevated putrescine, spermidine, and ornithine decarboxylase activity, reflecting changes in polyamine metabolism no measurable effects in low-dose group (Dunbar et al. 1988b)... 

The mechanisms by which antitumor-promoters suppress the tumor promotion are not known, but may be due to the following effects (i) inhibition of polyamine metabolism (ii) inhibition of arachidonic acid metabolism (iii) protease inhibition (iv) induction of differentiation (v) inhibition of oncogene expression (vi) inhibition of PKC and (vii) inhibition of oxidative DNA damage [3,6,91]. The polyamine content of cells is correlated to their proliferative, and often, their neoplastic capabilities. A key enzyme in the polyamine biosynthetic pathway, ornithine decarboxylase (ODC), catalyzes the convertion of ornithine to putrescine. Phorbol ester promoters such as TPA cause increased ODC activity and accumulation of polyamines in affected tissues. Diacylglycerol activated PKC, and the potent tumor promoter, TPA, binds to, and activates PKC, in competition with diacylglycerol. PKC stimulation results in phosphorylation of regulatory proteins that affect cell proliferation. Some chemopreventive agents have inhibitory activity towards PKC. Refer to recent review articles for further discussion [3,6,91]. 

Polyamines like spermidine and spermine, which bind tightly to nucleic acids and are abundant in rapidly proliferating cells, are present in parasitic helminths in amounts comparable to those in vertebrate cells. As the enzymes necessary for their synthesis are lacking in adult parasitic flatworms, it is assumed that these compounds are obtained from the host (Bacchi and Yarlett, 1 995). In F. hepatica a polyamine N-acetyltransferase has been characterized, that is thought to play a major role in the polyamine metabolism of this parasite by inactivating excess amines (Aisien and Walter, 1993). 

Liu W., Liu R., Schreiber S. S., and Baudry M. (2001). Role of polyamine metabolism in kainic acid excitotoxicity in organotypic hippocampal slice cultures. J. Neurochem. 79 976-984. 

Wallace, H.M., Fraser, A.V. Inhibitors of polyamine metabolism review article. Amino Acids 26 (2004) 353-365. 

OBER, D THOLL, D., MARTIN, W., HARTMANN, T Homospermidine synthase of Rhodopseudomonas viridis Substrate specificity and effects of the heterologously expressed enzyme on polyamine metabolism of Escherichia coli. J. Gen. Appl. Microbiol., 1996,42,411-419. 

Pegg, A.E. Polyamine metabolism and its importance in neoplastic growth and a target for chemotherapy. Cancer Res. 1988, 48, 759. 

Seiler, N. (1980). On the role of GABA in vertebrate polyamine metabolism. Physiol. Chem. Phys. 12 41 I 429. 

Sessa, A. and Perin, A. (1994). Diamine oxidase in relation to diamine and polyamine metabolism. Agents Actions 43 69-77. 

Inhibits cellular proliferation through alterations in polyamine metabolism Detoxifies activated carcinogens via glutathione S transferase inhibition... 

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