Polyamines metabolic pathway

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. 

Diamine Oxidase Diamine oxidase (DAO, his-taminase) is a degradative enzyme of the polyamine metabolic pathway that is expressed in mature epithelium lining the rodent intestinal villi (Luk et al., 1980). Diminished blood concentrations, measurable by tritiated water assay, have been shown to correlate well with tissue expression... 

Diamine oxidase (DAO) is a highly active degradative enzyme of the polyamine metabolic pathways, catabolizes a variety of substrates including histamine and diamines, and is localized to the mature villus epithelial cells of rodent intestinal mucosa (Wolvekamp and de Bruin 1994 John-Baptiste et al. 2012). Although blood DAO activity level correlates with both DAO expression in the villi of the small intestinal mucosa and the severity of small intestinal mucosal lesions induced by anticancer drugs, DAO measurement is confounded by the fact that plasma levels rise markedly upon heparin stimulation prior to blood draws, with peak elevations between 30 and 60 min (Luk et al. 1980, 1981 Tsunooka et al. 2004). 

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]. 

FIGURE 4 Metabolic pathway of polyamines. Increased levels of spermidine, spermine, putrescine, acetylspermidine, and acetylspermine without a change of ornithine in AD pathology were observed. One theory suggests that the NMDA receptor excitotoxicity is caused by an excess of spermidine and spermine due to ornithine decarboxylase activity induced by plaque and/or tangle deposition in specific brain regions. Reproduced from Ref. (112). 

Polyamine metabolism by parasites differs in several significant ways from the mammalian host these include, but are not limited to, enzyme half-life, turnover, substrate specificity, types and quantities of polyamines produced. The production of the novel bis glutathionyl spermidine adduct by trypanosomatids, its role as an antioxidant and the protein structure of trypanothione reductase is discussed with respect to the more conventional glutathione reductase system. The role of S-adenosylmethionine and decarboxylated S-adenosylmethionine as critical precursors in the biosynthesis of the higher polyamines is explored with respect to differences in the function and control of the pathway by various parasites. Polyamine biosynthesis in parasites is sufficiently different from that of the host to afford multiple opportunities for drug development, these may be aimed directly at circumventing polyamine biosynthesis or at inhibiting precursors necessary for polyamine synthesis. 

The overall pathways of polyamine metabolism in pathogenic protozoa and helminths seem to be sufficiently different from the mammalian host to afford multiple opportunities for drug intervention. The important features are the long half-life of ODC in kinetoplastids coupled with poor polyamine transport and the apparently unregulated... 

Like purine metabolism, the polyamine biosynthetic pathway has served as another paradigm for rational therapeutic intervention in parasitic disease. Polyamine synthesis in T. brucei and Leishmania, like that in mammalian cells, is initiated by the enzyme ornithine decarboxylase (ODCase), although T. cruzi may synthesize polyamines by... 

Deficiency of either vitamin Bj or folate decreases the synthesis of methionine and SAM, thereby interfering with protein biosynthesis, a number of methylation reactions, and the synthesis of polyamines. In addition, the cell responds to the deficiency by redirecting folate metabolic pathways to supply increasing amounts of methyltetrahydrofolate this tends to preserve essential methylation reactions at the expense of nucleic acid synthesis. With vitamin Bj deficiency, methylenetetrahydro-folate reductase activity increases, directing available intracellular folates into the methyltetrahydrofolate pool (not shown in Figure 53-6). The methyltetrahydrofolate then is trapped by the lack of sufficient vitamin Bj to accept and transfer methyl groups, and subsequent steps in folate metabolism... 

Kevers, C. Le Gal, N. Monteiro, M. Dommes, J. Gaspar, T. (2000). Somatic embryogenesis of Panax ginseng in liquid cultures a role polyamines and their metabolic pathways. Plant Growth Regulation, Vol. 31, No. 3, pp 209-214, ISSN 0167-6903. 

The conclusion reached from these findings from the point of view of methionine metabolism in developing brain is that involvement of S-adenosylmethlonlne in methylation reactions is more important than its involvement in synthesis of polyamines. Furthermore, in its role as a methyl donor it is converted to S-adenosylhomocysteine by various methyltransferases, and the carbon skeleton is retained within the methionine-homocysteine cycle. The absence of an active transsulfuratlon pathway at these early stages of development supports the concept that the most important metabolic role of methionine in developing neural tissue is methylation. Thus metabolic pathways which involve loss of the methionine carbon skeleton, polyamine biosynthesis and transsulfuratlon, are minimal or absent in order to promote and conserve this remethylatlon cycle. These alterations in the pathways of methionine metabolism in developing tissue may also be necessary to compensate for the greater utilization of methionine for protein synthesis at this time. 

Sato T, Atomi H (2011) Novel metabolic pathways in Archaea. Curr Opin Microbiol 14 307-314 Schneider J, Wendisch VF (2011) Biotechnological production of polyamines by bacteria recent achievements and future perspectives. Appl Microbiol Biotechnol 91 17-30 Stetter KO (1996) Hypeithermophilic procaryotes. FEMS Microbiol Rev 18 149-158 Tabor CW, Tabor H (1985) Polyamines in microorganisms. Microbiol Rev 49 81-99 Terui Y, Ohnuma M, Hiraga K, Kawashima E, Oshima T (2005) Stabilization of nucleic acids by unusual polyamines produced by an extreme thermophUe, Thermus thetmophilus. Biochem J 388 427 33... 

Toumi I, Moschou PN, Paschalidis KA, Bouamama B, Salem-fnayou AB, Ghorbel AW, Mliki A, Roubelakis-Angelakis KA (2010) Abscisic acid signals reorientation of polyamine metabolism to orchestrate stress responses via the polyamine exodus pathway in grapevine. J Plant Physiol 167 519-525... 

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. 

Metabolism of polyamines has a direct action on cell proliferation. Thus, it is a therapeutic target for the design of antitumor agents. However, inhibition of ornithine decarboxylase (ODC) by specific inhibitors does not completely cancel the activity. This is due to the existence of other biosynthetic pathways (i.e., SAM-DC). These pathways are themselves regulated by polyamines. 

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