ormation of spermidine which in turn, is the substrate for spermine. The Odc mediated reaction, which in mammals requires the PLP cofactor, is considered the rate-limiting step but S-adenosylmethioninamine, the decarboxylated form of S-adenosylmethionine (AdoMet or SAM) supplied by Amd1, is also an important component for the synthesis of higher polamines. AdoMet, the universal methyl donor generated from methionine in the methionine cycle, can also be decarboxylated in the salvage arm of the cycle. The mammalian Amd1 is activated by putrescine and studies indicate that the polyamine interacts with the enzyme. Decarboxylated AdoMet is the aminopropyl donor for the formation of spermidine and spermine in the two consecutive reactions carried out by spermidine synthase Srm and spermine synthase Sms, respectively. Both enzymes are active as homodimers. Methylthioadenosine (MTA), the by-product of the two reactions, can inhibit the two enzymes with a stronger effect on spermine synthase. This effect is however minimal as MTA is rapidly converted to 1-phosphomethylthioribose by the action of MTA phosphorylase Mtap. The active Odc enzyme is a dimer but the weak affinity of the monomers causes the dimers and monomers to be in rapid equilibrium with each other. The monomers are recognized by the members of the antizyme family Oaz; formation of the complex inhibits Odc activity and also targets the enzyme for degradation. There are several Oaz genes; while they all inhibit Odc activity, some do not target Odc for degradation and others have a rather restricted expression pattern. The activity of antizyme is regulated by the antizyme inhibitor Azin1. Azin1 has high homology to Odc, binds antizyme more tightly than Odc, disrupts the Odc-antizyme complex and promotes/restores Odc activity. The reactions leading to the formation of higher polyamines are converted back to yield putrescine which is easier to excrete from cells. Spermidine/spermine N1-acetyl transferase Sat1 acetylates spermine and spermidine, using acetyl-CoA in the reaction. The acetylated polyamines are then oxidized to spermidine and putrescine, respectively by the action of FAD-dependent polyamine oxidase Paox. In addition, spermine can be converted back to spermidine by the action of flavoprotein spermine oxidase Smox. The oxidation reaction also produces hydrogen peroxide; the Smox catalyzed reaction may be of greater concern since Paox is a peroxisomal enzyme. Distinct transport systems appear to carry out the uptake and efflux of polyamines but they are not well characterized in higher organisms. The enzymes of polyamine metabolism are regulated at many levels and also present as multiple isoforms as a result of alternative splicing. Studies in yeast, worm and fly indicate that polyamines can increase life span and also promote stress resistance in plants. Polyamine levels increase with inflammation and also in tumors. Inhibitors for many of the enzymes have been developed but with few exceptions, such as DFMO, they appear to be of limited use. Difluoromethylornithine (DFMO) is an irreversible inhibitor of ODC. Polyamine analogs are also being developed to control/regulate polyamine metabolism: polyamine antimetabolites aim at depleting the intracellular polyamine concentration while the mimetics aim at displacing the natural polyamines from their binding sites. To see the ontology report for Gviewer, annotations and download, click here ...(less)