Polyamines is a family of molecules (i.e. putrescine, spermine, spermidine) derived from ornithine according to a decarboxylation/condensative process. More recently, it has been demonstrated that arginine can be metabolised according to the same pathway leading to agmatine formation. Polyamines are essential for the growth, the maintenance and the function of normal cells. The complexity of their metabolism and the fact that polyamines homeostasis is tightly regulated support the idea that polyamines are essential to cell survival. Multiple abnormalities in the control of polyamines metabolism might be implicated in several pathological processes (Moinard et al., 2005). Legend for the following figure:
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Spermine oxidase (SMOX, PAOh1, SMO) is a polyamine oxidase flavoenzyme that catalyses the oxidation of spermine (SPN) to spermidine (SPM). It plays an important role in the regulation of endogenous polyamine intracellular concentration. Five different isozymes are produced by alternative splicing with isozyme 3 being the major isoform and possessing the highest affinity for spermine. It is highly inducible by specific antitumor polyamine analogues (Wang et al. 2001).
Acetylated spermidine (NASPM) is oxidised by the flavoenzyme polyamine oxidase (PAOX, with FAD as cofactor) to produce putrescine (PTCN). PAOX is involved in the back-conversion of polyamines and thus the regulation of their intracellular concentrations (Vujcic et al. 2003).
Acetylated spermine (NASPN) is oxidised by the flavoenzyme polyamine oxidase (PAOX, woth FAD as cofactor) to produce spermidine (SPM). PAOX is involved in the back-conversion of polyamines and thus the regulation of their intracellular concentrations (Vujcic et al. 2003).
Antizyme is a non-competitive inhibitor of ODC that is synthesized in response to an increase in polyamine concentration. Tight binding of the antizyme to the ODC monomer forming a heterodimer prevents enzymatic activity. The region of antizyme interacting with ODC is contained in a section involving residues 106–212 in the COOH-terminal half of the antizyme molecule. The induction of antizyme thus leads to a loss of active ODC protein (Pegg, 2006 and references cited in that review).
A novel pathway has been described for ODC degradation during oxidative stress, which is regulated by NAD(P)H quinone oxidoreductase (NQO1). In this pathway, the 20S proteasome has been shown to degrade unfolded ODC monomers. This event does not require the COOH-terminal domain. NQO1 binds to ODC and stabilizes it. If this interaction is disrupted with dicoumarol, it sensitizes ODC monomers to degradation by the 20S proteasome independent of both antizyme and ubiquitin. The details of the role of this pathway remains to be determined, but it could be involved in the nascent ODC chain turnover.
Agmatine is polyamine formed by decarboxylation of L-arginine by arginine decarboxylase (ADC). Human ADC is a 460-amino acid protein that shows about 48% identity to mammalian ornithine decarboxylase (ODC) but has no ODC activity.
Antizyme inhibitor blocks the effects of antizyme on ODC. It has substantial similarity to ODC itself but has no ODC activity. It binds to antizyme more tightly than ODC displacing ODC from the antizyme-ODC complex. Recent studies have shown that antizyme inhibitor is able to disrupt the interaction between all forms of mammalian antizyme and ODC (Murakami et al., 1996, Nilsson et al., 2000, Mangold and Leberer, 2005).
As it hydrolyzes a guanidino group within agmatine and also contains signature amino acid residues that act as ligand binding sites for the potential Mn(++) cofactor, agmatinase is classified as a member of the arginase superfamily (Morris, 2003).
The N1-acetylation of spermidine and spermine by spermidine/spermine acetyltransferase (SSAT) is a crucial step in the regulation of the cellular polyamine levels in eukaryotic cells. The kinetics of this enzyme has been already elucidated (Hedge et al. 2007).
Spermidine/spermine N1-acetyltransferase (Spd/Spm acetyltransferase) is the rate-limiting enzyme in the catabolism of polyamines. Defects in SAT1 may be the cause of keratosis follicularis spinulosa decalvans (KFSD).
Spermidine/spermine N1-acetyltransferase (Spd/Spm acetyltransferase) is the rate-limiting enzyme in the catabolism of polyamines. Defects in SAT1 may be the cause of keratosis follicularis spinulosa decalvans (KFSD).
The protein encoded by this gene belongs to the spermidine/spermine synthases family. This gene encodes an ubiquitous enzyme of polyamine metabolism. Defects in SMS are the cause of Snyder-Robinson syndrome (SRS).
Spermidine synthase is one of four enzymes in the polyamine-biosynthetic pathway and carries out the final step of spermidine biosynthesis. This enzyme catalyzes the conversion of putrescine to spermidine using decarboxylated S-adenosylmethionine as the cofactor.
S-Adenosylmethionine decarboxylase belongs to a small class of amino acid decarboxylases that use a covalently bound pyruvate as a prosthetic group. It is an essential enzyme for polyamine biosynthesis and provides an important target for the design of anti-parasitic and cancer chemotherapeutic agents. It catalyzes the formation of the aminopropyl group donor in the biosynthesis of the polyamines spermidine and spermine. These pyruvoyl-dependent decarboxylases also form amines such as histamine, decarboxylated S-adenosylmethionine, phosphatidylethanolamine (a component of membrane phospholipids), and -alanine (a precursor of coenzyme A), which are all of critical importance in cellular physiology and provide important targets for drug design.
The N1-acetylation of spermidine and spermine by spermidine/spermine acetyltransferase (SSAT) is a crucial step in the regulation of the cellular polyamine levels in eukaryotic cells. The kinetics of this enzyme has been already elucidated (Hedge et al. 2007).
The rapid turnover of ODC is brought about by the 26S proteasome. Proteolytic processing of ODC is highly unusual in that ubiquitination is not required for this degradation. Instead, a non-covalent association with antizyme directs ODC to the proteasome. Antizyme increases the degradation of ODC by enhancing its interaction with the proteasome (Pegg, 2006).
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