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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Wei SJ, Williams JG, Dang H, Darden TA, Betz BL, Humble MM, Chang FM, Trempus CS, Johnson K, Cannon RE, Tennant RW.; ''Identification of a specific motif of the DSS1 protein required for proteasome interaction and p53 protein degradation.''; PubMedEurope PMCScholia
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This CandidateSet contains sequences identified by William Pearson's analysis of Reactome catalyst entities. Catalyst entity sequences were used to identify analagous sequences that shared overall homology and active site homology. Sequences in this Candidate set were identified in an April 24, 2012 analysis.
Equilibrium between 5'-methylthio ribose-1-phosphate and 5'-methylthio ribulose-1-phosphate is catalyzed by 5'-methylthio ribose-1-phosphate isomerase. (Kabuyama et al, 2009)
In the last step MOB gets transaminated to methionine. The reaction was confirmed in yeast, where several transaminases catalyze it, which appears to be also the case in rat. At the moment, the human enzymes involved are unknown but due to homology to the respective enzyme in the parasite Crithidia fasciculata we feel supported to state that human GOT is probably one of the involved transaminases. (Berger et al, 2001)
Acireducone (1,2-Dihydroxy-3-oxo-5'-methylthiopentene) is oxidized using acireductone dioxygenase and dioxygen. There are two reactions possible, dependent on the metal cofactor: the alternative product 3-methylthiopropionate using nickel was confirmed in Klebsiella. In eukaryotes using iron(II) the result is 4-methylthio-2-oxobutanoate (MOB). (Ju et al, 2006)
Acireductone synthase (also: enolase-phosphatase E1) catalyzes the dephosphorylation and conversion to enolate of 2,3-dioxo-5'-methylthiopentane-1-phosphate, yielding acireductone. (Wang et al, 2005)
The human enzyme with 5'-methylthio ribulose-1-phosphate isomerase activity is probably produced from the APIP gene, according to its orthology with the yeast Mde1p enzyme.
MTA phosphorylase catalyzes the cleavage of adenine from S-methylthioadenosine (MTA) and subsequent phosphorylation of the product, yielding 5'-methylthio ribose-1-phosphate (Kamatani et al. 1981). The active form of the enzyme is a homotrimer (Della Ragione et al. 1985). Mutations in the gene are associated with a rare bone dysplasia and cancer syndrome, DMS-MFH (Camacho-Vanegas et al. 2012).
Equilibrium between 5'-methylthio ribose-1-phosphate and 5'-methylthio ribulose-1-phosphate is catalyzed by 5'-methylthio ribose-1-phosphate isomerase. (Kabuyama et al, 2009)
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).
Cytosolic creatine kinase catalyzes the reaction of creatine and ATP to form phosphocreatine and ADP. The active form of the enzyme is a dimer. Monomers of the cytosolic enzyme occur in two isoforms, B and M, so called because of their abundance in brain and muscle respectively. The enzyme is widely expressed in the body and many tissues express both isoforms. Both homo- (BB, MM) and heterodimers (BM) are catalytically active.
Creatine kinase octamers associated with the inner mitochondrial membrane catalyze the reaction of creatine and ATP to form phosphocreatine and ADP. Two mitochondrial creatine kinase proteins have been identified, one encoded by CKMT1A and B that is found in many tissues and one encoded by CKMT2 that is found in sarcomeres (Haas et al. 1988; Haas and Straus 1990). Studies of sarcomeric creatine kinase octamers suggest that their organization and association with phospholipids in the inner mitochondrial membrane may facilitate energy transfer from ATP generated in the mitochondrial matrix to cytosolic phosphocreatine (Khuchua et al. 1998; Schlattner et al. 2004).
The SLC6A8 transport protein associated with the plasma membrane mediates the uptake of extracellular creatine and a sodium ion (Sora et al. 1994). Molecular and biochemical studies of patients deficient in SLC6A8 protein confirm this function in vivo (e.g., Salomons 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).
Arginase 2 (ARG2) trimer catalyzes the hydrolysis of arginine to form urea and ornithine (Cama et al. 2003). ARG2 is localized to the mitochondrion (Gotoh ea 1996). The enzyme is expressed in many tissues in addition to liver and while its function appears to mitigate the effects of ARG1 deficiency on urea synthesis, its normal physiological roles have not been fully defined (Iyer et al. 1998).
Mitochondrial N acetylglutamate synthetase (NAGS) catalyzes the reaction of glutamate and acetyl-CoA to form N-acetylglutamate and CoA. NAGS is activated by arginine and the N-acetylglutamate produced in the reaction in turn is required to activate carbamoyl synthetase I. Consistent with this regulatory role in urea synthesis, NAGS mutations in humans are associated with hyperammonemia (Caldovic et al. 2002; Morizono et al. 2004).
At the beginning of this reaction, 1 molecule of 'NH4+', 1 molecule of 'HCO3-', and 1 molecule of 'ATP' are present. At the end of this reaction, 1 molecule of 'Carbamoyl phosphate', 1 molecule of 'ADP', and 1 molecule of 'Orthophosphate' are present.
This reaction takes place in the 'mitochondrial matrix' and is mediated by the 'carbamoyl-phosphate synthase (ammonia) activity' of 'carbamoyl-phosphate synthetase I dimer'.
Mitochondrial ornithine transcarbamoylase (OTC) catalyzes the reaction of ornithine and carbamoyl phosphate to form citrulline (Horwich et al. 1984). The enzyme is a homotrimer (Shi et al. 2001).
Cytosolic Arginase 1 (ARG1) trimer catalyzes the hydrolysis of arginine to yield ornithine and urea (DiCostanzo et al. 2005). Patients expressing mutated forms of the enzyme with diminished in vitro arginase activity can accumulate arginine to pathogenic levels in the blood (e.g., Uchino et al. 1995).
Cytosolic argininosuccinate lyase (ASL) catalyzes the reversible reaction of argininosuccinate to form fumarate and arginine. The enzyme is a homotetramer (Turner et al. 1997). The function of the human enzyme in vivo is inferred from the defective argininosuccinate lyase enzyme activity observed in patients with mutant forms of the ASL gene (e.g., Walker et al. 1990).
Cytosolic argininosuccinate synthase (ASS1 tetramer) catalyzes the reaction of aspartate (L-Asp), citrulline (L-Cit), and ATP to form argininosuccinate (ARSUA), AMP, and pyrophosphate (PPi). The function of the human enzyme in vivo is inferred from the hypercitrullinemia observed in patients with defective forms of the enzyme (e.g., Engel et al. 2009). The enzyme is active as a homotetramer (O'Brien 1980; Karlberg et al. 2008) and binds NmrA-like family domain-containing protein 1 (NMRAL1). NMRAL1 is a redox sensor protein that can undergo restructuring and subcellular redistribution in response to changes in intracellular NADPH/NADP+ levels. Under normal NADPH levels, it can form an asymmetrical dimer with one subunit occupied by one NADPH molecule, hiding the binding site for ASS1 thus impairing its activity and reducing the production of nitric oxide (Zheng et al. 2007, Zhao et al. 2008).
The mitochondrial ornithine transporters SLC25A15 and SLC25A2 mediate the exchange of cytosolic ornithine for citrulline from the mitochondrial matrix. SLC25A15 was the first protein shown to have this function, identified because mutations in the protein are associated with elevated levels of ammonia, ornithine, and citrulline in affected individuals (Camacho et al. 1999). The second transporter, SLC25A2, identified later, is also expressed in normal cells and their apparently partly redundant function may explain the relatively mild symptoms associated with SLC25A15 deficiency compared to other defects of the urea cycle (Fiermonte et al. 2003).
Glycine amindinotransferase, localized to the mitochondrial intermembrane space, catalyzes the reaction of arginine and glycine to form guanidinoacetate and ornithine. The active form of the enzyme is a dimer (Humm et al. 1997 {EMBO J]; Humm et al 1997 [Biochem J]). Its function in vivo has been confirmed by molecular and biochemical studies of patients deficient in the enzyme (Item et al. 2001).
Cytosolic guanidinoacetate methyltransferase catalyzes the reaction of S-adenosylmethionine and guanidinoacetate to form S-adenosylhomocysteine and creatine (Stockler et al. 1996).
Cytosolic phosphocreatine spontaneously hydrolyzes to yield creatinine and orthophosphate (Borsook and Dubnoff 1947). Creatinine cannot be metabolized further and is excreted from the body in the urine. Creatinine formation proceeds at a nearly constant rate and the amount produced by an individual is a function of muscle mass, so urinary creatinine output is clinically useful as a normalization factor in assays of urinary output of other molecules. Iyengar et al. (1985) have suggested that an alternative reaction sequence, proceeding via phosphocreatinine but also spontaneous, may contribute to creatinine formation.
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ornithine
transportersAnnotated Interactions
ornithine
transportersThis reaction takes place in the 'mitochondrial matrix' and is mediated by the 'carbamoyl-phosphate synthase (ammonia) activity' of 'carbamoyl-phosphate synthetase I dimer'.