Spermidine synthase

SPERMIDINE SYNTHASE Ammonia as a substrate or product, ADENINE DEAMINASE ADENOSINE DEAMINASE [Pg.722]

Ornithine decarboxylase is specifically inhibited by the enzyme-activated inhibitor a-difluoromethyl-ornithine, which can cure human infection with Trypanosoma brucei (African sleeping sickness) by interfering with polyamine synthesis.243-2443 In combination with inhibitors of spermidine synthase or S-adenosylmethionine decarboxylase,245 it can reduce polyamine levels and growth rates of cells. Another powerful inhibitor that acts on both ornithine and adenosylmethionine decarboxylases is the hydroxy-lamine derivative l-aminooxy-3-aminopropane 246... 

Identification of Plasmodium falciparum spermidine synthase active site binders through structure-based virtual screening. J Med Chem 51(9/2777-2786... 

The first committed step in TA and nicotine biosynthesis is catalyzed by putrescine JV-methyltransferase (PMT) (Fig.7.4).82 A PMT cDNA isolated from tobacco showed extensive homology to spermidine synthase from mammalian and bacterial sources.83 A-Methylputrescine is oxidatively deaminated to 4-aminobutanal, which undergoes spontaneous cyclization to form the reactive A-methyl-A1-pyrrolinium cation. Although the enzymes involved are unknown, the A-methyl-A1-pyrrolinium cation is thought to condense either with acetoacetic acid to yield hygrine as a precursor to the tropane ring, or with nicotinic acid to form nicotine. 

HASHIMOTO, T., TAMAKI, K., SUZUKI, K.I., YAMADA, Y Molecular cloning of plant spermidine synthases. Plant Cell Physiol., 1998,39, 73-79. 

A recently discovered MT that catalyzes the N-methylation of phosphoethanolamine in the first committed step leading to the production of choline, a precursor of the osmoprotectant glycine betaine, appears to be a novel type of a plant MT.47,48 The enzyme, PEAMT, appears to be a head-to-tail gene fusion of duplicated MTs of an SMOMT type gene. Interestingly, PEAMT functions as a monomeric protein, in contrast to the homodimeric SMOMTs. Another NMT, putrescine NMT, is most similar to spermidine synthase from mammals, and bears no sequence identity to other plant MTs beyond several residues critical for SAM binding.42,49... 

Two enz)mies of pyrrolidine alkaloid formation responsible for the conversion of putrescine to the N-methylpyrrolinium ion have been investigated in some detail. PMT, partially purified from cultures of Hyoscyamus niger and fully characterized from Datura stramonium, has been cloned by differential screening of complementary deoxyribonucleic acid (cDNA) libraries from high- and low-nicotine-yielding N. tabacum plants (Hibi et ah, 1994). The enzyme shows considerable sequence homology to spermidine synthase but is distinct from this enz)mie as it only shows PMT activity when expressed in Escherichia coli. MPO has been isolated in pure form from N. tabacum transformed root cultures (McLauchlan et ah, 1993). It is quite widely spread in... 

Figure 2.4 Biosynthesis of the pyrrolizidine alkaloid. senecionine-N-oxide. ODC, ornithine decarboxylase ADC, arginine decarboxylase SPDS, spermidine synthase HHS, homospermidine synthase. (See Plate 9 in colour plate section.)...

Dufe, V. T., Qiu, W., Muller, I. B., Hui, R., Walter, R. D., and Al-Karadaghi, S. (2007). Crystal structure of Plasmodium falciparum spermidine synthase in complex with the substrate decarboxylated S-adenosylmethionine and the potent inhibitors 4MCHA and Ado-DATO. ]. Mol. Biol. 373,167-177. 

Haider, N., Eschbach, M. L., Dias Sde, S., Gilberger, T. W., Walter, R. D., and Luersen, K. (2005). The spermidine synthase of the malaria parasite Plasmodium falciparum Molecular and biochemical characterisation of the polyamine synthesis enzyme. Mol. Biochem. Parasitol. 142,224-236. 

Most pyrrolizidine alkaloids are esters of basic alcohols known as necine bases. The most frequently studied pyrrolizidine alkaloids are formed from the polyamines, putrescine and spermidine, and possess one of three common necine bases retronecine, heliotridine, and otonecine. Putrescine is utilized exclusively as a substrate in secondary metabolism, whereas spermidine is a universal cell-growth factor involved in many physiological processes in eukaryotes. Spermidine biosynthesis begins with the decarboxylation of SAM by SAM decarboxylase 165). The aminopropyl group is then transferred from decarboxylated SAM to putrescine by spermidine synthase to form spermidine (Scheme 5). Putrescine can be produced from ornithine by ODC. However, putrescine is derived from the arginine-agmatine pathway in pyrrolizidine alkaloid-producing plants due to the absence of ODC activity 166). 

Spermidine 4 was biosynthesized from putrescine 2 (NC4N), obtained by ornithine 1, and adenosyl-L-methionine (activated C3 unit). S -Adenosyl-L-methioninamine (decarboxylated 5-adenosyl-L-methionine) donates an aminopropyl group to putrescine 2 to form spermidine 4 in a reaction catalyzed by spermidine synthase. Homospermidine 3 is formed from two moles of putrescine 2 in an NAD" -dependent reaction catalyzed by HSS. Moreover, HSS catalyzes the NADI-dependent transfer of an aminobutyl group of spermidine 4 to putrescine 2 to form homospermidine 3. 

Among these polyamines, putrescine is biosynthesized from ornithine by decarboxylation with ornithine decarboxylase. Putrescine receives a propyl-amino rmit (C3N unit) from decarboxylated SAM (S-adenosylmethionine) to form spermidine. SAM is derived from methionine. Spermidine synthase catalyzes this biosynthetic process. Spermine is formed from spermidine through the addition of a C3N unit from a decarboxylated SAM unit under the catalysis of spermine synthase [3]. 

Fig. 2. Biogenetic links between A primary metabolism and B the alkaloid-specific pathway. CAP, N-carbamoylputrescine GABA, 4-aminobutyric acid. Inhibitors DFMA, a-difluorome-thylarginine, HEH, /1-hydroxyethylhydrazine. Enzymes 1, arginine decarboxylase 2, agmatine iminohydrolase 3, JV-carbamoylputrescine amidohydrolase 4, diamine oxidase 5, pyrroline dehydrogenase (NAD+-dependent) 6, spermidine synthase 7, a putrescine-producing poly-amine oxidase (H H-insensitive) 8, homospermidine synthase 9, an HEH-sensitive polyamine oxidase...

Figure 16 Calculated STD intensities of putrescine in the presence of spermidine synthase nsing CORCEMA" and a range of different values of the dissociation constant and the correlation time of the protein. (Reprodnced from Ref. 44. Elsevier, 2008.)...

Nambeesan S, Datsenka T, Femizzi MG, Malladi A, Mattoo AK, Handa AK (2010) Ovtaexpiession of yeast spermidine synthase impacts ripening, senescence and decay symptrans in tranato. Plant J 63 836-847... 

Neily MH, Matsukura C, Mauconrt M, Bemillon S, Debrnde C, Moing A, Yin YG, Saito T, Mori K, Asamizu E, Rolin D, Moiiguchi T, Ezura H (2011) Enhanced polyamine accumulation alters carotenoid metahohsm at the transcriptional level in tomato fruit overexpressing spermidine synthase. J Plant Physiol 168 242-252... 

Putrescine, which is produced by decarboxylation of ornithine, and also arises from agmatine with catalysis by agmatinase, becomes the starting compound for the biosynthesis of spermidine and spermine. These reactions are catalysed by spermidine synthase and spermine synthase, respectively, involving S-adenosyl-L-methionine (for short AdoMet or SAM), and take place from bacteria to mammals (Figure 10.16). S-Adenosyl-L-methionine amide (dSAM) formed by decarboxylation of SAM provides trimethylene amine residue for this biosynthesis, which yields S-methyl-5 -thioadenosine (MTA). 

Specific activities of S-adenosylmethionine decarboxylase (A) and spermidine synthase (B) in rhesus monkey brain during development. From Sturman and Gaull, 1975. 

A Wadsworth-Emmons reaction on an adenosine 5 -aldehyde derivative was a key step in the synthesis of adenosylspermidine (214), an inhibitor of spermidine synthase. ... 

Figure 4.13 Biosynthesis of pyrrolizidine alkaloids showing the sites of action of enzymes for which corresponding genes have been isolated. Enzyme abbreviations SAMDC, S-adenosylmethionine decarboxylase HSS, homospermidine synthase SS, spermidine synthase.

The three-dimensional structure of the PMT active site is not known. The protein structure of a Thermotoga maritima spermidine synthase obtained by protein crystallisation (229) suggested that those amino acids of the SPDS active site that were continuously different between PMTs and SPDS were responsible for the differences in co-substrate acceptance. Mutagenesis of those two amino acids in the D. stramonium PMT with the idea of changing PMT activity into spermidine synthase, however, resulted in a complete loss of catalytic activity (88). A refined protein model of PMT constructed as a consequence of the result discouraged the concept of comparable substrate and co-substrate binding in PMT and SPDS. Rather, the substrate putrescine binds differentially at the active sites of both enzymes. 

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