Decarboxylase S-adenosylmethionine

One of the most compelling targets in the polyamine biosynthesis pathway has been S-adenosylmethionine decarboxylase (SAM-DC). This target was chemically validated with the discovery of trypanocidal activity of MDL-73811 nearly two decades ago. Work to understand the unique kinetics for inhibition of this enzyme in T. brucei has shown that a catalytically... 

Aminooxy compounds can be viewed as O-ethers of HA and are discussed here in terms of their potential anticancer activity. Thus, l-aminooxy-3-aminopropane (APA) is a potent reversible inhibitor of mammalian ornithine decarboxylase (ODC) and of S-adenosylmethionine decarboxylase (SAMDC) , and 6 -(5 -deoxy-5 -adenosyl)methylsul-fonium 0-ethylhydroxylamine (AMA) was reported to be an efficient reversible inhibitor of the latter enzyme . 

S-Adenosylmethionine decarboxylase is the first enzyme in the biosynthetic pathway to spermidine (Chapter 24). Whether isolated from bacteria, yeast, animals, or other eukaryotes, this enzyme always contains a bound pyruvoyl group.273 274b Both the... 

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... 

Similarly, candidate leads discovered in the ODC assay could act by inhibiting H. contortus ODC or yeast S-adenosylmethionine decarboxylase [40], A single confirmed positive was tested for inhibition of both enzymes in assays using extracts of the recombinant S. cerevisiae. The compound, stilbamidine isethionate, was shown in these experiments to inhibit S-adenosylmethionine decarboxylase, but not ODC [40], and no further work was done with it. 

Other pyruvate-containing enzymes include aspartate -decarboxylase from Escherichia coli, the enzyme that catalyzes the formation of -alanine for the synthesis of pantothenic acid (Section 12.2.4) proline reductase from Clostridium sticklandiv, phosphatidylserine decarboxylase from E. coli and phenylalanine aminotransferase from Pseudomonas fluorescens. Phospho-pantetheinoyl cysteine decarboxylase, involved in the synthesis of coenzyme A (Section 12.2.1), and S-adenosylmethionine decarboxylase seem to be the only mammalian pyruvoyl enzymes (Snell, 1990). 

Stanek, J., Caravatti, G., Capraro, H.-G., Furet, P, Mett, H., Schneider, P, Regenass, U. S-Adenosylmethionine decarboxylase inhibitors new aryl and heteroaryl analogues of methylglyoxal bis(guanylhydrazone). J. Med. Chem. 1993, 36, 46-54. 

Birkholtz, L. M., Wrenger, C., Joubert, F., Wells, G. A., Walter, R. D., and Louw, A. I. (2004). Parasite-specific inserts in the bifunctional S-adenosylmethionine decarboxylase/ornithine decarboxylase of Plasmodium falciparum modulate catalytic activities and domain interactions. Biochem.. 377,439-448. 

Muller, S., Da dara, A., Luersen, K., Wrenger, C., Das Gupta, R., Madhubala, R., and Walter, R. D. (2000). In the human malaria parasite Plasmodium falciparum, polyamines are synthesized by a bifunctional ornithine decarboxylase, S-adenosylmethionine decarboxylase.. Biol. Chem. 275,8097-8102. 

Pyruvoyl cofactor is derived from the posttranslational modification of an internal amino acid residue, and it does not equilibrate with exogenous pyruvate. Enzymes that possess this cofactor play an important role in the metabolism of biologically important amines from bacterial and eukaryotic sources. These enzymes include aspartate decarboxylase, arginine decarboxylase," phosphatidylserine decarboxylase, . S-adenosylmethionine decarboxylase, histidine decarboxylase, glycine reductase, and proline reductase. ... 

Wright, P. S., Byers, T. L., Cross-Doersen, D. E., McCann, P. P. and Bitonti, A. J. (1991) Irreversible inhibition of S-adenosylmethionine decarboxylase in Plasmodium falciparum-infected erythrocytes Growth inhibition in vitro. Biochem. Pharmacol. 41 1713-1718. 

Treatment of Caco-2 cells with 50 pg/ml of procyanidin-emiched (PE) extracts from cocoa caused a 70% growth inhibition with a blockade of the cell cycle at the G2/M phase. PE extracts caused a significant decrease of ODC and S-adenosylmethionine decarboxylase activities, two key enzymes of polyamine biosynthesis, which might be an important target in the antiproliferative effects of cocoa polyphenols. ... 

H2. Hannonen, P., Raina, A., and Janne, J., Polyamine synthesis in the regenerating rat liver Stimulation of s-adenosylmethionine decarboxylase, and spermidine and spermine synthases after partial hepatectmny. Biochim. Biophys. Acta 273,... 

Fig. 20.3 Pathway of methionine metabolism. The numbers represent the following enzymes or sequences (1) methionine adenosyltransferase (2) S-adenosylmethionine-dependent transmethylation reactions (3) glycine methyltransferase (4) S-adenosylhomocysteine hydrolase (5) betaine-homocysteine methyltransferase (6) 5-methyltetrahydrofolate homocysteine methyltransferase (7) serine hydroxymethyltransferase (8) 5,10-methylenetetrahydrofolate reductase (9) S-adenosylmethionine decarboxylase (10) spermidine and spermine synthases (11) methylthio-adenosine phosphorylase (12) conversion of methylthioribose to methionine (13) cystathionine P-synthase (14) cystathionine y-lyase (15) cysteine dioxygenase (16) cysteine suplhinate decarboxylase (17) hypotaurine NAD oxidoreductase (18) cysteine sulphintite a-oxoglutarate aminotransferase (19) sulfine oxidase. MeCbl = methylcobalamin PLP = pyridoxal phosphate...

Tyramine methyltransferase from barley roots Norbelladine-O-mediyltransferase from amarylis bulbs ImidazoIe-N-methyltransferase from guinea pig brain (2.1.1.8) Hydroxyindole-O-methyltransferase from pineal (2.1.1.4) Homocysteine-S-methyltransferase from yeast (2.1.1.10 ) S-Adenosylmethionine cyclotransfeiase from yeast (2.5.1.4) S-Adenosylmethionine decarboxylase from E. coli... 

Table 2. Activities of Ornithine and S-Adenosylmethionine Decarboxylases and Concentrations of Putrescine and Spermidine in Human Brain and Liver...

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

The cyclopentene derivative 82 has been prepared from 2, 3 -0-isopropylidene-5 -thioadenosine, and was an irreversible inhibitor of S-adenosylmethionine decarboxylase. ... 

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.

Secrist, in a plenary lecture, has described the synthesis of new substrate analogues as inhibitors of S-adenosylmethionine decarboxylase. The compounds made were of type (31), where E is a... 

Giles TN, Graham DE (2008) Crenarchaeal arginine decarboxylase evolved from an S-adenosylmethionine decarboxylase enzyme. J Biol Chem 283 25829-25838... 

Kim AD, Graham DE, Seeholzer SH, Markham GD (2000) S-Adenosylmethionine decarboxylase from the archaeon Methanococcus jannaschii identification of a novel family of pyruvoyl enzymes. J Bacteriol 182 6667-6672... 

Lu ZJ, Markham GD (2004) Catalytic properties of the archaeal S-adenosylmethionine decarboxylase from Methanococcus jannaschii. J Biol Chem 279 265-273... 

Ruan H, Shantz LM, Pegg AE, Morris DR (1996) The upstream open reading frame of the mRNA encoding S-adenosylmethionine decarboxylase is a polyamine-responsive translational control element. J Biol Chem 271 29576-29582... 

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