Ornithine decarboxylase polyamine synthesis

Protein synthesis initiation by IF-2 Protein synthesis elongation hy EF-Tu and EF-G Polyamine synthesis by ornithine decarboxylase rRNA synthesis by RNA polymerase Acetyl-CoA carboxylase"... 

Ornithine decarboxylase is a pyridoxal dependent enzyme. In its catalytic cycle, it normally converts ornithine (7) to putrisine by decarboxylation. If it starts the process with eflornithine instead, the key imine anion (11) produced by decarboxylation can either alkylate the enzyme directly by displacement of either fluorine atom or it can eject a fluorine atom to produce viny-logue 12 which can alkylate the enzyme by conjugate addidon. In either case, 13 results in which the active site of the enzyme is alkylated and unable to continue processing substrate. The net result is a downturn in the synthesis of cellular polyamine production and a decrease in growth rate. Eflornithine is described as being useful in the treatment of benign prostatic hyperplasia, as an antiprotozoal or an antineoplastic substance [3,4]. 

Genetic factors influence the rate of not only synthesis of proteins but also their breakdown, i.e., the rate of turnover. As we have seen in Chapter 10, some enzymes are synthesized as inactive proenzymes which are later modified to active forms, and active enzymes are destroyed, both by accident and via deliberate hydrolytic pathways. Protein antienzymes may not only inhibit enzymes but may promote their breakdown.35 An example is the antienzyme that controls ornithine decarboxylase, a key enzyme in the synthesis of the polyamines that are essential to growth.36,37 As with all cell constituents, the synthesis of enzymes and other proteins is balanced by degradation. 

Tire synthesis of polyamines is tightly regulated. The PLP-dependent ornithine decarboxylase is present in very low concentrations226 and apparently has the shortest half-life ( 10 min) of any mammalian... 

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... 

Ornithine decarboxylase (ODC) is the first enzyme in the polyamine biosynthesis pathway. Polyamines play essential roles in cell proliferation and differentiation and participate in macromolecular synthesis. Inhibitors of ODC block aspects of tumor promotion and induce cellular differentiation in several animal carcinogenesis models. Thus induction of ODC has been implicated as being important to carcinogenesis, and ODC activity is an intermediate biomarker of cell proliferation in studies... 

The half-lives of proteins range over several orders of magnitude (Table 23.1). Ornithine decarboxylase, at approximately 11 minutes, has one of the shortest half-lives of any mammalian protein. This enzyme participates in the synthesis of polyamines, which are cellular cations essential for growth and differentiation. The life of hemoglobin, on the other hand, is limited only by the life of the red blood cell, and the lens protein, crystallin, by the life of the organism. 

Aminopropylation The transfer of decarboxylated SAMe is crucial to the synthesis of polyamines (spermine, spermidine, putresdne). Together with ornithine decarboxylase, SAMe determines the synthesis rate of polyamines, which are essential for cell regeneration. At 30 — 60 minutes, the half-fife of SAMe decarboxylase is very short and thus readily adaptable to various metabolic situations. 

Efiornithine, Eflomithine acts ty inhibiting the enzyme ornithine decarboxylase (ODC) in the hair follicles of the human skin (93). The enzyme is necessary for the synthesis of polyamines. Animal data indicates that inhibiting ODC inhibits cell division and synthetic function and therefore inhibits hair growth. It is postulated that eflomithine causes irreversible inhibition of the enzyme. 

Like helminths, some protozoans also require polyamines for their cell growth, membrane stabilization and as cofactors for macromolecular synthesis. Trypanosomes have been found to possess putrescine and spermidine, but not spermine. The precursor of the polyamine biosynthesis in protozoans is ornithine, which is de-carboxylated in the presence of ornithine decarboxylase to form putrescine. Other polyamines are formed from putrescine as discussed in chapter 2 (Sec. 5.3). 

Wrenger, C., Luersen, K., Krause, T., Muller, S., and Walter, R. D. (2001). The Plasmodium falciparum bifunctional ornithine decarboxylase, S-adenosyl-L-methionine decarboxylase, enables a well balanced polyamine synthesis without domain-domain interaction. ]. Biol. Chem. 276,29651-29656. 

Synthesis of polyamines in the majority of cells is initiated by ornithine decarboxylase (ODC EC 4.1.1.17), which catalyses the conversion of ornithine to putrescine (Fig. 7.1) (4,13). In mammalian cells ODC undergoes rapid induction and has a short half-life. In the parasitic protozoa so far examined (T. b. brucei, P. falciparum, L. donovani and T. vaginalis), ODC has a long half-life as judged from the rate of decay of activity in the presence of cycloheximide (14-17). In African trypanosomes the slow turnover of ODC appears to be attributable to the absence of a 36 amino acid region (PEST sequence) on the COOH-terminal end (18,19). In mammalian cells, this is... 

Like purine metabolism, the polyamine biosynthetic pathway has served as another paradigm for rational therapeutic intervention in parasitic disease. Polyamine synthesis in T. brucei and Leishmania, like that in mammalian cells, is initiated by the enzyme ornithine decarboxylase (ODCase), although T. cruzi may synthesize polyamines by... 

NO has a cytostatic effect by inhibiting ATP synthesis [99] via Kreb s cycle (aconitase inhibition, [100]), glycolysis (GADPH inhibition) and mitochondrial respiration (NAD ubiquinone oxydoreductase and succinate ubiquinone oxydoreductase inhibitions, [101]). Another pathway is the ornithine decarboxylase inhibition. This enzyme is implicated in polyamine production necessary to cell proliferation and its activity is inhibited by NO in human colon cancer cells HT-29 and Caco-2 [102]. Furthermore NO directly inactivates ribonucleotide reductase [103] of TA3 cancer cells (murine breast cancer cells) [104]. This enzyme controlling DNA synthesis catalyses desoxyribonucleotides synthesis, and its inhibition blocks cells in S phase. This inhibition is rapid and reversible in K562 and TA3 cells [105]. 

Eflomithine inhibits ornithine decarboxylase it irreversibly inhibits both mammalian and try-panosomal enzymes, thereby preventing the synthesis of polyamines needed for cell division. The parasite and human enzymes are equally susceptible to eflomithine, but the mammalian enzyme is turned over rapidly, whereas the parasite enzyme is stable. T. brucei rhodesiense cells are less sensitive to eflomithine inhibition than T. brucei gambiense cells, and effective levels generally cannot be achieved clinically. 

The IGF-I-independent actions of GH are exerted primarily in hepatocytes. GH administration is followed by an early increase in the synthesis of 8 to 10 proteins, among which are IGF-I, a2-macroglobulin, and the serine protease inhibitors Spi 2.1 and Spi 2.3. Expression of the gene for ornithine decarboxylase, an enzyme active in polyamine synthesis (and, therefore, in the regulation of cell proliferation), is also significantly increased by GH. 

Metcalf et al. (23) reported the synthesis of efiornithine (difluoromethyl ornithine [DFMO]) in 1978. Their interest arose from the desire to prepare ornithine decarboxylase (ODC) inhibitors as tools for studying the role of polyamines as regulators of growth processes. Ornithine decarboxylase catalyzes the conversion of ornithine to putrescine (1,4-diaminobutane), which in turn leads to the formation of the polyamines, spermine, and spermidine. It was not until 1980 that Bacchi et al. (24) demonstrated the potential of DFMO in the treatment of trypanosomiasis. 

A more dramatic difference is seen with ornithine decarboxylase (EC 4.1.1.17). This enzyme catcJyses the rale-limiting step in polyamine synthesis, and its activity in many tissues and organisms correlates well with the rate of DNA synthesis and cell proliferation. Its turnover is one of the most rapid of all enzymes, generally having a half-life of less than 20 min. Bullfield et al. (1988) have found a 20-fold higher activity in the skeletal muscle from the broiler strain compared with that in a layer strain of domestic fowl at one week of age. TTiis increased activity is almost certainly achieved by an increase in fcs with little change in fca-... 

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