Ornithine decarboxylases

The enzyme that catalyzes the decarboxylation of ornithine to putrescine is a key factor in the biosynthesis of polyamines ornithine decarboxylase is involved in the control of cell regulation, differentiation, and growth. 

The assay described by Haraguchi et al (1980) involves a preparation on CellexP, a conversion to the fluorescent derivative with fiuorescamine, and separation on HPLC. 

The column was LiChrosorb RP-18, and the separation was carried out by elution with a gradient of 45 to 80% methanol and 0.1 M ammonium chloride in an acetate buffer (pH. 4.0). 

The incubation mixture contained ornithine, pyridoxyl phosphate, and the enzyme. After incubation for 1 hour, the reaction was terminated with perchloric acid. The precipitate was removed by centrifugation, the supernatant extracted with chloroform-methanol (2 1), and the aqueous layer applied to a CellexP column. The putrescine was eluted, reacted with fluorescamine, and quantitated by HPLC. 

The enzyme was from rat intestinal mucosa and was partially purified by a 20 to 80% precipitation with ammonium sulfate. 

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This technique can be applied to prepare DL-a-fluoromethylputrescme (5-fluoropentane 1,4-diamine), a potent irreversible inhibitor of E colt ornithine decarboxylase, from 4-phthalimido-l -butyryl chloride, diazomethane, and hydro gen fluonde-pyridine [94 95]... 

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]. 

Eflornithine (difluoromethylornithine, DFMO) inhibits the ornithine decarboxylase of the polyamine pathway, in both the trypanosome and the mammalian cell, by acting as an irreversible competitor of the natural substrate ornithine. Inhibition of ornithine decarboxylase results in depletion of the polyamines, putrescine, spermidine and spermine, which are essential for cell proliferation. Eflornithine selectively harms the parasite and not the mammalian cells, despite acting as an ornithine decarboxylase inhibitor in both cell types. This selectivity is explained by the lower rate of ornithine decarboxylase production in the parasite, as compared to mammalian cells. Due to the high turnover rate, mammalian cells are capable of quickly replenishing inhibited ornithine decarboxylase by newly... 

MAJUMDAR A p (1990) Role of tyrosine kinases in gastrin induction of ornithine decarboxylase in colonic mucosa. Am J Physiol. 259 (4 Ptl) G626-G630. 

Guyton, K. Dolan, P. M. Kensler, T. W. Quinone methide mediates in vitro induction of ornithine decarboxylase by the tumor promoter butylated hydroxytoluene hydroperoxide. Carcinogenesis 1994, 15, 817-821. 

Xanthine oxidase (1-Lactamase Ornithine decarboxylase Steroid 5a-reductase Thymidylate synthase Aromatase... 

Biosynthesis of polyamines is essential for growth and multiplication of T. brucei, hence discovery of drug candidates that inhibit enzymes in the polyamine biosynthesis pathway represent an attractive approach to development of trypanocides. The consequences of gene knockout of ornithine decarboxylase (ODC), the target of eflornithine (3), have been further characterized and suggest that new inhibitors of this enzyme may be particularly effective [18]. 

Eflornithine, DL-a-difluoromethylornithine Ornithine decarboxylase Suicide substrate... 

Administration of single oral doses of 90 or 120 mg/kg mirex by gavage to female Sprague-Dawley rats resulted in induction of hepatic ornithine decarboxylase activity there was, however, no evidence of significant damage to deoxyribonucleic acid (DNA) as measured by alkaline elution (Mitra et al. 1990). 

In agreement with hepatic functional activity studies conducted with mirex, chlordecone administered orally to female Sprague-Dawley rats at 1/5 and 3/5 of the LDso (19 and 57 mg/kg, respectively) caused a significant increase in ornithine decarboxylase activity, but there was no evidence of DNA damage at either level (Kitchin and Brown 1989). 

In animal studies, mirex (a nonmutagenic hepatocarcinogen) promoted mouse skin squamous carcinomas and papillomas after initiation with 7,12-dimethyl-benz[a]anthracene (DMBA) for 1 week. Mirex, also, potentiated the promotional potency of the phorbol ester tumor promoter, 12-0 -tetradecanoylphorbol-13-acetate (TPA). There was a 90% incidence (activation) of the c-Ha-ras tumor gene in these co-promoted tumors. When both mirex and TPA gave a similar tumor yield, only the TPA response was associated with biochemical markers of enhanced cell proliferation, induction of epidermal ornithine decarboxylase activity and increased DNA synthesis, and hyperplasia. Thus, there is evidence for a dual effect of mirex during co-promotion first, as an independent tumor promoter with a mechanism different than that of phorbol esters and second, as a compound that also potentiates skin tumor promotion by TPA (Meyer et al. 1993, 1994 Moser et al. 1992, 1993). 

Pretreatment of rats with difluoromethylornithine (DFMO), an inhibitor of ornithine decarboxylase, prior to exposure to a tremorigenic dose of chlordecone, also resulted in inhibition of the tremor (Tilson et al. 1986b). DFMO was more effective if given 5 hours prior to the chlordecone than if given 24 hours prior to exposure. The DFMO was ineffective if given 19 hours after chlordecone exposure. These results suggest an interaction of the polyamine synthetic pathway with tremors produced by chlordecone. The mechanism of the interaction is unclear but may involve effects of polyamines on intracellular calcium homeostasis. Persons being treated with DFMO for cancer or protozoal infections would be likely to have reduced tremor severity after exposure to chlordecone. 

Bondy SC, Hong JS. 1987. Modulation of adrenal ornithine decarboxylase by chlordecone, p,p -DDT and permethrin. Neurotoxicology 8(l) 15-22. 

Mitra A, Richards I, Kitchin K, et al. 1990. Mirex induces ornithine decarboxylase in female rat liver. J Biochem Toxicol 5(2) 119-124. 

Tilson HA, Emerich D, Bondy SC. 1986a. Inhibition of ornithine decarboxylase alters neurological responsiveness to a tremorigen. Brain Res 379(1) 147-150... 

Yarbrough JD, Grimley JM, Karl PI. 1986b. Relationship of ornithine decarboxylase and thymidine kinase to mirex-induced liver growth. Am J Physiol 251 G859-G865. 

The 26S proteasome also degrades non-ubiquitylated proteins [71]. The short-lived enzyme ornithine decarboxylase (ODC) and the cell-cycle regulator p21Cip provide well documented examples of ubiquitin-independent proteolysis by the 26S en-... 

Murakami, Y. et al. Ornithine decarboxylase is degraded by the 26S proteasome without ubiquitination. Nature 1992, 360, 597-9. 

Zhang, M., Pickart, C. M., and CoEFiNO, P. Determinants of proteasome recognition of ornithine decarboxylase, a ubiquitin-independent substrate. Embo J 2003, 22, 1488-96. 

Murakami, Y., Matsueuji, S., Hayashi, S. I., Tanahashi, N., and Tanaka, K. ATP-Dependent inactivation and sequestration of ornithine decarboxylase by the 26 S proteasome are prerequisites for degradation. Mol Cell Biol 1999, 39, 7216-27. 

Kameji, T., Hayashi, S., Igarashi, K., Tamura, T., Tanaka, K., and Ichihara, a. Ornithine decarboxylase is degraded by the 26 S proteasome without ubiquitination. Nature 1992, 360, 597-599. 

ATP- and antizyme-dependent endoproteolysis of ornithine decarboxylase to oligopeptides by the 26S proteasome. J. Biol. Chem. 1994, 269, 17382-17385. 

Yatin SM, Yatin M, Aulick T, Ain KB, Butterfield DA. (1999). Alzheimer s amyloid beta-peptide associated free radicals increase rat embryonic neuronal polyamine uptake and ornithine decarboxylase activity protective effect of vitamin E. Neurosci Lett. 263(1) 17-20. 

Endo Y Simultaneous induction of histidine and ornithine decarboxylases and changes in their product amines following the injection of Escherichia coli lipopolysaccharide into mice. Biochem Pharmacol 1982 31 1643-1647. 

Rodriquez-Jerez, J., Mora-Ventura, M.T., Lopez-Sabater, E.I. and Hemandez-Herrero, M. (1994). Histidine, lysine, and ornithine decarboxylase bacteria in Spanish salted semipreserved anchovies, J. Food Prot., 57, 784. 

Savage RE Jr., DeAngelo AB, Guion C, et al. 1987. Studies on the mechanism of action of chloroform stimulation of rat hepatic ornithine decarboxylase (ODC). Res Commun Chem Pathol Pharmacol 58 97-113. 

Savage RE Jr., Nofzinger K, Bedell C, et al. 1989. Chloroform-induced multiple forms of ornithine decarboxylase Differential sensitivity of forms to enhancement by diethyl maleate and inhibition by ODC-antizyme. J Toxicol Environ Health 27 57-64. 

Savage RE Jr., Pereira MA, DeAngelo AB. 1988. Chloroform induction of ornithine decarboxylase antizyme (ODC-AZ) in male rat liver. J Toxicol Environ Health 1 97-101. 

II. 1, 5,6f Odd -151 kbR 12A1.1 0 Ornithin-Decarboxylase 1, checkpoint that guards against tumourogenesis 2... 

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