Of ornithine

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... 

Transamination is not restricted to a-amino groups. The 5-amino group of ornithine—but not the e-amino group of lysine—readily undergoes transamination. Serum levels of aminotransferases are elevated in some disease states (see Figure 7-11). 

L-Ornithine transcarbamoylase catalyzes transfer of the carbamoyl group of carbamoyl phosphate to ornithine, forming citrulline and orthophosphate (reaction 2, Figure 29-9). While the reaction occurs in the mitochondrial matrix, both the formation of ornithine and the subsequent metabolism of citmlline take place in the cytosol. Entry of ornithine into mitochondria... 

Hyperammonemia Type 2. A deficiency of ornithine transcarbamoylase (reaction 2, Figure 29-9) produces this X chromosome-linked deficiency. The mothers also exhibit hyperammonemia and an aversion to high-protein foods. Levels of glutamine are elevated in blood, cerebrospinal fluid, and urine, probably due to enhanced glutamine synthesis in response to elevated levels of tissue ammonia. 

Tuchman M et al The biochemical and molecular spectrum of ornithine transcarbamoylase deficiency. J Inherit Metab Dis 1998 21 40. 

Since pyrimidine catabolites are water-soluble, their overproduction does not result in clinical abnormalities. Excretion of pyrimidine precursors can, however, result from a deficiency of ornithine transcar-bamoylase because excess carbamoyl phosphate is available for pyrimidine biosynthesis. 

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. 

Also N, N -bisprotected pyrazole-l-carboxamidines are applied for preparation of guanidines.[91,[9al A variation of this reaction permitted the copper salt of ornithine to be converted to the copper salt of arginine [10]... 

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]. 

Carbamyl phosphate condenses with ornithine to yield citrulline in the ornithine transcarbamylase (OTC) reaction. OTC is encoded on band p21.1 of the X chromosome, where the gene contains 8 exons and spans 85 kb of DNA. The activity of this enzyme is directly related to dietary protein. There may be tunneling of ornithine transported from the cytosol to OTC, with the availability of intramitochondrial ornithine serving to regulate the reaction. 

The underlying biochemical defect is a failure of mitochondrial uptake of ornithine. This results in a failure of citrulline synthesis and a consequent hyperammonemia. Urinary orotic acid is high, presumably because of underutilization of carbamyl phosphate. In contrast, excretion of creatine is low, reflecting the inhibition of glycine trans-amidinase by excessive levels of ornithine. 

The cause is defective transport of dibasic amino acids by the proximal tubule and intestine. The transport defect occurs at the basolateral rather than the luminal membrane. Hyperammonemia reflects a deficiency of intra-mitochondrial ornithine. An effective treatment is oral citrulline supplementation, which corrects the hyperammonemia by allowing replenishment of the mitochondrial pool of ornithine. 

A series of 1-aminoalkanediphosphonic acids has been reported by the treatment of the N-phenylthiourea derivatives of a>-diethoxyphos-phinoylaldehydes with triphenyl phosphite.343 This constitutes an approach toward the analogues of aspartic and glutamic acid in which both carboxylate sites have been replaced by phosphonic acid functions. A similar approach has also been reported to be of use for the preparation of (diphenyl ester) phosphonate analogues of ornithine, lysine, and homolysine.344345... 

Hamilton, R., Walker, B., and Walker, B.J., A convenient synthesis of N-pro-tected diphenyl phosphonate ester analogues of ornithine, lysine and homolysine, Tetrahedron Lett., 34, 2847, 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. 

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. 

However Henseleit showed there was a correlation between the concentration of ornithine and the magnitude of the effect on urea production. That the absolute amounts of ornithine were so small provided Krebs with arguments for the idea that the ornithine acted catalytically. 

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. 

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

Answer E. Given these symptoms, the defect is in the urea cycle and the elevated orotate suggests deficiency of ornithine transcarbamoylase. 

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. 

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