Ornithine decarboxylase regulation

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-... 

Wang, and C. H. Cho. Interactions of EGF and ornithine decarboxylase activity in the regulation of gastric mucus synthesis in cigarette smoke exposed rats. Chin J Physiol 1999 42(3) 137-143. 

Ornithine decarboxylase catalyzes the conversion of ornithine into putrescine. Like other polyamines, the latter is involved in the regulation of cell development. Inhibition of this enzyme has been an important goal in medicinal chemistry. In this context, difluoroornithine has been shown to be an excellent inhibitor... 

Metabolism of polyamines has a direct action on cell proliferation. Thus, it is a therapeutic target for the design of antitumor agents. However, inhibition of ornithine decarboxylase (ODC) by specific inhibitors does not completely cancel the activity. This is due to the existence of other biosynthetic pathways (i.e., SAM-DC). These pathways are themselves regulated by polyamines. 

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... 

This sequence is followed closely by an element of secondary structure, most often a pseudoknot.486 492 Eukaryotic frameshifts are almost always in the -1 direction, the exception being found in the mammalian mRNA for antizyme, a negative regulator of ornithine decarboxylase (Chapter 24, p. 1382).493 The frame-shift occurs at an initially in-frame termination codon (UGA), which is followed by a pseudoknot. 

Ornithine decarboxylase catalyzes the transformation of ornithine to the polycationic bases, putresine, spermine, and spermidine. These compounds exert regulatory effects on cell growth. It has been shown that quercetin (10 to 30 pmol/mouse) markedly suppressed the stimulatory effect of the transporters associated with antigen processing (TPA) on ornithine decarboxylase (ODC) activity and on skin tumor formation in mice initiated with dimethylbenzanthracene. Such inhibition may be related to the activation of the catalytic site, which is under nonconventional regulation by small molecules. Also, the synthetic flavonoid flavone acetic acid was shown to inhibit the activity of ODC in stimulated human peripheral blood lymphocytes and human colonic lamina propria lymphocytes. 

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. 

Polyamine biosynthesis is associated with regulation of a number of metabolic functions including growth of cells in most of the living organisms. In mammals, ornithine is the precursor of aliphatic polyamines. Putrescine, formed by decarboxylation of the former by ornithine decarboxylase, is the first amine formed in polyamine biosynthesis. Putrescine gives rise to the other two polyamines, spermine and spermidine by successive addition of 3-aminopropyl residues derived from S-adenosyl-L-methionine (SAM) in the presence of different enzymes [44] (Chart 7). 

Bateman, 1994). Coleman and colleagues (1994) have documented rapid exchange between subunits of dimeric ornithine decarboxylase and suggest that this exchange facilitates regulation by antizyme. In contrast, there is no evidence for a rapid equilibrium between subunits of the 14-subunit chaperone GroEL (A. Horwich, personal communication), or in a number of other multisubunit enzymes (Distefano et al., 1990 Perry et al., 1992 Wente and Schachman, 1987). The potential importance of subunit exchange to sHsp function is discussed further below. 

Degradation rates also affect enzyme concentration and hence reaction rates. One of the most highly regulated enzymes in the body, ornithine decarboxylase, is regulated, in large part, by control of the amount of enzyme present. We now examine some of these processes in more detail. 

Russell, K.H. and Haddox, M.K., Cyclic AMP-mediated induction of ornithine decarboxylase in normal and neoplastic growth, Adv. Enzyme Regul, 17, 61, 1979. 

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. 

Geshauler C. et al., Rotenoids mediate potent chemopreventive activity through transcriptional regulation of ornithine decarboxylase, Nature AfeJ., 1,260,1995. 

Polyamines are formed from ornithine and SAM, thus aflEording an alternative fate for this purine derivative (P3). The polyamines, as well as adenosine, regulate transmethylation (Hll, L3). Ornithine decarboxylase is produced in greater quantity in rapidly dividing cells (B17, D7, Rl, RIO). Levels of S-adenyosylmethionine decarboxylase are also increased in such tissues (H2, R9). There is evidence that this increase is cyclic AMP mediated (B7), This ties these compounds although indirectly to adenosine concentrations. 

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