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PubMed1986

The ornithine requirement of urea synthesis. Formation of ornithine from glutamine in hepatocytes.

In hepatocytes, urea synthesis from glutamine is independent of added ornithine, even when rates are high after stimulation of glutamine metabolism by dibutyryl cyclic AMP, phenylephrine or vasopressin. Incubation with glutamine increases tissue [ornithine]. The increases parallel those of [N-acetylglutamate] under different conditions. The ornithine requirement of urea synthesis increases with increasing supply of ammonia. A function of the unique, highly regulated, glutaminase of liver may be to regulate ornithine synthesis.

Ammonium Chloride↗
PubMed1990

Action of ornithine alpha-ketoglutarate, ornithine hydrochloride, and calcium alpha-ketoglutarate on plasma amino acid and hormonal patterns in healthy subjects.

Ornithine alpha-ketoglutarate (OKG) has been useful as an adjuvant of enteral and parenteral nutrition. However, its metabolism and mechanism of action remain unclear although it is known that alpha-ketoglutarate (alpha KG) and ornithine (ORN) follow, in part, common metabolic pathways. Six fasting healthy male subjects underwent three separate oral load tests: (i) they received 10 g of OKG (i.e., 3.6 g of alpha KG and 6.4 g of ORN); (ii) 6.4 g of ORN as ornithine hydrochloride, and (iii) 3.6 g of alpha KG as calcium alpha-ketoglutarate. Blood was drawn 15 times over a five-hour period for measurements of plasma amino acids, alpha KG, insulin, and glucagon. After OKG and ORN administration, plasma ORN peaked at 60-75 min (494 +/- 91 and 541 +/- 85 mumol/L). The increase in plasma alpha KG was very small. OKG, alpha KG, and ORN all increased glutamate concentrations at 60 min (mean: +43%, +68%, +68%, respectively, p less than 0.05 compared to basal values). However, only OKG increased proline and arginine levels at 60 min (mean: +35%, p less than 0.01 and mean: +41%, p less than 0.05). Furthermore, glutamate, proline, and arginine concentrations correlated linearly with ornithine levels at 60 min. Finally, OKG increased insulinemia and glucagonemia (mean: +24% at 15 min, p less than 0.05 and +30% at 60 min, p less than 0.01, respectively). These data provide evidence that the combination of ORN and alpha KG modifies amino acid metabolism in a way which is not observed when they are administered separately. In addition, the OKG-mediated increase in insulin levels probably does not appear to result from a direct action of ORN on pancreatic secretion.

Administration, Oral↗
PubMed1989

Ornithine aminotransferase activity, tissue ornithine concentrations and polyamine metabolism.

1. Inactivation of L-ornithine:2-oxoacid aminotransferase (OAT) by 5-fluoromethylornithine (5FMOrn), a specific inactivator of OAT, causes a great elevation of tissue ornithine (Orn) concentrations. 2. Inhibition of L-ornithine decarboxylase (ODC) by 2-difluoromethylornithine (DFMO) had no effect on Orn concentrations. 3. The combined administration of 5FMOrn and DFMO produced a 2- to 3-fold greater enhancement of tissue Orn concentrations than treatment with 5FMOrn alone. 4. The increase of tissue Orn concentrations had a long-lasting enhancing effect on polyamine metabolism. 5. In the brain this could be demonstrated by the elevation of putrescine and spermidine concentrations and the increase of spermidine turnover rate. 6. In visceral organs polyamine concentrations were not elevated because polyamines can be eliminated by transport. 7. In line with this notion is the fact that urinary polyamine excretion was increased for several days, even after a single dose of 5FMOrn. 8. Inhibitors of 4-aminobutyric acid:2-oxoglutarate aminotransferase which are also inactivators of OAT had the same effect on polyamine excretion as 5FMOrn.

Animals↗
PubMed1975

Stable multisubstrate adducts as enzyme inhibitors. Potent inhibition of ornithine decarboxylase by N-(5'-phosphopyridoxyl)-ornithine.

The synthesis of several N-(5'-phosphopyridoxyl)-amino acids is described. These compounds, analogs of the Schiff base intermediate involved in enzyme-catalyzed decarboxylation, are potent inhibitors of the cognate amino acid decarboxylases. Kinetic studies using partially purified rat liver ornithine decarboxylase, have shown that N-(5'-phosphopyridoxyl)-ornithine inhibits the enzyme in a non-competitive manner with respect to both ornithine and pyridoxal-5'-phosphate. These findings suggest that the inhibitor binds to the holoenzyme active site in place of the Schiff base intermediate.

Animals↗
PubMed1983

Subcellular distribution of ornithine decarboxylase in rat liver and accessibility of the enzyme to alpha-difluoromethylornithine, an irreversible inhibitor of ornithine decarboxylase.

The subcellular localisation of ornithine decarboxylase and of its synthetic irreversible inhibitor, alpha-difluoromethylornithine, was investigated in control rat livers and in livers of animals in which the enzyme was induced by partial hepatectomy or by treatment with dexamethasone. Ornithine decarboxylase activity was distributed in normal rat liver between the nuclear (40%, mainly nucleolar) and the cytosolic (43%) fractions. Cytosolic liver ornithine decarboxylase was markedly induced after partial hepatectomy or treatment with dexamethasone, whereas the enzyme associated with the nuclear fraction was not induced by these procedures. The irreversible inhibitor was found only in the cytosol fraction and was totally absent from the nuclear fraction.

Animals↗
PubMed1990

Ornithine decarboxylase activity in prostate and tumor: a feasibility study for PET with L-[5-14C]- and L-[5-14C]ornithine.

The aim of this study is to investigate the possibility of measuring ornithine decarboxylase (ODC) activity in tissues such as prostate and tumor, by PET. The ODC activity in vitro and the distribution of L-[1-14C]- and L-[5-14C]ornithine were studied in prostate, tumor, liver and kidney. For the animal models, rats bearing Walker 256 carcinosarcoma, were used. Our results indicate that the ODC activity in prostate is correlated with the difference in uptake between L-[1-14C]- and L-[5-14C]ornithine. Measurement of ODC activity in tumor by PET demands a tumor with an ODC activity comparable to that of prostate. Such a tumor will show a sufficient difference in uptake, which can be detected by PET.

Animals↗
PubMed2007

Does the ornithine-alpha-ketoglutarate ratio influence ornithine alpha-ketoglutarate metabolism in healthy rats?

Ornithine alpha-ketoglutarate (OKG) is a salt composed of 2 molecules of ornithine (ORN) and one molecule of alpha-ketoglutarate (alphaKG). OKG has been used successfully via oral, enteral, and parenteral routes to improve protein status in patients with chronic and acute protein depletion, but its mechanism of action, which is probably multifactorial, is still unclear. A specific metabolic interaction between alphaKG and ORN has been shown to be a key factor in the effects of OKG, but the impact of the ORN/alphaKG ratio (2 molecules of ORN for 1 molecule of alphaKG) has never been discussed. To clarify this point, young (3 weeks old) male Wistar rats in the postabsorptive state received 5 g/kg of either OKG or a mono-ornithine alphaKG (MOKG) salt (ORN/alphaKG ratio = 1:1) in amounts that were either isonitrogenous or isomolar to OKG, or a saline solution (controls) and were killed 1 hour later. In a second experiment, a kinetic study was performed in which rats were killed 1, 2, 3, or 6 hours after OKG, MOKG, or saline administration. Amino acid contents were analyzed in the plasma, liver, jejunal and ileal mucosae, and the extensor digitorum longus (EDL) muscle. The major metabolites detected after intake of OKG or MOKG (ie, ORN, proline [PRO], and glutamate; OKG and MOKG vs control, P < .05) together with the absence of increased arginine and citrulline levels suggested that ORN was mainly metabolized by the ORN aminotransferase pathway, leading to glutamate and PRO production with accumulation persisting at 6 hours postadministration. This study provides new and important data on the influence of the ORN/alphaKG ratio on OKG metabolism: MOKG-treated rats presented less intestinal ORN than OKG-treated rats (MOKG vs OKG, P < .05), suggesting that ORN/alphaKG ratio influences the rate of ORN availability and metabolism. In addition, the metabolic interaction between ORN and alphaKG (ie, in the presence of alphaKG, ORN metabolism is partially diverted toward PRO production), which is characteristic of OKG metabolism, still takes place even if the salt contains only 1 molecule of ORN instead of two.

Animals↗
PubMed1981

alpha-Ethynyl and alpha-vinyl analogues of ornithine as enzyme-activated inhibitors of mammalian ornithine decarboxylase.

alpha-Ethynyl- and alpha-vinylornithine were designed and synthesized as potential enzyme-activated inhibitors of mammalian ornithine decarboxylase. These two new inhibitors produce both immediate and time-dependent inhibition of rat liver ornithine decarboxylase in vitro. The inhibitions exhibition saturation kinetics. The apparent dissociation constants (KI) are 10 and 810 microM, and the times of half-inactivation at infinite concentration of inhibitor (t1/2) are 8.5 and 27 min, respectively, for alpha-ethynyl- and alpha-vinylornithine. In rats, alpha-ethynylornithine causes a rapid dose-dependent decrease of ornithine decarboxylase activity in prostate and, to a lesser extent, in thymus and testis.

Animals↗
PubMed1977

In vivo response of ornithine decarboxylase activity to growth hormone as demonstrated by oxidation of L-ornithine-1-14C in hypophysectomized rats.

An in vivo response of ornithine decarboxylase activity to growth hormone has been demonstrated. In hypophysectomized rats, found to oxidize ornithine at rates comparable to those of normal rats, an acute treatment of growth hormone 4 hours before injection of L-ornithine-1-14C caused a 39% increase in the peak specific activity of carbon dioxide and a 24% increase in the 14CO2 recovered in 5 hours. However, response was not observed when growth hormone was administered chronically rather than acutely.

Animals↗
PubMed1987

Primary and quaternary structure of the catabolic ornithine carbamoyltransferase from Pseudomonas aeruginosa. Extensive sequence homology with the anabolic ornithine carbamoyltransferases of Escherichia coli.

We have determined the complete nucleotide sequence of the arcB gene from Pseudomonas aeruginosa strain PAO and we have purified the arcB product, the catabolic ornithine carbamoyltransferase (EC 2.1.3.3), to apparent homogeneity from the same strain. The N-terminal amino acid sequence, the total amino acid composition and the subunit size of the purified enzyme were in agreement with nucleotide sequencing results, which predict a polypeptide of 336 amino acids (Mr 38,108). Crosslinking experiments suggest that the native enzyme (apparent Mr approx. 420,000) basically consists of a trimer aggregating to form nonamers or dodecamers. The arcB gene of P. aeruginosa had strong homology with the argF and argI genes which code for the anabolic ornithine carbamoyltransferase isoenzymes in Escherichia coli; 63% of the nucleotides and 57% of the amino acids were absolutely conserved in arcB and argF. This indicates a close evolutionary relationship between these genes although their products have different physiological functions in the cell. Under conditions of induction (energy depletion) the catabolic ornithine carbamoyltransferase represented greater than or equal to 10% of the total cellular protein. Like other highly expressed Pseudomonas genes, the arcB gene was found not to use seven codons which correspond to minor or weakly interacting tRNA species in E. coli.

Amino Acid Sequence↗
PubMed1999

A typical bacterial ornithine-containing lipid Nalpha-(D)-[3-(hexadecanoyloxy)hexadecanoyl]-ornithine is a strong stimulant for macrophages and a useful adjuvant.

Nalpha-[3-(Hexadecanoyloxy)hexadecanoyl]-ornithine is a typical bacterial ornithine-containing lipid (OL). The configuration of the 3-hydroxy fatty acids in the OL was proved to be D by using HPLC with chiral column. For this analysis, Nalpha-(D or L)-[3-(hexadecanoyloxy)hexadecanoyl]-L-ornithine were synthesized and used as standards. The typical bacterial OL, as well as the synthesized one, exhibited strong interleukin-1- and prostaglandin E2-inducing activities, and further, it induced the production of high IgG anti-tetanus toxoid antibodies in mice. The typical OL is expected to be utilized as a nontoxic, potent adjuvant.

Adjuvants, Immunologic↗
PubMed1981

Regulation of pathways of ornithine metabolism. Effects of thyroid hormone and diabetes on the activity of enzymes at the "ornithine crossroads' in rat liver.

There is a significant increase in four of the urea cycle enzymes in liver from hypothyroid rats, arginase alone showed an opposite trend; these changes are reversed by physiological doses of thyroxine; hyperthyroidism results in a significant decrease in ornithine transcarbamoylase activity. The pattern of change in thyroidectomized and alloxan-diabetic rats showed marked similarities in respect to urea cycle and ornithine-metabolizing enzymes which are discussed in the light of the common feature of hypoinsulinism of diabetes and depressed response to insulin in hypothyroidism. The profile of ornithine-metabolizing enzymes is consonant with the decreased protein synthesis and turnover in hypothyroidism.

Animals↗
PubMed1985

Equilibrium between active and inactive forms of rat liver ornithine decarboxylase mediated by L-ornithine and salts.

The mechanisms controlling the activity of ornithine decarboxylase (ODC) are complex and only partly understood. This study shows that ODC can exist as two different aggregation states, that differ in catalytic activity, the dimeric form being active and the monomeric form inactive. While L-ornithine shifts the association-dissociation equilibrium to the dimeric form, salts produce an opposite effect leading to subunit dissociation. alpha-DFMO, an enzyme-activated irreversible inhibitor of ODC, does not react with the monomeric form and therefore the influence of substrate and salts on the aggregation equilibrium must be taken into account in titration experiments with alpha-DFMO of the total amount of ODC in tissue preparations.

Animals↗
PubMed1984

Localization of ornithine decarboxylase in mutant CHO cells that overproduce the enzyme. Differences between the intracellular distribution of monospecific ornithine decarboxylase antibodies and radiolabeled alpha-difluoromethylornithine.

The intracellular localization of ornithine decarboxylase (ODC), a key enzyme in polyamine synthesis and cell growth, is a matter of present debate. Using two independent methods of analysis, we have attempted to determine the actual distribution of ODC in a mammalian cell. To overcome the problem of a normally very low cellular ODC content, we have used ODC overproducing mutant CHO cells. These mutant cells exhibit a 10-fold higher ODC activity than do the wild type cells. The localization of ODC protein in exponentially growing cells, was determined by indirect immunofluorescence microscopy (permeabilized whole-cell preparations and 1 micron sections), using a monospecific ODC antibody. The intracellular localization of catalytically active ODC was determined by light and electron microscope autoradiography following pulselabeling of cells with alpha-difluoromethyl(5-3H)ornithine (3H-DFMO) at the time of peak ODC activity. alpha-Difluoromethylornithine (DFMO) is an enzyme-activated irreversible inhibitor of ODC and binds covalently to the active enzyme. The specificity of this reaction in the cell was ascertained by immunoprecipitation of 3H-DFMO-labeled ODC. ODC (as determined by both methods) was present in all the cells of a serum-stimulated monolayer culture. The highest concentration of ODC protein and of catalytically active ODC was observed in the smallest and most rapidly proliferating cells. Polyploid and multinuclear cells always exhibited the lowest concentrations.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1988

Interrelationships between ornithine, glutamate, and GABA. II. Consequences of inhibition of GABA-T and ornithine aminotransferase in brain.

The objective of the present study was to compare the effects of elevation of GABA concentration and those of inactivation of L-ornithine: 2-oxoacid aminotransferase (OAT) on the in vivo metabolism of L-ornithine (Orn) in brain. Vigabatrin (4-aminohex-5-enoic acid) and gabaculine (5-amino-1,3-cyclohexadienyl carboxylic acid), two well known inactivators of GABA-T, were used to elevate brain GABA concentrations. The latter inactivates OAT also. Transamination of Orn is, from a quantitative point of view, a significant reaction in mouse brain. GABA is a feed-back regulator of OAT. Within GABAergic neurons Orn concentration may be regulated by endogenous GABA. Extensive inactivation of OAT causes a considerable increase of Orn concentration, both in synaptosomes and in non-synaptosomal compartments. The results are compatible with a role of Orn as precursor of glutamate and/or GABA in certain neurons.

4-Aminobutyrate Transaminase↗
PubMed1989

Ornithine aminotransferase activity, liver ornithine concentration and acute ammonia intoxication.

5-Fluoromethylornithine (5FMOrn) is a specific inactivator of L-ornithine:2-oxoacid aminotransferase (OAT). Inactivation of OAT causes the enhancement of L-ornithine (Orn) concentrations in all tissues. Intraperitoneal or oral administration of 10-50 mg/kg of 5FMOrn per day to albino mice rendered partial protection against lethal intoxication with 26 mmol/kg of ammonium acetate. The protective effect was maximal around 16 h after 5FMOrn administration, at the time when endogenous Orn concentrations were maximal. At this time protection by 5FMOrn against acute ammonia intoxication was comparable to that observed 1 h after the intraperitoneal administration of 10 mmol/kg of L-arginine. Pretreatment with 5FMOrn prevented the enhancement of excessive urinary excretion of orotic acid by ammonia intoxicated mice, and it enhanced urea formation in the liver. These biochemical effects demonstrate that 5FMOrn shifts Orn into the urea cycle, Orn which normally would be transaminated. Since even long-term treatment of mice with 5FMOrn did not reveal toxic effects, this compound may be considered for the treatment of certain conditional deficiencies of Orn or arginine.

Acetates↗
PubMed1982

The reaction of ornithine aminotransferase with ornithine.

Rat liver ornithine aminotransferase is found to exchange the pro-S hydrogen on the delta-carbon atom of ornithine exclusively, thus showing that the mammalian enzyme transfers the delta-amino group and not the alpha-amino group as has been demonstrated with the plant enzyme [Mestichelli, Gupta & Spenser (1979) J. Biol. Chem. 254, 640-647]. The enzyme also transfers the alpha-amino group of glutamate and the kinetics of the half reactions between the enzyme and both amino acids are compared. Rate and dissociation constants for both reactions are determined.

Amino Acids↗
PubMed2003

X-ray structure determination of Trypanosoma brucei ornithine decarboxylase bound to D-ornithine and to G418: insights into substrate binding and ODC conformational flexibility.

Ornithine decarboxylase (ODC) is a pyridoxal 5'-phosphate (PLP)-dependent enzyme that catalyzes the rate-determining step in the biosynthesis of polyamines. ODC is a proven drug target to treat African sleeping sickness. The x-ray crystal structure of Trypanosoma brucei ODC in complex with d-ornithine (d-Orn), a substrate analog, and G418 (Geneticin), a weak non-competitive inhibitor, was determined to 2.5-A resolution. d-Orn forms a Schiff base with PLP, and the side chain is in a similar position to that observed for putrescine and alpha-difluoromethylornithine in previous T. brucei ODC structures. The d-Orn carboxylate is positioned on the solvent-exposed side of the active site (si face of PLP), and Gly-199, Gly-362, and His-197 are the only residues within 4.2 A of this moiety. This structure confirms predictions that the carboxylate of d-Orn binds on the si face of PLP, and it supports a model in which the carboxyl group of the substrate l-Orn would be buried on the re face of the cofactor in a pocket that includes Phe-397, Tyr-389, Lys-69 (methylene carbons), and Asp-361. Electron density for G418 was observed at the boundary between the two domains within each ODC monomer. A ten-amino acid loop region (392-401) near the 2-fold axis of the dimer interface, which contributes several residues that form the active site, is disordered in this structure. The disordering of residues in the active site provides a potential mechanism for inhibition by G418 and suggests that allosteric inhibition from this site is feasible.

Allosteric Site↗