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PubMed1977

Factors influencing the activity of ornithine aminotransferase in isolated rat liver mitochondria.

1. The characteristics of ornithine catabolism by the aminotransferase pathway in isolated mitochondria were determined. 2. Ornithine synthesis from glutamate and glutamate gamma-semialdehyde produced by the oxidation of proline was studied. No ornithine was formed in the absence of rotenone. 3. The mechanism of ornithine transport was reinvestigated, and the existence of an ornithine+/H+ exchange system postulated. 4. The kinetics of ornithine transport, ornithine catabolism in intact mitochondria and ornithine aminotransferase activity in solubilized mitochondria were compared. It is concluded that ornithine aminotransferase activity in liver mitochondria is rate-limited by the transport of ornithine across the mitochondrial membrane, and that this enzyme is involved primarily in ornithine degradation rather than ornithine synthesis.

Animals↗

PubMed1975

The mechanism of ACTH stimulation of adrenal ornithine decarboxylase activity.

The mechanism of action of adrenocorticotrophin (ACTH) stimulation of rat adrenal orticotrophin (ACTH) stimulation of rat adrenal ornithine decarboxylase activity was investigated. ACTH induction or ornithine decarboxylase activity was not prevented by administration of drugs that inhibit adrenal steroid biosynthesis. A dose of ACTH that produced maximal levels of adrenal cyclic AMP did not induce ornthine decarboxylase activity. Ovine growth hormone, which caused no increase in adrenal cyclic AMP, stimulated adrenal ornithine decarboxyase activity. These observations suggest that the increase in adrenal ornithine decarboxylase activity stimulated by ACTH is not dependent upon steroidogenesis, nor is it dependent on the early peak of cyclic AMP, although it may be influenced by the sustained levels of tissue cyclic AMP that follow the administration of large doses of ACTH. Furthermore, it appears there may be a pathway of ornithine decarboxylase activation in the adrenal which is entirely independent of cyclic AMP mediation. The effects of hypophysectomy on adrenal ornithine decarboxylase response to ACTH were examined. In rats given ACTH 16 h after hypophysectomy, the increase in ornithine decarboxylase activity was delayed when compared with the response in animals given ACTH 1 h after hypophysectomy. Actinomycin D given during the first 3 h after ACTH in the 16 h hypophysectomized rat abolished the expected increase in ornithine decarboxylase activity. Thereafter, a progressive increase in ornithine decarboxylase activity was observed as the interval between ACTH and Actinomycin D administration was further increased. In contrast, Actinomycin D administered 15 min before ACTH in the 1 h hypophysectomized rat had no effect on the subsequent increase in ornithine decarboxylase activity, and actually progressively enhanced the response the longer its administration after ACTH was delayed. Cycloheximide abolished the response to ACTH in both the 1 h and the 16 h hypophysectomized rat. Thus, it appears that ACTH stimulates a post-transcriptional mechanism regulating ornithine decarboxylase activity in the acutely hypophysectomized animal, whereas, in the chronically hypophysectomized rat, ACTH must first stimulate transcription of new messenger RNA which is involved in regulation of adrenal ornithine decarboxylase synthesis.

Adrenal Glands↗

PubMed1979

Decarboxylation of ornithine and lysine in rat tissues.

The possibility that arginine and lysine might be decarboxylated by rat tissues was investigated. No evidence for decarboxylation of arginine could be found. Lysine decarbosylase (L-lysine carboxy-lyase, EC 4.1.1.18) activity producing CO2 and cadaverine was detected in extracts from rat ventral prostate, androgen-stimulated mouse kidney, regenerating rat liver and livers from rats pretreated with thioacetamide. These tissues all have high ornithine decarboxylase (L-ornithine carboxy-lyase, EC 4.1.1.17) activities. Lysine and ornithine decarboxylase activities were lost to similar extents on inhibition of protein synthesis by cycloheximide and on exposure to alpha-difluoromethylornithine. A highly purified ornithine decarboxylase preparation was able to decarboxylate lysine and the ratio of ornithine to lysine decarboxylase activities was constant throughout purification. Kinetic studies of the purified preparation showed that the V for ornithine was about 4-fold greater than for lysine, but the Km for lysine (9 mM) was 100-times greater than that for ornithine (0.09 mM). These experiments indicate that all of the detectable lysine decarboxylase activity in rat and mouse tissues was due to the action of ornithine decarboxylase and that significant cadaverine production in vivo would occur only when ornithine decarboxylase activity is high and lysine concentrations substantially exceed those of ornithine.

Animals↗

PubMed1979

Regulation of ornithine decarboxylase activity in rat ovarian cells in vitro.

Incubation of rat ovarian cell suspension with human choriogonadotropin (hCG) caused a marked enhancement of ornithine decarboxylase (EC 4.1.1.17) activity after a lag period of several hours. Even though ovarian ornithine decarboxylase could be induced in minimum essential medium by the hormone alone, supplementation of the medium with various sera greatly enhanced the stimulation of the enzyme activity. All the sera tested (human, fetal calf and horse) were able to stimulate ornithine decarboxylase activity even in the absence of hCG. Maximum stimulation of the enzyme activity by hCG and/or serum occurred in ovarian cell suspensions prepared from 30 to 33-day-old rats. There was a close correlation between the stimulation of ornithine decarboxylase activity and the accumulation fo cyclic AMP in response to the administration of the hormone (in the presence or absence of serum). However, while various sera alone markedly enhanced ovarian ornithine decarboxylase activity in vitro they, if anything, only marginally stimulated the accumulation of cyclic AMP and the secretion of progesterone in ovarian cells in the absence of gonadotropin. A similar dissociation of the stimulation of ornithine decarboxylase activity from the production of cyclic AMP and progesterone was likewise found when the ovarian cells were incubated in an enriched medium (M199) supplemented with albumin and lactalbumin hydrolysate in the absence of the hormone. Under these culture conditions ornithine decarboxylase activity was strikingly enhanced, greatly exceeding the stimulation obtained with various sera, while the accumulation of cyclic AMP and the secretion of progesterone remained virtually unchanged. Specific inhibition (up to 90%) of gonadotropin-induced ornithine decarboxylase activity by difluoromethyl ornithine or 1,3-diamino-2-propanol had little effect on the ability of the ovarian cells to respond to the hormone with increasing production of cyclic AMP and progesterone. While showing that rat ovarian ornithine decarboxylase can be induced in vitro by choriogonadotropin or various sera, our results indicate that the activation of the enzyme involves at least two different mechanisms: (i) One (in response to gonadotropin) involving a prior stimulation of cyclic AMP production, and (ii) another (in response to serum) that is not associated with increases in the accumulation of the cyclic nucleotide.

Adenosylmethionine Decarboxylase↗

PubMed1976

Polyamine and ornithine metabolism during the germination of conidia of Aspergillus nidulans.

1. The activities of ornithine decarboxylase, S-adenosylmethionine decarboxylase and ornithine-2-oxoglutarate aminotransferase were studied during the first 24 h of conidial germination in Aspergillus nidulans. 2. Increases (over 100-fold) in the activities of ornithine decarboxylase and S-adenosylmethionine decarboxylase occurred during the emergence of the germ-tube and before the doubling of DNA and this was followed by a sharp fall in the activities of both enzymes by 16h. 3. The increase in ornithine decarboxylase could be largely suppressed if 0.6 mM-putrescine was added to the growth medium. 4. Low concentrations of cycloheximide, which delayed germination by 2h, caused a corresponding delay in the changes in ornithine decarboxylase activity. 5. Ornithine-2-oxoglutarate aminotransferase activity increased steadily during the first 24h of germination. 6. Ornithine or arginine in the growth medium induced higher activity of ornithine-2-oxoglutarate aminotransferase, but did not affect ornithine decarboxylase activity. 7. The significance of these enzyme changes during germination is discussed.

Adenosylmethionine Decarboxylase↗

PubMed1976

Subcellular localization of ornithine decarboxylase in liver of control and growth-hormone-treated rats.

1. Ornithine-2-oxo acid aminotransferase activity was inhibited by amino-oxyacetate (10(-5) M). This permitted the measurement of ornithine decarboxylase in the presence of mitochondria by using the 14CO2-trapping technique. 2. Subcellular fractionation of rat liver by differential centrifugation, followed by the assay of ornithine decarboxylase in the presence of amino oxyacetate and of marker enzymes for each fraction, demonstrated that ornithine decarboxylase was located in the cytosol. 3. The greatly increased ornithine decarboxylase activity observed after growth-hormone administration was also found to be localized in the cytosol. 4. The Km of ornithine decarboxylase from rat liver for ornithine was 28 muM. Administration of growth hormone 4 h before death did not affect the apparent affinity of ornithine decarboxylase for ornithine.

Aminooxyacetic Acid↗

PubMed1979

Diamine-induced inhibition of liver ornithine decarboxylase.

Repeated injections of 1,3-diaminopropane, a potent inhibitor of mammalian ornithine decarboxylase, induced protein-synthesis-dependent formation of macromolecular inhibitors or ;antienzymes' [Heller, Fong & Canellakis (1976) Proc. Natl. Acad. Sci. U.S.A.73, 1858-1862] to ornithine decarboxylase in normal rat liver. Addition of the macromolecular inhibitors, produced in response to repeated injections of diaminopropane, to active ornithine decarboxylase in vitro resulted in a profound loss of the enzyme activity, which, however, could be partly recovered after passage of the enzyme-inhibitor mixture through a Sephadex G-75 columin in the presence of 0.4m-NaCl. This treatment also resulted in the appearance of free inhibitor. In contrast with the separation of the enzyme and inhibitory activity after combination in vitro, it was not possible to re-activate, by using identical conditions of molecular sieving, any inhibited ornithine decarboxylase from cytosol fractions obtained from animals injected with diaminopropane. However, the idea that injection of various diamines, also in vivo, induces acute formation of macromolecular inhibitors, which reversibly combine with the enzyme, was supported by the finding that the ornithine decarboxylase activity remaining after diaminopropane injection appeared to be more stable to increased ionic strength than the enzyme activity obtained from somatotropin-treated rats. Incubation of the inhibitory cytosol fractions with antiserum to ornithine decarboxylase did not completely abolish the inhibitory action of either the cytosolic inhibitor or the antibody. A single injection of diaminopropane produced an extremely rapid decay of liver ornithine decarboxylase activity (half-life about 12min), which was comparable with, or swifter than, that induced by cycloheximide. However, although after cycloheximide treatment the amount of immunotitrable ornithine decarboxylase decreased only slightly more slowly than the enzyme activity, diaminopropane injection did not decrease the amount of the immunoreactive protein, but, on the contrary, invariably caused a marked increase in the apparent amount of antigen, after some lag period. The diamine-induced increase in the amount of the immunoreactive enzyme protein could be totally prevented by a simultaneous injection of cycloheximide. These results are in accord with the hypothesis that various diamines may result in rapid formation of macromolecular inhibitors to ornithine decarboxylase in vivo, which, after combination with the enzyme, abolish the catalytic activity but at the same time prevent the intracellular degradation of the enzyme protein.

Animals↗

PubMed1976

Hormonal regulation of renal ornithine decarboxylase activity in the rat.

The regulation of the activity of the renal enzyme ornithine decarboxylase (L-ornithine carboxy-lyase, EC 4.1.1.17) was examined in the rat. In the intact animal adapted to a light/dark cycle of 14 hours and 10 hours, respectively, the level of renal ornithine decarboxylase activity was rhythmical and paralleled the diurnal rhythm in plasma corticosteroid concentration. Renal ornithine decarboxylase activity and plasma corticosterone were highest during the early hours of darkness and lowest during the hours of light. Following hypophysectomy, the level of renal ornithine decarboxylase activity declined rapidly and remained low and without a demonstrable diurnal rhythm. When pituitary hormone levels were temporarily restored in the hypophysectomized rat by the injection of pituitary extract, renal ornithine decarboxylase activity increased rapidly, reached a peak within 8 hours, and returned toward pre-injection levels by 12 hours. Exogenous growth hormone, ACTH and cortisol each increased renal ornithine decarboxylase activity in the hypophysectomized rat, with the highest levels of activity being achieved with growth hormone. Other pituitary hormones (FSH, LH, TSH and prolactin) were ineffective. After bilateral adrenalectomy, renal ornithine decarboxylase activity retained a rhythmical pattern similar to that observed in the intact rat, but the levels were increased. Growth hormone and cortisol increased renal ornitine decarboxylase activity in the adrenalectomized-hypophysectomized animal to the same extent as in the hypophysectomized animal, but ACTH was almost totally ineffective. These data suggest that the pituitary plays a major role in the regulation of renal ornithine decarboxylase activity in the rat, primarily through the rhythmical secretion of growth hormone and ACTH.

Adrenal Cortex Hormones↗

PubMed1977

Arginine catabolism in Neurospora: cycling of ornithine.

We measured the metabolism of ornithine in Neurospora during the transition from minimal medium to arginine-supplemented medium. Within an hour after arginine supplementation, the amount of intracellular ornithine (95% of which had been stored in vesicles) dropped by 65%, even though the catabolism of arginine produces as much ornithine as had been produced on minimal medium. The arginine level in the cell rose 10-fold. Ornithine flux through the catabolic enzyme ornithine aminotransferase increased fivefold, but flux through the mitochondrial enzyme ornithine transcarbamylase (leading to arginine synthesis) was only 20% of the rate seen on minimal medium. During this transition to arginine catabolism, the enzymes of the arginine pathway operate as an ornithine cycle, but at a restricted rate. We suggest the hypothesis that high levels of arginine may inhibit the movement of ornithine into the vesicles and into the mitochondria.

Arginine↗

PubMed1978

Arginine biosynthesis in Neisseria gonorrhoeae: enzymes catalyzing the formation of ornithine and citrulline.

Many of the Neisseria gonorrhoeae strains isolated from patients require arginine for growth in a defined medium. As a basis for genetic studies of these Arg- strains, we examined two biosynthetic enzymes of Arg+ (nonrequiring) gonococci. Cell-free extracts contained (i) glutamate acetyltransferase, which catalyzes the formation of L-ornithine from alpha-N-acetyl-L-ornithine, and (ii) ornithine transcaramylase, which catalyzes the reaction between L-ornithine and carbamyl phosphate, yielding L-citrulline. Arg- strains were unable to utilze alpha-N-acetyl-L-ornithine for growth lacked significant activity of glutamate acetyltransferase, and activity was gained by Arg+ clones derived by DNA-mediated transformation. Some of the Arg- patient isolates were unable to use either alpha-N-acetyl-L-ornithine or L-ornithine in place of arginine, and two separate steps of genetic transformation were required to yield Arg+ cells. Extracts of these doubly auxotrophic cells lacked glutamate acetyltransferase activity, but, unexpectedly, they displayed normal ornithine transcarbamylase activity. This finding illustrates the importance of identifying the products specified by arg loci during genetic studies of arginine auxotrophy.

Acetyltransferases↗

PubMed1977

Production of monospecific antibodies to rat liver ornithine decarboxylase and their use in turnover studies.

Two forms of ornithine decarboxylase (L-ornithine carboxy-lyase, EC 4.1.1.17) were purified from the livers of rats which had been treated with thioacetamide for 16 h (for details, see miniprint to Obenrader, M.F., and Prouty, W. F. (1977) J. Biol. Chem. 252, 2860-2865). The enzyme was purified over 7,000-fold from liver cytosol with an overall yield of 8%. Enzyme activity was eluted finally in two distinct fractions by chromatography on activated thiol-Sepharose 4B. Both forms appear to be dimeric proteins having molecular weights of approximately 100,000 by equilibrium sedimentation and analysis on a calibrated Sephadex G-200 column. The apparent subunits are approximately 50,000 daltons as determined by electrophoresis on polyacrylamide gels in the presence of sodium dodecyl sulfate. Since electrophoresis in the presence of detergent is the only method used here to indicate subunits, the possibility that conditions of sample preparation resulted in splitting of a labile protein cannot be excluded from consideration. Ornithine decarboxylase has a very broad pH-activity curve with an optimum that shifts from pH 7.0 to pH 7.8 as the enzyme is purified. The apparent Km values for a highly purified mixture of the two forms of enzyme for L-ornithine and pyridoxal 5'-phosphate were determined to be 0.13 mM and 0.25 micronM, respectively. Both sodium and potassium chloride were shown to inhibit enzymatic activity; 50% inhibition occurred at 270 mM for each when Km amounts or ornithine were used. Rat liver ornithine decarboxylase antiserum was prepared in rabbits using Form I of the enzyme as the antigen. The antibody was shown to precipitate quantitatively the ornithine decarboxylase activity isolated from induced rat liver and rat ventral prostate. The specificity of the antiserum was demonstrated by rocket immunoelectrophoresis and by gel electrophoresis in the presence of sodium dodecyl sulfate using immunoprecipitates obtained from enzyme preparations labeled either in vivo, with [3H]leucine, or in vitro, by reductive methylation using formaldehyde and sodium [3H]borohydride. The antibody preparation has been used in a titration method to assess the half-life of antigen in livers of rats induced for ornithine decarboxylase by injection of thioacetamide. In two experiments, the t1/2 of activity at the height of induction, following injection of cycloheximide, was 19 and 24 min, while the t1/2 of disappearance of antigen was 28 and 33 min, respectively. In each experiment the t1/2 for antigen was significantly longer than the t1/2 for loss of enzyme activity. Enzyme levels appear to be modulated primarily by synthesis and degradation of antigen. Furthermore, the observation that enzyme activity is lost with a shorter t1/2 than antigen is consistent with the idea that denaturation is an initial step in the degradation of this enzyme...

Age Factors↗

PubMed1977

Human ornithine transcarbamylase. Purification and characterization of the enzyme from normal liver and the liver of a Reye's syndrome patient.

Ornithine transcarbamylase was purified and characterized from normal human liver. The properties of this enzyme were compared to those of ornithine transcarbamylase purified from the liver of a patient with Reye's syndrome. The enzyme isolated from both sources appeared virtually identical for a variety of biochemical characteristics. The native molecular weight of ornithine transcarbamylase is 110,000 as determined by gel filtration. Electrophoresis of the enzyme, dissociated by sodium dodecyl sulfate, indicated that the enzyme exists as a trimer of identical or similar subunits of 36,500 daltons. Ornithine transcarbamylase from normal liver has an isoelectric point of 7.95, and the value for the enzyme from the Reye's syndrome liver was 8.05. No evidence of multiple species was found during the purification or subsequent characterization of the enzyme. The enzyme exhibited normal Michaelia-Menten kinetics, and the apparent Michaelis constants for L-ornithine and carbamyl phosphate are 0.20 mM and 0.09 mM, respectively. Inhibitor studies established the structural requirements for L-ornithine antagonists. L-Norvaline is the best competitive inhibitor of the enzyme with respect to L-ornithine. This study indicated that the reduced level of ornithine transcarbamylase activity commonly observed in Reye's syndrome is not necessarily due to structural or functional alterations of the enzyme.

Female↗

PubMed1976

Fungal ornithine esterases: relationship to iron transport.

Extracts of Fusarium roseum (ATCC 12822) contain an enzyme which hydrolyzes the ornithine ester bonds of fusarinine C, a cyclic trihydroxamic acid produced by this organism. The methyl ester of Ndelta-dinitrophenyl-L-ornithine is also a substrate for the enzyme, and an assay was devised using this substrate. The enzyme exhibits a sharp maximum of activity at pH 7.5 and is extremely temperature sensitive. It is strongly inhibited by HgCl2 and p-chloromercuribenzoate, and it is competitively inhibited by Ndelta-dinitrophenyl-D-ornithine methyl ester (Ki = 0.3mM). Methyl esters of glycine, L-alanine, dinitrophenyl-L-alanine, dinitrophenyl-beta-alanine, and Ndelta-dinitrophenyl-Nalpha-acetyl-L-ornithine are not substrates, although Nepsilon-dinitrophenyl-L-lysine methyl ester is as effective as the ornithine derivative. Nonspecific lipases do not hydrolyze ornithine esters, nor does trypsin. The three ester bonds of fusarinine C are progressively hydrolyzed by the enzyme to eventually yield the monomer, fusarinine. The ferric chelate of fusarinine C is not hydrolyzed. An enzyme from Penicillium sp. was isolated with identical properties toward Nbeta-dinitro-phenyl-L-ornithine methyl ester as substrate. It also hydrolyzes N,N',N"-triacetylfusarinine C, a cyclic trihydroxamate containing Nalpha-acetylornithine ester bonds, which is produced by this organism. This substrate is hydrolyzed to Nalpha-acetylfusarine. In contrast to the Fusarium enzyme, this enzyme is fully active toward the ferric trihydroxamate chelate. However, replacement of iron by aluminum leads to a completely inactive substrate. Production of the enzyme is severely suppressed by iron in the growth medium. It is proposed that these specific ornithylesterases provide a mechanism of cellular iron release by hydrolysis of the ferric ionophores, and that an iron-exchange step occurs prior to, and is a prerequisite for, hydrolysis of the ester bonds.

Biological Transport, Active↗

PubMed1977

Dissociation of increases in levels of 3':5'-cyclic AMP and 3':5'-cyclic GMP from induction of ornithine decarboxylase by the tumor promoter 12-O-tetradecanoyl phorbol-13-acetate in mouse epidermis in vivo.

A single application of 17 nmol of 12-O-tetradecanoyl phorbol-13-acetate (TPA) to mouse skin caused a marked (200- to 400-fold) induction of ornithine decarboxylase (EC 4.1.1.17, L-ornithine carboxy-lyase) activity in mouse epidermal and epidermal-dermal preparations. No change in the basal level of 3':5'-cyclic AMP occurred in epidermal-dermal preparations within 30 min of TPA application. Intraperitoneal injection of the beta-agonist isoproterenol resulted in a dose-dependent accumulation of 3':5'-cyclic AMP occurred in epidermal-dermal preparations within 30 min of TPA application. Intraperitoneal injection of the beta-agonist isoproterenol resulted in a dose-dependent accumulation of 3':5'-cyclic AMP 10 min after injection, but caused no induction of ornithine decarboxylase. When isoproterenol was injected 10 min prior to an application of either 1.7 or 17 nmol of TPA, the magnitude of the ornithine decarboxylase induction was the same as induction with TPA alone. Topical application of 17 nmol of TPA caused no increase in the level of 3':5'-cyclic GMP present in the mouse epidermal-dermal preparations 2-20 min after application. Intraperitoneal injection of 1.75 mumol of dibutyryl 3':5'-cyclic GMP and/or butyryl derivatives of cyclic GMP caused a 6-fold increase in the level of cyclic GMP and/or butyryl derivatives of cyclic GMP in epidermal-dermal preparations within 5 min of injection, and the level remained elevated for at least 20-30 min. This dose of dibutyryl 3':5'-cyclic GMP was incapable of inducing ornithine decarboxylase. Injection of dibutyryl 3':5'-cyclic GMP 5 min before application of 1.7 nmol of TPA or 30 min before application of 17 nmol of TPA did not alter the magnitude of the ornithine decarboxylase induction produced by TPA alone. These results suggest that early increases in the total intracellular levels of either 3':5'-cyclic AMP or 3':5'-cyclic GMP are not part of the mechanism by which TPA induces ornithine decarboxylase in the epidermis.

Animals↗

PubMed1976

In vivo hormonal induction of ornithine decarboxylase in rat kidney.

Single pharmacological doses of parathyroid hormone, calcitonin, vasopressin, d-aldosterone, or L-triiodothyronine produced a significant increase in the ornithine decarboxylase activity of rat kidney. The activity of kidney ornithine decarboxylase was also enhanced by other hormones, such as pentagastrin and serotonin, which, although they are not known to modify kidney physiology, are secreted by cells having close relationships to the calcitonin-secreting parafollicular cells. The induction of the enzyme was observed in hypophysectomized rats, with or without some other hormone-secreting glands remaining. However, the magnitude of the stimulation elicited by the hormones was somewhat diminished in animals still having the endocrine gland whose hormone was being tested. The maximal stimulation of kidney ornithine decarboxylase activity by parathyroid hormone, calcitonin, vasopressin, L-triiodothyronine, pentagastrin, and serotonin occurred at 4 h after the hormone injection. The enhancement in ornithine decarboxylase activity produced by d-aldosterone was maximal at 3 h after the injection of the hormone. The content of ornithine in the kidney was found to be virtually unchanged whatever the type of hormone treatment. No statistically significant increases in renal ornithine decarboxylase activity of hypophysectomized animals were observed after injection of melatonin or of vitamin D3. Since the stimulating hormones possess clearly different mechanisms of action, the role of cyclic AMP as a general mediator of ornithine decarboxylase induction is questioned.

Adrenalectomy↗

PubMed1978

Ornithine as a possible marker of cancer.

The nonprotein amino acid ornithine is the major source of polyamines in mammalian physiological systems. Increased urinary polyamine levels have been demonstrated in humans with varied types of cancers. The metabolism of DL-[1-14C]ornithine monohydrochloride in rats with either Walker 256 carcinoma or chemically induced methylcholanthrene tumors was studied. Following the i.p. injection of 3 muCi[14C]ornithine per 100 g body weight, the decarboxylation of ornithine-yielding 14CO2 was monitored by utilizing the vibrating reed electrometer-ionization chamber model of Davidson and Schwabe. Tumor-bearing animals showed significant increases in ornithine metabolism as compared to controls; for Walker 256 the tumor-bearing animal to control ratio rose from 1.16 to 1.78, for methylcholanthrene implants it rose from 1.19 to 1.82, and for methylcholanthrene paintings it rose from 1.00 to 2.20. With tumor regression ornithine levels of metabolism in the tumor-bearing animals returned to base line or nearly base-line levels. These results encourage us in our attempt to develop ornithine as a biological marker of cancer.

Animals↗

PubMed1979

The importance of ornithine as a precursor for proline in mammalian cells.

Ornithine aminotransferase catalyzes the reversible transamination of L-ornithine to delta1-pyrroline-5-carboxylate, the immediate precursor of proline. The direction and flux through this pathway in mammalian cells has not been established. Glutamate has generally been considered to be the most important precursor for proline biosynthesis, but recent studies in xiphoid cartilage indicate that a significant fraction of cellular proline is derived from ornithine. Using newly isolated mutant Chinese hamster ovary cells with defined defects in the proline biosynthetic pathways, we now have established that cells can grow at a maximal rate with ornithine as the sole source of proline. Furthermore, we have measured the rate of proline formation from ornithine (1.6 nmol/h/10(6) cells); Future studies with these mutant Chinese hamster ovary cells may offer insight into the regulatory mechanism which coordinates proline biosynthesis from ornithine and glutamate.

Animals↗

PubMed1977

Some genetical aspects of ornithine metabolism in Aspergillus nidulans.

A possible minor route of ornithine catabolism in Aspergillus nidulans might begin with the ornithine decarboxylase reaction and end with the succinic semialdehyde dehydrogenase reaction. It is therefore of interest that the putative structural genes for these two enzymes, puA and ssuA, respectively, are tightly linked group II. However, this linkage is unlikely to have regulatory significance because ileA, the structural gene for threonine dehydratase, separates them. The gene order in this region is ssuA-ileA-puA-mauB-anB. (mauB- mutations result in loss of monoamine oxidase whilst anB- mutations lead to aneurin auxotrophy.) 2. An auxotrophy for ornithine or putrescine in A. nidulans occurs in double mutants lacking arginase and blocked before ornithine in the arginine biosynthetic pathway. Some residual ornithine synthesis in such double mutants can be catalysed by ornithine delta-transaminase, especially if it is synthesised constitutively.

Aspergillus nidulans↗