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At least 19 recordsLinked to original sources
PubMed2001

Selection of several classes of mimosine-degradation-defective Tn3Hogus-insertion mutants of Rhizobium sp. strain TAL1145 on the basis of mimosine-inducible GUS activity.

Rhizobium sp. strain TAL1145 that nodulates Leucaena leucocephala degrades mimosine, a toxin produced by this tree legume. A cosmid clone, pUHR263, containing approximately 25 kb cloned DNA was isolated by plating Escherichia coli cells containing the cosmid clone library of TAL1145 on a minimal medium in which 3-hydroxy-4-pyridone (HP), a degradation product of mimosine, was used as the source of nitrogen. Cosmid pUHR263 was mutagenized by random insertions of Tn3Hogus, a transposon that makes transcriptional gus fusions when it is inserted in a gene in the correct orientation. Various pUHR263::Tn3Hogus derivatives that showed mimosine-inducible or mimosine-repressible GUS activities when transferred to the Rhizobium sp. strain TAL1145 were selected. Mutants of TAL1145 were constructed by transferring these Tn3Hogus insertions into the TAL1145 chromosome through double-homologous recombination. These mutants were classified into five classes on the basis of defects in mimosine degradation. The growth of these mutants was inhibited to different extents by mimosine applied to the growth medium. Mimosine forms a red-colored Fe-mimosine complex when FeCI3 is added to the medium. The inhibitory effect of Fe-mimosine on growth of the mutants was much less than that of mimosine.

Bacterial Proteins↗
PubMed2003

The mid genes of Rhizobium sp strain TAL1145 are required for degradation of mimosine into 3-hydroxy-4-pyridone and are inducible by mimosine.

Mimosine is a toxin present in the tree-legume leucaena (Leucaena leucocephala), including its root nodules and the root exudates. The leucaena-nodulating Rhizobium sp. strain TAL1145 degrades mimosine (Mid(+)) and utilizes it as a source of carbon and nitrogen. Twelve TAL1145 mutants defective in mimosine degradation (Mid(-)) were made through Tn3Hogus, TnphoA or kanamycin-resistance-cassette insertions. A 5.0 kb PstI fragment of TAL1145, subcloned from a cosmid clone containing mid genes for mimosine degradation, complemented most of the Mid(-) mutants. Sequencing this fragment and the adjacent 0.9 kb PstI fragment identified five genes, midA, midB, midC, midD and midR, of which the first three genes encode ABC transporter proteins involved in mimosine uptake, while midD encodes an aminotransferase required for degrading mimosine into 3-hydroxy-4-pyridone, and midR is a regulatory gene encoding a LysR-type transcriptional activator. The location of MidA in the periplasm was shown by making two midA : : phoA fusions, which made active alkaline phosphatase in the periplasm. The various mid : : gus and midA : : phoA fusions were inducible by mimosine, and a midD : : gus fusion mutant showed beta-glucuronidase activity in the leucaena nodules, indicating that midD is expressed in the nodules. Similarly, a midA : : phoA fusion expressed alkaline phosphatase activity in the leucaena nodules, indicating that mimosine induces midA transcription in the bacteroids. mid genes are specific for the Mid(+) strains of leucaena Rhizobium and are absent in strains of other Rhizobium, Sinorhizobium and Bradyrhizobium spp.

Bacterial Proteins↗
PubMed1994

Mimosine, a Toxin Present in Leguminous Trees (Leucaena spp.), Induces a Mimosine-Degrading Enzyme Activity in Some Rhizobium Strains.

Thirty-seven Rhizobium isolates obtained from the nodules of leguminous trees (Leucaena spp.) were selected on the basis of their ability to catabolize mimosine, a toxin found in large quantities in the seeds, foliage, and roots of plants of the genera Leucaena and Mimosa. A new medium containing mimosine as the sole source of carbon and nitrogen was used for selection. The enzymes of the mimosine catabolic pathway were inducible and were present in the soluble fraction of the cell extract of induced cells. On the basis of a comparison of the growth rates of Rhizobium strains on general carbon and nitrogen sources versus mimosine, the toxin appears to be converted mostly to biomass and carbon dioxide. Most isolates able to grow on mimosine as a source of carbon and nitrogen are also able to utilize 3-hydroxy-4-pyridone, a toxic intermediate of mimosine degradation in other organisms.

Journal Article↗
PubMed1999

Effects of mimosine and 2,3-dihydroxypyridine on fiber shedding in Angora goats.

The effects of intravenous infusion of mimosine or 2,3-dihydroxypyridine (2,3-DHP) and the effects of oral dose level of mimosine on fiber shedding in Angora goats were determined. In one experiment, 20 mature Angora wethers (36+/-1.9 kg BW) were infused for 2 d with 79, 102, or 135 mg/(kg BW.d) of mimosine, 90 mg/(kg BW.d) of 2,3-DHP, or saline. At 7 d after infusion began, fiber shedding was observed in all goats receiving mimosine but not in any goats infused with 2,3-DHP or saline. Fiber shedding varied among goats; in some goats, fiber shedding was complete and occurred without hand-plucking, whereas in others fiber was retained by nonshed fibers but could be removed by hand-plucking. Nonshed fibers were larger in diameter and more likely to be medullated (P < .05) compared with hand-plucked fibers. Mean plasma mimosine concentration at 24 and 48 h after infusion began was 79 and 98 micromol/L (P < .05), respectively, and greater (P < .05) for mimosine infused at 135 than at 102 mg/(kg BW.d) (89, 68, and 108 micromol/L for mimosine infused at 79, 102, and 135 mg/[kg BW.d], respectively; SE 9.5). In another experiment, oral dosing of eight Angora bucks (23+/-.5 kg BW) with 400 or 600 mg/kg BW of mimosine rapidly increased plasma mimosine concentration, which reached approximately 100 and 160 micromol/L at 5 h after dosing; however, periods of time during which plasma mimosine concentrations were comparable to those in the first experiment were considerably shorter. Oral mimosine dosing did not induce fiber shedding in 7 d. After 31 d, fiber was retained by nonshed fibers but could be removed by hand-plucking or could only be partially removed with difficulty by hand-plucking. There were no toxic effects of mimosine or 2,3-DHP administration; only minor, short-term inhibitions of feed intake by mimosine were noted in some goats. In conclusion, mimosine holds promise as a safe means to remove fiber of Angora goats; further research is necessary to characterize the seasonality of follicle activity and to develop convenient means of mimosine delivery.

Administration, Oral↗
PubMed2000

Mimosine is a cell-specific antagonist of folate metabolism.

Iron deficiency and iron chelators are known to alter folate metabolism in mammals, but the underlying biochemical mechanisms have not been established. Although many studies have demonstrated that the iron chelators mimosine and deferoxamine inhibit DNA replication in mammalian cells, their mechanism of action remains controversial. The effects of mimosine on folate metabolism were investigated in human MCF-7 cells and SH-SY5Y neuroblastoma. Our findings indicate that mimosine is a folate antagonist and that its effects are cell-specific. MCF-7 cells cultured in the presence of 350 microm mimosine were growth-arrested, whereas mimosine had no effect on SH-SY5Y cell proliferation. Mimosine altered the distribution of folate cofactor forms in MCF-7 cells, indicating that mimosine targets folate metabolism. However, mimosine does not influence folate metabolism in SH-SY5Y neuroblastoma. The effect of mimosine on folate metabolism is associated with decreased cytoplasmic serine hydroxymethyltransferase (cSHMT) expression in MCF-7 cells but not in SH-SY5Y cells. MCF-7 cells exposed to mimosine for 24 h have a 95% reduction in cSHMT protein, and cSHMT promoter activity is reduced over 95%. Transcription of the cSHMT gene is also inhibited by deferoxamine in MCF-7 cells, indicating that mimosine inhibits cSHMT transcription by chelating iron. Analyses of mimosine-resistant MCF-7 cell lines demonstrate that although the effect of mimosine on cell cycle is independent of its effects on cSHMT expression, it inhibits both processes through a common regulatory mechanism.

Cell Cycle↗
PubMed2000

Effects of mimosine on fiber shedding, follicle activity, and fiber regrowth in Spanish goats.

Ten 2-yr-old Spanish wethers (58.2 +/- 7.21 kg BW) were used to determine effects of 2-d intravenous infusion of mimosine (beginning on January 8) on fiber shedding, follicle activity, and fiber regrowth. Primary and secondary follicle activity on d 0 were 43 +/- 6.2% and 96 +/- 1.7%, respectively. Five wethers were infused with mimosine at 120 mg/(kg BW x d) and the other five received saline. At 7 to 10 d after the start of infusion, all five goats infused with mimosine exhibited shedding, whereas shedding by controls was not observed. Cashmere fiber shedding score (5-point scale: 1 = no shedding, 5 = excessive shedding) on d 4 was greater for mimosine goats than for controls (1.2 vs 2.0; P < .001), and shedding score for wethers receiving mimosine was greater (P < .05) on d 12, 16, and 20 than on d 0 and 4 (4.1 to 4.6 vs 1.4 and 2.0). Guard hair shedding score for goats receiving mimosine was greatest (P < .01) among the days after infusion for d 12 and greater (P < .01) on d 16 than on d 0 and 4. Nonetheless, cashmere fiber yield from combed fleece of mimosine goats (average of 73%) was much greater than for a clipping of the uncombed side (average of 28%) when the cashmere fiber shedding score exceeded 4.0. Secondary follicle activity on d 12 was lower (P < .01) for mimosine than for control wethers (6.8 vs 67.7%), and secondary follicle activity for mimosine-infused goats on d 12 was lower (P < .01) than on d 0 (98.9%), 4 (98.3%), and 20 (99.5%). Mimosine infusion resulted in no detectable fiber regrowth in wk 4 to 7 after the start of infusion, but regrowth rate in the following two 4-wk periods was similar for mimosine and control wethers. In conclusion, 2-d intravenous infusion of mimosine at 120 mg/(kg BW x d) in the winter induced cashmere shedding but had less effect on guard hairs, suggesting future potential use of chemicals such as mimosine to remove cashmere fiber.

Animals↗
PubMed1999

Oxidative stress during selenium deficiency in seedlings of Trigonella foenum-graecum and mitigation by mimosine. Part I. Hydroperoxide metabolism.

Oxidative stress during selenium (Se) deficiency in the seedlings of Trigonella foenum-graecum grown for 72 h was investigated and the response to supplemented levels of Se (0.5-1 ppm) and mimosine (0.05-1 mM) was evaluated. Beneficial effects of Se was maximal at 0.75 ppm. Mimosine, a toxic amino acid, was also found to be beneficial to the growth of the seedlings exposed up to 0.2 mM. When compared to the stressed seedlings, mitochondrial oxygen uptake from seedlings of Se (0.75 ppm) group and mimosine (0.2 mM) group exhibited threefold enhancement in state 3 respiration rate and a controlled state 4 rate, with respiratory control ratios of 5-8. Upon supplementation at the optimal levels, superoxide dismutase (SOD) activities were enhanced fourfold with Se and eightfold with mimosine in the mitochondria. The soluble activity in mimosine groups increased twofold, but only by 75% in Se groups. Peroxidase activity registered a significant increase by threefold in mitochondria and fourfold in soluble fraction in both Se and mimosine groups. Exposure to Se or mimosine exhibited a differential response in the mitochondrial catalase and ascorbate peroxidase (Asc-Px) activities. In the Se groups, both catalase and Asc-Px in mitochondria decreased by 50-60%, which was contrasted by 60% increase in Asc-Px activity and 40% in catalase activity in mimosine groups. Supplementation with either Se or mimosine evoked similar responses of increases with respect to soluble catalase by twofold to threefold and Asc-Px by 90%. The results of the present study reveal (1) the prevalence of oxidative stress in T. foenum-graecum during Se deficiency, (2) enhanced mitochondrial functional efficiency mediated by Se and mimosine independently, and (3) an antioxidative role for mimosine during Se deficiency. The study demonstrates for the first time that mimosine, a naturally occurring toxic amino acid, could be a beneficial growth factor in concentrations between 0.1 and 0.2 mM.

Ascorbate Peroxidases↗
PubMed1999

Oxidative stress during selenium deficiency in seedlings of Trigonella foenum-graecum and mitigation by mimosine Part II. Glutathione metabolism.

Adaptive alterations in glutathione (GSH) metabolism were studied during oxidative stress induced by selenium (Se) deficiency in germinating seedlings of Trigonella foenum-graecum grown for 72 h and the response to supplementation individually of Se or mimosine was explored. Growth enhancement with improved mitochondrial efficiency was elicited by supplementation of Se at 0.5-0.75 ppm or mimosine at 0.1-0.2 mM. Total thiol and protein levels of mitochondrial and soluble fractions, in general, did not vary significantly with supplementation of either Se or mimosine except that the mitochondrial protein levels in mimosine groups (0.1-0.2 mM) decreased by 20-30%. Mitochondrial glutathione peroxidase (GSH-Px) increased by twofold in activity toward H2O2, cumene hydroperoxide (CHP), and t-butyl hydroperoxide (tBHP) in Se groups, and by 50-60% increase toward H2O2 and CHP but by a twofold enhancement in enzyme activity with tBHP in mimosine groups. Soluble GSH-Px activity increased by 30-40% only in mimosine groups and remained unaltered in Se groups. Glutathione S-transferase activity (GST) in the soluble fraction of both Se and mimosine groups increased dramatically by fivefold to sixfold. Distinct differences were noted in the response of the stressed seedlings toward exposure to Se or mimosine and included a decline in glutathione reductase (GR) activity by 50-60% in both mitochondria and soluble fractions of Se groups and an increase in GR activity of the mitochondria by twofold and of the soluble enzyme activity by 30% in the mimosine groups. Mimosine exposure resulted in a dose-dependent decrease in the gamma-glutamyl transpeptidase levels, but, in contrast, a significant enhancement by 50% was noted in the Se group at 0.75 ppm. The results including the differential response of GR activity to Se or mimosine supplementation are reflective of an effective reductive environment in Se groups and increased turnover of GSH in the presence of mimosine.

Glutathione↗
PubMed1996

Effects of mimosine administered to a perfused area of skin in Angora goats.

The effect of mimosine on a perfused area of skin tissue was studied using an isolated perfusion technique. Four mature Angora wethers (body weight 35 (SE 2.3) kg) were cannulated bilaterally with indwelling silicone catheters in the superficial branches of the deep circumflex iliac artery and vein. Mimosine (40 mg/kg metabolic weight (W)0.75) per d) was infused intra-arterially into one iliac artery of each goat for 3 d and saline was infused in the contralateral (control) iliac artery. Iliac venous blood samples were taken from both sides along with arterial samples from the carotid artery. Mimosine infusion elevated plasma mimosine in the carotid artery (52.6 (SEM 19.21) mumol/l) and iliac vein on the saline-treated side to 54.1 (SEM 16.31) mumol/l and in the iliac vein on the mimosine-treated side to 191.3 (SEM 19.14) mumol/l (P < 0.01). Mimosine decreased feed intake (2.3 v. 0.6 kg/d, SEM 0.29; P < 0.001) and water consumption (5.2 v. 1.3 litres/d, SEM 0.67; P < 0.001). Mimosine did not cause defleecing in the area of infusion and was cleared from the bloodstream within 12 h of cessation of infusion. The following effects were also observed during mimosine infusion: decrease in plasma amino acids to half pre-infusion values (methionine 22.7 v. 13.1 mumol/l, SEM 1.41; lysine 95.9 v. 37.4 mumol/l, SEM 4.28; P < 0.001); decreases in plasma triiodothyronine (1495 v. 695 ng/l, SEM 43.1; P < 0.001), thyroxine (61.5 v. 19.5 micrograms/l, SEM 1.8; P < 0.001) and insulin (28.7 v. 17.3 microIU/ml, SEM 1.89; P < 0.01) concentrations; increase in plasma cortisol (14 v. 62 micrograms/l, SEM 0.35; P < 0.001) concentration; decreases in levels of plasma Zn and Mg (0.97 v. 0.49 mg/l, SEM 0.063; P < 0.001 and 21.4 v. 14.6 mg/l, SEM 1.74; P < 0.001 respectively). All reported variables returned to their normal values 24 h after cessation of mimosine infusion except feed intake which was affected for a longer period. Mohair length and diameter were not affected by mimosine infusion. The toxicity of mimosine may be due to the drastic depletion of Zn and Mg in the blood as mimosine possesses very strong chelating properties and is excreted in the urine as a chelate.

Animals↗
PubMed1999

Mimosine arrests proliferating human cells before onset of DNA replication in a dose-dependent manner.

The synchronization effects of the plant amino acid mimosine on proliferating higher eukaryotic cells are still controversial. Here, I show that 0.5 mM mimosine can induce a cell cycle arrest of human somatic cells in late G1 phase, before establishment of active DNA replication forks. The DNA content of nuclei isolated from mimosine-treated cells was determined by flow cytometry. The presence or absence of DNA replication forks in these isolated nuclei was then detected by DNA replication run-on assays in vitro. Treatment of asynchronously proliferating HeLa or EJ30 cells for 24 h with 0.5 mM mimosine resulted in a population synchronized in late G1 phase. S phase entry was inhibited by 0.5 mM mimosine in cells released from a block in mitosis or from quiescence. When added to early S phase cells, 0.5 mM mimosine did not prevent S phase transit, but delayed progression through late stages of S phase after a lag of 4 h, eventually resulting in a G1 phase population by preventing entry into the subsequent S phase. In contrast, lower concentrations of mimosine (0.1-0.2 mM) failed to prevent S phase entry, resulting in cells containing active DNA replication foci. The G1 phase arrest by 0.5 mM mimosine was reversible upon mimosine withdrawal. This synchronization protocol using 0.5 mM mimosine can be exploited for studying the initiation of human DNA replication in vitro.

Cell Division↗
PubMed1975

Fate of mimosine administered orally to sheep and its effectiveness as a defleecing agent.

Mimosine was administered orally to Merino sheep once daily for periods of 1-3 days, either as the isolated compound or in the foliage of Leucaena leucocephala. A single daily dose of mimosine of 450 or 600 mg/kg body weight was effective for defleecing sheep. A daily dose rate of 300 mg/kg was effective for defleecing sheep if given on two successive days. The effectiveness of a treatment for defleecing sheep was related to the concentration of mimosine in plasma following dosing; defleecing ensued when the concentration of mimosine in plasma was maintained above 0-1 mmol/l for at least 30 h. The main products excreted in urine were mimosine and 3,4-dihydroxypyridine (DHP); small amounts of mimosinamine were also excreted. During the first day following dosing, the major excretory product was mimosine; DHP was an important component during the second and third days. In the three days following the start of dosing, between 32 and 53% of the mimosine given was accounted for as mimosine in the urine. Following an intravenous infusion of mimosine, no DHP was detected in urine; most of the mimosine was excreted intact but a small amount (c. 9%) was excreted as mimosinamine.

Administration, Oral↗
PubMed2004

Mimosine attenuates serine hydroxymethyltransferase transcription by chelating zinc. Implications for inhibition of DNA replication.

L-mimosine is a naturally occurring plant amino acid and iron chelator that arrests the cell cycle in the late G(1) phase, although its mechanism of action is not known. Some studies indicate that mimosine prevents the initiation of DNA replication, whereas other studies indicate that mimosine disrupts elongation of the replication fork by impairing deoxyribonucleotide synthesis by inhibiting the activity of the iron-dependent enzyme ribonucleotide reductase and the transcription of the cytoplasmic serine hydroxymethyltransferase gene (SHMT1). In this study, the mechanism for mimosine-induced inhibition of SHMT1 transcription was elucidated. A mimosine-responsive transcriptional element was localized within the first 50 base pairs of the human SHMT1 promoter by deletion analyses and gel mobility shift assays. The 50-base-pair sequence contains a consensus zinc-sensing metal regulatory element (MRE) at position -44 to -38, and mutation of the MRE attenuated mimosine-induced transcription repression. Mimosine treatment eliminated MRE- and Sp1-binding activity in nuclear extracts from MCF-7 cells but not in nuclear extracts from a mimosine-resistant cell line, MCF-7/2a. MCF-7 cells cultured in zinc-depleted medium for more than 16 days were viable and lacked cytoplasmic serine hydroxymethyltransferase protein, confirming that mimosine inhibits SHMT1 transcription by chelating zinc. The disruption of DNA-protein interactions by zinc chelation provides a general mechanism for the inhibitory effects of mimosine on nuclear processes, including replication and transcription. Furthermore, this study establishes that SHMT1 is a zinc-inducible gene, which provides the first mechanism for the regulation of folate-mediated one-carbon metabolism by zinc.

Chelating Agents↗
PubMed1995

Mimosine, a novel inhibitor of DNA replication, binds to a 50 kDa protein in Chinese hamster cells.

We recently demonstrated that the plant amino acid, mimosine, is an extremely efficacious inhibitor of DNA replication in mammalian cells [P. A. Dijkwel and J. L. Hamlin (1992) Mol. Cell. Biol. 12, 3715-3722; P. J. Mosca et al. (1992) Mol. Cell. Biol. 12, 4375-4383]. Several of its properties further suggested that mimosine might target initiation at origins of replication, which would make it a unique and very useful inhibitor for studying the regulation of DNA synthesis. However, mimosine is known to chelate iron, a cofactor for ribonucleotide reductase. Thus, the possibility arose that mimosine functions in vivo simply by lowering intracellular deoxyribonucleotide pools. In the present study, we show that, in fact, it is possible to override mimosine inhibition in vivo by adding excess iron; however, copper, which is not a substitute for iron in ribonucleotide reductase, is equally effective. Evidence is presented that mimosine functions instead by binding to an intracellular protein. We show that radiolabeled mimosine can be specifically cross-linked to a 50 kDa polypeptide (termed p50) in vitro. Binding to p50 is virtually undetectable in CHO cells selected for resistance to 1 mM mimosine, arguing that p50 is the biologically relevant target. p50 is not associated with the cellular membrane fraction and, hence, is probably not a channel protein. Furthermore, the binding activity does not vary markedly as a function of cell cycle position, arguing that p50 is not a cyclin. Finally, both iron and copper are able to reverse the mimosine-p50 interaction in vitro, probably explaining why both metal ions are able to overcome mimosine's inhibitory effect on DNA synthesis in vivo.

Animals↗