Mimosine

Biochim Biophys Acta. 1998 Nov 19;1448(1):51-60.

Antiproliferative and antifibrotic effects of mimosine on adult cardiac fibroblasts.[Pubmed: 9824667 ]

Prolyl 4-hydroxylase catalyzes the hydroxylation of collagen pro-alpha chains for the deposition of cardiac collagen. The effect of prolyl 4-hydroxylase on synthesis and degradation of collagen was studied in cultured adult cardiac fibroblasts using Mimosine, a prolyl 4-hydroxylase inhibitor.
METHODS AND RESULTS:
Mimosine inhibited [3H]thymidine incorporation in cultured fibroblasts in a dose-dependent manner (100-600 microM). Immunofluorescence in fibroblasts and biochemical detection of mature type I collagen in culture serum revealed a strong inhibition of synthesis and secretion of mature collagens, respectively, in the presence of 200 microM Mimosine. Western blot analysis for procollagen was carried out in cultured fibroblasts, and 200 microM Mimosine treatment was associated with increased intracellular accumulation of procollagen from 4.14+/-0.27 to 10. 19+/-0.37 (arbitrary units). Immunofluorescence studies confirmed a marked increase of intracellular procollagens in fibroblasts treated with Mimosine, which suggests a loss of coordinated monomeric procollagen synthesis and secretion of triple helical mature collagens. Modest inhibition of collagen type I mRNA abundance was observed in Mimosine-treated fibroblasts, whereas no effect was noted for mRNAs of collagen type III, alpha-prolyl 4-hydroxylase or beta-prolyl 4-hydroxylase when compared to untreated control values. Treatment of fibroblasts with 200 microM Mimosine was associated with elevation of matrix metalloproteinase (MMP)-9 activity. The cytotoxicity of Mimosine treatment was found minimal at the concentrations indicated above.
CONCLUSIONS:
Thus the antifibrotic effects induced by Mimosine on cultured adult cardiac fibroblasts was associated with inhibition of prolyl 4-hydroxylase and diminished extracellular secretion of procollagen, despite the reactive elevation of intracellular procollagen synthesis. We suggest that specific inhibition of prolyl 4-hydroxylase may provide a novel therapeutic approach for the modulation of cardiac fibrosis.

Cytometry. 1991;12(3):242-6.

Mimosine reversibly arrests cell cycle progression at the G1-S phase border.[Pubmed: 1903691 ]

It has previously been demonstrated that the compound Mimosine inhibits cell cycle traverse in late G1 phase prior to the onset of DNA synthesis (Hoffman BD, Hanauske-Abel HM, Flint A, Lalande M: Cytometry 12:26-32, 1991; Lalande M: Exp Cell Res 186:332-339, 1990). These results were obtained by using flow cytometric analysis of DNA content to compare the effects of Mimosine on cell cycle traverse with those of aphidicolin, an inhibitor of DNA polymerase alpha activity.
METHODS AND RESULTS:
We have now measured the incorporation of bromodeoxyuridine into lymphoblastoid cells by flow cytometry to determine precisely where the two inhibitors act relative to the initiation of DNA synthesis. It is demonstrated here that Mimosine arrests cell cycle progression at the G1-S phase border. The onset of DNA replication occurs within 15 min of releasing the cells from the Mimosine block. In contrast, treatment with aphidicolin results in the accumulation of cells in early S phase.
CONCLUSIONS:
These results indicate that Mimosine is a suitable compound for affecting the synchronous release of cells from G1 into S phase and for analyzing the biochemical events associated with this cell cycle phase transition.

J Biol Chem. 2005 Jan 7;280(1):396-400.

Mimosine attenuates serine hydroxymethyltransferase transcription by chelating zinc. Implications for inhibition of DNA replication.[Pubmed: 15531579]

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).
METHODS AND RESULTS:
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.
CONCLUSIONS:
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.

Aust J Biol Sci. 1975 Feb;28(1):69-84.

Effects of mimosine, a potential chemical defleecing agent, on wool growth and the skin of sheep.[Pubmed: 1167194]

METHODS AND RESULTS:
Twenty-two Merino sheep were dosed with various amounts of L-Mimosine, given either as an intravenous or an intraperitoneal injection, or as a continuous intravenous infusion for periods of 1-4 days. Single injections of Mimosine (1-16 g) had no effect on the strength of wool, and wool growth rates were not appreciably altered by injections of small amounts (4 g or less). Injections of larger amounts slightly reduced both length growth rate and diameter of tibres during the 4 days after dosing. The effects of intravenous infusions of Mimosine depended on the rate and the duration of administration. Small amounts (0.5 or 1 g/day given for 4 days) has no effects on the strength of wool or on wool growth rates. Infusions of a total of 8 g, either at the rate of 2 or 8 g/day, weakened the wool but not sufficiently to allow the sheep to be defleeced. Both these treatments caused a temporary reduction in length growth rate and in diameter of fibres, and transient degenerative changes were observed in wool follicles. A region of the fibres representing 1-2 days' growth was constricted to about half the pre-infusion diameter when 8 g was given for 1 day. Infusions of at least 8 g Mimosine over a period of 1 1/2-2 days were effective for defleecing all sheep dosed. This corresponded to a daily rate of infusion of about 80 mg/kg. No toxic effects were observed with infusions given for periods of 2 days. Defleecing was judged to be possible by 6-7 days after the start of infusion, and was readily carried out by about 14 days. Defleecing was associated with follicle retrogression and an abrupt cessation of wool growth within 2 days of the start of the infusions.
CONCLUSIONS:
It was estimated that fibre growth stopped for about 10 dyas; regrowth was first observed 17-18 days from the beginning of dosing. Low rates of infusion of Mimosine (up to 2 g/day) resulted in plasma levels below 0.1 mmol/l. Infusion at the rate of 4 g/day or above, which produced defleecing, quickly resulted in levels of Mimosine in plasma above 0.1 mmol/l; after 2 days the concentration was steady at aboug 0.2 mmol/l. Injections of 8 or 16 g Mimosine resulted in very large, but transient, rises of the level in plasma.

J Biol Chem. 1995 Apr 21;270(16):9597-606.

Mimosine arrests DNA synthesis at replication forks by inhibiting deoxyribonucleotide metabolism.[Pubmed: 7721891 ]

Mimosine has been reported to specifically prevent initiation of DNA replication in the chromosomes of mammalian nuclei. To test this hypothesis, the effects of Mimosine were examined in several DNA replication systems and compared with the effects of aphidicolin, a specific inhibitor of replicative DNA polymerases.
METHODS AND RESULTS:
Our results demonstrated that Mimosine inhibits DNA synthesis in mitochondrial, nuclear, and simian virus 40 (SV40) genomes to a similar extent. Furthermore, Mimosine and aphidicolin were indistinguishable in their ability to arrest SV40 replication forks and mammalian nuclear chromosomal replication forks. In contrast to aphidicolin, Mimosine did not inhibit DNA replication in lysates of mammalian cells supplied with exogenous deoxyribonucleotide triphosphate precursors for DNA synthesis. Mimosine also had no effect on initiation or elongation of DNA replication in Xenopus eggs or egg extracts containing high levels of deoxyribonucleotide triphosphates. In parallel with its inhibitory effect on DNA synthesis in mammalian cells, Mimosine altered deoxyribonucleotide triphosphate pools in a manner similar to that reported for another DNA replication inhibitor that affects deoxyribonucleotide metabolism, hydroxyurea.
CONCLUSIONS:
Taken together, these results show that Mimosine inhibits DNA synthesis at the level of elongation of nascent chains by altering deoxyribonucleotide metabolism.