Contribution of 4-methylthio-2-oxobutanoate and its transaminase to the growth of methionine-dependent cells in culture

Ogier, G; Chantepie, Jacqueline; Deshayes, Christian; Chantegrel, Bernard; Charlot, Carole; Doutheau, Alain; Quash, G.

doi:10.1016/0006-2952(93)90304-f

Cited by 23 publications

(23 citation statements)

References 37 publications

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“…In the pyridoxyl-ornithine derivative POB, the 5 ¶-phosphate group is eliminated and the carboxyl group is esterified with methanol. The rationale behind the design was that this compound together with the additional hydrophobic BOC group of the q-amino group of ornithine has no negative net charge and very likely crosses the cell membrane as it was reported for several pyridoxyl-amines (30, 31) and pyridoxyl-methionine analogues (32). Intracellular pyridoxal kinase, an enzyme that seems to tolerate (31,33), is expected to phosphorylate this compound after it has been taken up by the cells whereas the carboxymethyl ester will be hydrolyzed intracellularly.…”

Section: Discussionmentioning

confidence: 99%

New transition state–based inhibitor for human ornithine decarboxylase inhibits growth of tumor cells

Grossenbacher

Gehring

2007

Molecular Cancer Therapeutics

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Pyridoxal 5 ¶-phosphate (PLP) -dependent ornithine decarboxylase (ODC) is the key enzyme in polyamine synthesis. ODC is overexpressed in many tumor cells and thus a potential drug target. Here we show the design and synthesis of a coenzyme-substrate analogue as a novel precursor inhibitor of ODC. Structural analysis of the crystal structure of human ODC disclosed an additional hydrophobic pocket surrounding the E-amino group of its substrate ornithine. Molecular modeling methods showed favorable interactions of the BOC-protected pyridoxylornithine conjugate, termed POB, in the active site of human ODC. The synthesized and purified POB completely inhibited the activity of newly induced ODC activity at 100 Mmol/L in glioma LN229 and COS7 cells. In correlation with the inhibition of ODC activity, a timedependent inhibition of cell growth was observed in myeloma, glioma LN18 and LN229, Jurkat, COS7, and SW2 small-cell lung cancer cells if DNA synthesis and cell number were measured, but not in the nontumorigenic human aortic smooth muscle cells. POB strongly inhibited cell proliferation not only of low-grade glioma LN229 cells in a dose-dependent manner (IC 50 f50 Mmol/L) but also of high-grade glioblastoma multiforme cells. POB is much more efficient in inhibiting proliferation of several types of tumor cells than A-DL-difluoromethylornithine, the best known irreversible inhibitor of ODC. [Mol Cancer Ther 2007;6(6):1831 -9]

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Section: Discussionmentioning

confidence: 99%

New transition state–based inhibitor for human ornithine decarboxylase inhibits growth of tumor cells

Grossenbacher

Gehring

2007

Molecular Cancer Therapeutics

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“…We have intensely tried to directly assess the transport characteristics of BAT5 by measuring the transport of [ 35 S]-labeled MTOB (prepared as described in Ogier et al, 1993) into chloroplasts from wild-type and bat5 mutant plants. Arabidopsis chloroplasts were isolated according to Kunst et al (1988) and used for transport studies in silicone oil filtering centrifugation experiments (Fliege et al, 1978).…”

Section: Mtob Transport Experimentsmentioning

confidence: 99%

The Plastidic Bile Acid Transporter 5 Is Required for the Biosynthesis of Methionine-Derived Glucosinolates inArabidopsis thaliana

et al. 2009

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Aliphatic glucosinolate biosynthesis is highly compartmentalized, requiring import of 2-keto acids or amino acids into chloroplasts for side chain elongation and export of the resulting compounds into the cytosol for conversion into glucosinolate. Aliphatic glucosinolate biosynthesis in Arabidopsis thaliana is regulated by three R2R3-MYB transcription factors, the major player being High Aliphatic Glucosinolate 1 (HAG1/MYB28). Here, we show that BAT5, which belongs to the putative bile acid transporter family, is the only member of this family that is transactivated by HAG1/MYB28, HAG2/ MYB76, and HAG3/MYB29. Furthermore, two isopropylmalate isomerases genes, IPMI1 and IPMI2, and the isopropylmalate dehydrogenase gene, IPMDH1, were identified as targets of HAG1/MYB28 and the corresponding proteins localized to plastids, suggesting a role in plastidic chain elongation reactions. The BAT proteins also localized to plastids; however, only mutants defective in BAT5 function contained strongly reduced levels of aliphatic glucosinolates. The bat5 mutant chemotype was rescued by induced overexpression of BAT5. Feeding experiments using 2-keto acids and amino acids of different chain length suggest that BAT5 is a plastidic transporter of (chain-elongated) 2-keto acids. Mechanical stimuli and methyl jasmonate transiently induced BAT5 expression in inflorescences and leaves. Thus, BAT5 was identified as the first transporter component of the aliphatic glucosinolate biosynthetic pathway.

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“…Evidence from two studies suggests that the majority of methionine produced through the salvage pathway is transformed to S-adenosylmethionine (SAM), whereas methionine synthesized through the de novo pathway by homocysteine methylation is predominantly used for protein synthesis (2,3). SAM, in its turn, is required for the formation of spermidine and spermine, which have been suggested to affect cell proliferation (4), and is the primary methyl donor for DNA methylation, which regulates gene expression.…”

Section: Introductionmentioning

confidence: 99%

Methionine-Dependence Phenotype in the de novo Pathway in BRCA1 and BRCA2 Mutation Carriers with and without Breast Cancer

Beetstra

Suthers

Dhillon

et al. 2008

Cancer Epidemiology, Biomarkers &Amp; Prevention

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Methionine-dependence phenotype (MDP) refers to the reduced ability of cells to proliferate when methionine is restricted and/or replaced by its immediate precursor homocysteine. MDP is a characteristic of human tumors in vivo, human tumor cell lines, and normal somatic tissue in some individuals. It was hypothesized that MDP is a risk factor for developing breast cancer in BRCA (BRCA1 and BRCA2) germline mutation carriers. To test the hypothesis, human peripheral blood lymphocytes of BRCA carriers with and without breast cancer and healthy non-carrier relatives (controls) were cultured for 9 days in medium containing either 0.1 mmol/L L-methionine or 0.2 mmol/L D,L-homocysteine, with the ratio of viable cell growth in both types of medium after 9 days used to calculate the methionine-dependence index (MDI), a measure of MDP. We also tested whether MDP was associated with common polymorphisms in methionine metabolism. Viable cell growth, MDI, and polymorphism frequency in MTRR (A66G and C524T) and MTHFR (A1298C and A1793G) did not differ among the study groups; however, MDI tended to be higher in BRCA carriers with breast cancer than those without and was significantly increased in MTHFR 677T allele carriers relative to wild-type carriers (P = 0.017). The presence of MTR A2756G mutant allele and MTHFR C677T mutant allele in carriers was associated with increased breast cancer risk [odds ration, 3.2 (P = 0.16; 95% confidence interval, 0.76-13.9) and 3.9 (P = 0.09; 95% confidence interval, 0.93-16.3), respectively]. The results of this study support the hypothesis that defects in methionine metabolism may be associated with breast cancer risk in BRCA carriers. (Cancer Epidemiol Biomarkers Prev 2008;17(10):2565 -71)

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Contribution of 4-methylthio-2-oxobutanoate and its transaminase to the growth of methionine-dependent cells in culture

Cited by 23 publications

References 37 publications

New transition state–based inhibitor for human ornithine decarboxylase inhibits growth of tumor cells

New transition state–based inhibitor for human ornithine decarboxylase inhibits growth of tumor cells

The Plastidic Bile Acid Transporter 5 Is Required for the Biosynthesis of Methionine-Derived Glucosinolates inArabidopsis thaliana

Methionine-Dependence Phenotype in the de novo Pathway in BRCA1 and BRCA2 Mutation Carriers with and without Breast Cancer

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