Posttranscriptional Regulation of Mammalian Methionine Synthase by B12

Gulati, Sneha; Brody, Lawrence C.; Banerjee, Ruma

doi:10.1006/bbrc.1999.0696

Cited by 32 publications

(28 citation statements)

References 30 publications

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“…5) requires vitamin B12 as a cofactor for its conversion of homocysteine to methionine and conversion of 5-methyltetrahydrofolate to its active form, tetrahydrofolate. It has long been established that activity of this enzyme is partially determined by availability of its cofactor vitamin B12 (Gulati et al 1999). MTRR (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…The two linking phrases, ''has variant'' and ''has association,'' were used throughout the CMAP models. Inside of the webaccessible maps, the icon is a link to the literature reference(s) for the citation supporting the knowledge proposition that ends with the object upon which the icon sits (Gulati et al 1999). B12 limitation has also been shown to reduce MTR enzyme activity (Brunaud et al 2003).…”

Section: Utilizes Gene Products Frommentioning

confidence: 99%

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Concept mapping One-Carbon Metabolism to model future ontologies for nutrient–gene–phenotype interactions

et al. 2014

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Advances in the development of bioinformatic tools continue to improve investigators' ability to interrogate, organize, and derive knowledge from large amounts of heterogeneous information. These tools often require advanced technical skills not possessed by life scientists. User-friendly, low-barrier-to-entry methods of visualizing nutrigenomics information are yet to be developed. We utilized concept mapping software from the Institute for Human and Machine Cognition to create a conceptual model of diet and health-related data that provides a foundation for future nutrigenomics ontologies describing published nutrient-gene/polymorphism-phenotype data. In this model, maps containing phenotype, nutrient, gene product, and genetic polymorphism interactions are visualized as triples of two concepts linked together by a linking phrase. These triples, or ''knowledge propositions,'' contextualize aggregated data and information into easy-to-read knowledge maps. Maps of these triples enable visualization of genes spanning the One-Carbon Metabolism (OCM) pathway, their sequence variants, and multiple literature-mined associations including concepts relevant to nutrition, phenotypes, and health. The concept map development process documents the incongruity of information derived from pathway databases versus literature resources. This conceptual model highlights the importance of incorporating information about genes in upstream pathways that provide substrates, as well as downstream pathways that utilize products of the pathway under investigation, in this case OCM. Other genes and their polymorphisms, such as TCN2 and FUT2, although not directly involved in OCM, potentially alter OCM pathway functionality. These upstream gene products regulate substrates such as B12. Constellations of polymorphisms affecting the functionality of genes along OCM, together with substrate and cofactor availability, may impact resultant phenotypes. These conceptual maps provide a foundational framework for development of nutrient-gene/polymorphism-phenotype ontologies and systems visualization.

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Section: Discussionmentioning

confidence: 99%

Section: Utilizes Gene Products Frommentioning

confidence: 99%

Concept mapping One-Carbon Metabolism to model future ontologies for nutrient–gene–phenotype interactions

et al. 2014

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“…We focused on obtaining protein expression profiles owing to the studies from our laboratory (24,29) 1 having revealed they are regulated at the translational level, which limits the utility of the existing mRNA profiles of these genes. Our study provided insights into tissue specific variations in the expression of the three enzymes, which could be particularly useful in correlative analyses of polymorphic variants in these enzymes and specific types of cancers.…”

Section: Discussionmentioning

confidence: 99%

“…Samples for each cell line were run in duplicate in at least three separate experiments. The antibodies for MS, MSR, and CBS were generated in-house and used as described previously (20,24,25). The antibodies for P450 reductase were a generous gift from Dr. Bettie Sue Masters (The University of Texas Health Science Center, San Antonio, TX).…”

Section: Methodsmentioning

confidence: 99%

Expression Profiling of Homocysteine Junction Enzymes in the NCI60 Panel of Human Cancer Cell Lines

et al. 2005

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Methionine metabolism provides two key cellular reagents: S-adenosylmethionine and glutathione, derived from the common intermediate, homocysteine. A majority of cancer cells exhibit a methionine-dependent phenotype whereby they are unable to grow in medium in which methionine is replaced by its precursor, homocysteine. Additionally, CpG island hypermethylation of tumor suppressor gene promoters is observed in a background of global hypomethylation in cancerous cells. In this study, we have profiled the expression levels of the homocysteine junction enzymes, methionine synthase (MS), MS reductase (MSR), and cystathionine B-synthase (CBS) in the NCI60 panel of cancer cell lines. The doubling time of non-small lung cell cancer lines, which exhibit the lowest levels of MS within the panel, was significantly correlated with expression of MS. The ratio of MS to MSR varied over a 5-fold range in the different cell types, which may modulate methionine synthesis. Interestingly, markedly reduced CBS expression was seen in the methionine-dependent prostate cancer cell line, PC-3, but not in the methionine-independent cell line, DU-145. However, neither provision of the transsulfuration pathway product, cysteine, nor overexpression of CBS rescued the growth impairment, indicating that reduced CBS was not responsible for the methionine-dependent phenotype in this cell line. (Cancer Res 2005; 65(4): 1554-60)

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“…B 12 supplementation to cells in culture increases the activity of MS (9,10) and this regulation is exerted at a translational level (8,11). Addition of B 12 to normal medium results in a reequilbration of the MS message from the inactive ribonucleoprotein pool to the active polysomal pool (8).…”

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confidence: 99%

Translational regulation of human methionine synthase by upstream open reading frames

Çöl

Oltean

Banerjee

2007

Biochimica et Biophysica Acta (BBA) - Gene Structure and Expres

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Methionine synthase is a key enzyme poised at the intersection of folate and sulfur metabolism and functions to reclaim homocysteine to the methionine cycle. The 5′ leader sequence in human MS is 394 nucleotides long and harbors two open reading frames (uORFs). In this study, regulation of the main open reading frame by the uORFs has been elucidated. Both uORFs downregulate translation as demonstrated by mutation of the upstream AUG codons (uAUG) either singly or simultaneously. The uAUGs are capable of recruiting the 40S ribosomal complex as revealed by their ability to drive reporter expression in constructs in which the luciferase is fused to the uORFs. uORF2, which is predicted to encode a 30 amino acid long polypeptide, has a clustering of rare codons encoding arginine and proline. Mutation of a tandemly repeated rare codon for arginine at positions 3 and 4 in uORF2 to either common codons for the same amino acid or common codons for alanine, result in complete alleviation of translation inhibition. This suggests a mechanism for ribosome stalling and demonstrates that the cis-effects on translation by uORF2 is dependent on the nucleotide sequence but is apparently independent of the sequence of the encoded peptide. This study reveals complex regulation of the essential housekeeping gene, methionine synthase, by the uORFs in its leader sequence. Keywordsmethionine; upstream open reading frame; methionine synthase; gene regulation Homocysteine is an intermediate in methionine metabolism and is cleared via the concerted actions of three enzymes, methionine synthase (MS) 1 , cystathionine β-synthase and betaine homocysteine methyltransferase (1). Of these, only MS is present ubiquitiously and reclaims homocysteine to the methionine cycle via a transmethylation reaction (2). In contrast, betaine homocysteine methyltransferase, which also catalyzes the remethylation of homocysteine, has a very restricted tissue distribution being present only in liver and kidney. Cystathionine β-synthase commits homocysteine to the transsulfuration pathway that leads to synthesis of cysteine, and is present in some but not all tissues (2).

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Posttranscriptional Regulation of Mammalian Methionine Synthase by B12

Cited by 32 publications

References 30 publications

Concept mapping One-Carbon Metabolism to model future ontologies for nutrient–gene–phenotype interactions

Concept mapping One-Carbon Metabolism to model future ontologies for nutrient–gene–phenotype interactions

Expression Profiling of Homocysteine Junction Enzymes in the NCI60 Panel of Human Cancer Cell Lines

Translational regulation of human methionine synthase by upstream open reading frames

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