A New Series of S-Adenosyl-L-Methionine Synthetase Inhibitors

Lavrador, Karine; Allart, Brigitte; Guillerm, D.; Guillerm, Georges

doi:10.3109/14756369809021481

Cited by 9 publications

(14 citation statements)

References 17 publications

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“…Intracellular de novo serine and glycine biosynthesis represents a major glycolysis deviating pathway in many cancers (illustrated in Figure 1). Stable isotopic tracing revealed increased levels of [2- 13 C] glycine and [2- 13 C] serine in the leukemic cell lines MOML13 and K562 when cultured in media containing [2- 13 C] fructose and [2- 13 C] glucose (75). Elevated serine and glycine intracellular titers in these cells were attributed to increased activity of 3phosphoglycerate dehydrogenase (PHGDH).…”

Section: Serine and Glycine And One Carbon Metabolismmentioning

confidence: 99%

Targeting Amino Acid Metabolic Vulnerabilities in Myeloid Malignancies

et al. 2021

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Tumor cells require a higher supply of nutrients for growth and proliferation than normal cells. It is well established that metabolic reprograming in cancers for increased nutrient supply exposes a host of targetable vulnerabilities. In this article we review the documented changes in expression patterns of amino acid metabolic enzymes and transporters in myeloid malignancies and the growing list of small molecules and therapeutic strategies used to disrupt amino acid metabolic circuits within the cell. Pharmacological inhibition of amino acid metabolism is effective in inducing cell death in leukemic stem cells and primary blasts, as well as in reducing tumor burden in in vivo murine models of human disease. Thus targeting amino acid metabolism provides a host of potential translational opportunities for exploitation to improve the outcomes for patients with myeloid malignancies.

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Section: Serine and Glycine And One Carbon Metabolismmentioning

confidence: 99%

Targeting Amino Acid Metabolic Vulnerabilities in Myeloid Malignancies

et al. 2021

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“…Among the methionine analogs, cyclic 5-membered ring amino acids bind with optimal affinity to all of the isozymes tested [206]. Recent studies with 4,5-epoxide and 4,5-epithio methionine analogs have provide inhibitors with affinity as high as 7 µM for recombinant rat liver MAT, although none were found to irreversibly inhibit the enzyme by covalent modification [207]. The slow binding and high affinity were associated with a protein conformational change after the initial binding, events that were attributed to ionization of one of the -NH-groups when the compound is bound to two metal ions at the active site [161].…”

Section: Mat Inhibitorsmentioning

confidence: 99%

Methionine Adenosyltransferase (S‐Adenosylmethionine Synthetase)

Pajares

Markham

2011

Advances in Enzymology - And Related Areas of Molecular Biology

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10.3. Thermal Unfolding 10.4. Association of MAT III to form MAT I: Role of the Disulfide C35-C61 10.5. Complementary Folding Data Obtained in MAT Proteins of Different Origins 11. MAT Inhibitors 12. Role of MAT in Diseases 12.1. Cognitive and Neurodegenerative Diseases 12.2. Human Mutations in MAT1A Gene: Hypermethioninemia and Demyelination 12.3. MAT and Cancer 12.4. MAT and Ethanol 2. MAMMALIAN MATs Early studies on mammalian MATs showed the existence of this activity in all the tissues studied, the highest being observed in liver. However, complex kinetics were obtained which made the results difficult to interpret until the presence of several isoenzymes was realized. Separations carried out on phenyl Sepharose columns showed elution of three peaks with different hydrophobic character; these were named according to the order of elution as MAT I, II and III. All these isoenzymes share some characteristics such as the Mg 2+ dependence of their 9/14/2012 Page 6 of 80 activity (S 0.5 !1 mM), stimulation by K + ions, and their AdoMet-inducible tripolyphosphatase activity [4, 5]. 2.1. MAT I/III isoenzymes Since their discovery, these isoenzymes were known as liver-specific forms of MAT, until Lu et al. in 2003 [6] showed their presence also in pancreas. Several laboratories have reported in depth studies of MAT I and III which have been carried out using adult liver. The differences can be summarized as follows: i) MAT I is a tetramer whereas MAT III is a dimer, with respective Mr appearing as 200 and 110 kDa upon gel filtration chromatography, ii) their Km values for methionine are in the micromolar range for MAT I (60-120 µM) and in the millimolar range for MAT III (1 mM) [7, 8]; iii) MAT III can be activated by DMSO at physiological concentrations of methionine (60 µM) and is highly hydrophobic (eluting from phenyl Sepharose columns at 50% DMSO (v/v)); and, iv) AdoMet inhibits MAT I and activates MAT III. Some of these differences are normally used to distinguish between isoenzymes in activity assays. Both purified proteins show a common single band (designated "1) of approximately 48 kDa on SDS-PAGE, and antibodies raised against the dimer form recognized both, thus suggesting that a single type of subunit arranged in two assemblies could explain the presence of both oligomers [7]. Further experiments that supported this hypothesis included peptide mapping of the purified isoenzymes [7], dissociation of the tetramer to the dimer using LiBr [9] or N-ethylmaleimide (NEM) modification [10]. The final confirmation came upon cloning of a single cDNA [11, 12] followed by overexpresion in E. coli cells [13], which showed in vivo production of dimers and tetramers. This single subunit type is a product of the MAT1A gene that contains nine exons and eight introns spanning !20 kb [14], and has been localized by fluorescence in situ hybridization to the human chromosome 10q.22 [15]. Animal models, as well as the analysis of human samples, led to the identification of changes in the MAT I/III ratio in pathological conditi...

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“…Finally, knowledge of the active site structure can allow design of specific inhibitors or activators other than those based on the structures of the substrates or products. This has not been the case for MAT to date, since the best inhibitors found with applicability to cell biology have been based on the methionine structure (LcisAMB and AEP) [86,87], whereas the high affinity intermediate analogue diimidotriphosphate [88] is impermeable to cells, and no transition state analogues are available. However, the anticipated availability of new inhibitors may increase the analysis of their in vivo effects, and may open new ways of treating a broad number of diseases ranging from cirrhosis to Parkinson’s.…”

Section: Understanding Pathologic Behavior Of Mutant Proteins Throughmentioning

confidence: 99%

Structure-function relationships in methionine adenosyltransferases

Markham

Pajares

2008

Cell. Mol. Life Sci.

124

151

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Methionine adenosyltransferases (MAT) are the family of enzymes that synthesize the main biological methyl donor, S-adenosylmethionine. The high sequence conservation among catalytic subunits from bacteria and Eukarya preserves key residues that control activity and oligomerization, which is reflected in the protein structure. However, structural differences among complexes with substrates and products have led to proposals of several reaction mechanisms. In parallel, folding studies are starting to explain how the three intertwined domains of the catalytic subunit are produced, and the importance of certain intermediates in attaining the active final conformation. This review analyzes the available structural data and proposes a consensus interpretation that facilitates an understanding of the pathological problems derived from impairment of MAT function. In addition, new research opportunities directed toward clarification of aspects that remain obscure are also identified.Keywords methionine adenosyltransferase; S-adenosylmethionine synthetase; crystal structure; reaction mechanism; folding; mutants; hepatic disease Methionine is a non-polar amino acid characterized by the presence of a methyl group attached to a sulfur atom located in its side chain. In addition to its role in protein synthesis, large amounts of this amino acid are used for the synthesis of S-adenosylmethionine (AdoMet) by methionine adenosyltransferases (MAT) in a reaction that is the rate-limiting step of the methionine cycle ( Figure 1) [1,2]. The MAT catalyzed reaction combines methionine, ATP and water to produce AdoMet, pyrophosphate and inorganic phosphate; the enzyme requires both Mg 2+ and K + ions for maximal activity [1,2]. AdoMet participates in a large number of reactions, due to its ability to donate all the groups surrounding the sulfur atom. SAM radical proteins use the 5′-deoxyadenosyl moiety of AdoMet to synthesize biotin, among other compounds. Also, after decarboxylation AdoMet participates in polyamine synthesis, rendering 5′-deoxy-5′ methylthioadenosine (MTA) [3] that is recycled for methionine synthesis through the methionine salvage pathway [4]. Methyltransferases use AdoMet to obtain the methyl groups used to synthesize a large number of compounds, such as phospholipids and neurotransmitters, and in each case S-adenosylhomocysteine (AdoHcy) is formed. AdoHcy can act in many cases as a potent inhibitor of these enzymes. The AdoMet/AdoHcy ratio is known as the methylation index, with its normal value in mammalian cells being approximately three [1]. Maintenance * Author to whom correspondence should be addressed at: Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), Arturo Duperier 4, 28029 Madrid, Spain. (Phone: 34-915854414; FAX: 34-915854010; email: mapajares@iib.uam.es) NIH Public Access Author ManuscriptCell Mol Life Sci. Author manuscript; available in PMC 2010 February 1. Published in final edited form as:Cell Mol Life Sci. 2009 February ; 66(4): 636-648. doi:10.1007/s00018-008-8516-1....

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A New Series of S-Adenosyl-L-Methionine Synthetase Inhibitors

Cited by 9 publications

References 17 publications

Targeting Amino Acid Metabolic Vulnerabilities in Myeloid Malignancies

Targeting Amino Acid Metabolic Vulnerabilities in Myeloid Malignancies

Methionine Adenosyltransferase (S‐Adenosylmethionine Synthetase)

Structure-function relationships in methionine adenosyltransferases

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