Synthesis of Two Stable Nitrogen Analogues of <i>S</i>-Adenosyl-<scp>l</scp>-methionine

Thompson, Mark J.; Mekhalfia, Abdelaziz; Hornby, and David P.; Blackburn, G. Michael

doi:10.1021/jo9907742

Cited by 33 publications

(19 citation statements)

References 30 publications

(34 reference statements)

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“…The crystal structure of the Ecm1⅐aza-AdoMet complex reveals virtually no difference compared with the Ecm1-AdoMet structure. This is in contrast to the case of the E. coli MetJ repressor, whereby MetJ/AdoMet and MetJ/aza-AdoMet crystal structures reveal major differences in the conformation and protein contacts of the methionine components of AdoMet versus aza-AdoMet ligands (34). However, given that Ecm1 makes no direct contacts to the AdoMet methyl carbon or the AdoMet sulfur (the latter atom being substituted by nitrogen in the aza compound), it is not surprising that the Ecm1/AdoMet and Ecm1/aza-AdoMet structures are so similar.…”

Section: Discussioncontrasting

confidence: 65%

“…The pK a of the tertiary amine of aza-AdoMet is reported to be 7.1 (31,34), in which case the nitrogen center would be predominantly uncharged under the conditions used here to assay Ecm1 activity, but predominantly charged under the conditions used to grow the crystals. However, it is unlikely that the relatively low inhibitory potency of aza-AdoMet is caused only by the absence of a positive charge equivalent to the AdoMet sulfonium group, because the neutral AdoHcy product is itself an effective competitor for the methyl donor site.…”

Section: Discussionmentioning

confidence: 99%

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Encephalitozoon cuniculi mRNA Cap (Guanine N-7) Methyltransferase

Hausmann

Zheng

Fàbrega

et al. 2005

Journal of Biological Chemistry

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The Encephalitozoon cuniculi mRNA cap (guanine N-7) methyltransferase Ecm1 has been characterized structurally but not biochemically. Here we show that purified Ecm1 is a monomeric protein that catalyzes methyl transfer from S-adenosylmethionine (AdoMet) to GTP. The reaction is cofactor-independent and optimal at pH 7.5. Ecm1 also methylates GpppA, GDP, and dGTP but not ATP, CTP, UTP, ITP, or m The 5Ј cap of eukaryotic messenger RNA consists of 7-methyl guanosine linked via an inverted 5Ј-5Ј triphosphate bridge to the initiating nucleoside of the transcript. The cap is formed by three enzymatic reactions: (i) the 5Ј-triphosphate end of the pre-mRNA is hydrolyzed to a diphosphate by RNA 5Ј-triphosphatase; (ii) the diphosphate RNA end is capped with GMP by

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Section: Discussioncontrasting

confidence: 65%

Section: Discussionmentioning

confidence: 99%

Encephalitozoon cuniculi mRNA Cap (Guanine N-7) Methyltransferase

Hausmann

Zheng

Fàbrega

et al. 2005

Journal of Biological Chemistry

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“…In this analog, the polarization of the methyl group is dependent on the protonation state of its tertiary ␥-amine (pK a ϳ7.1), which mimics the AdoMet sulfonium cation (40,47). Under basic conditions, the methyl group is relatively unpolarized due to the amine's deprotonation.…”

Section: Resultsmentioning

confidence: 99%

Catalytic Roles for Carbon-Oxygen Hydrogen Bonding in SET Domain Lysine Methyltransferases

Couture

Hauk

Thompson

et al. 2006

Journal of Biological Chemistry

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SET domain enzymes represent a distinct family of protein lysine methyltransferases in eukaryotes. Recent studies have yielded significant insights into the structural basis of substrate recognition and the product specificities of these enzymes. However, the mechanism by which SET domain methyltransferases catalyze the transfer of the methyl group from S-adenosyl-L-methionine to the lysine ⑀-amine has remained unresolved. To elucidate this mechanism, we have determined the structures of the plant SET domain enzyme, pea ribulose-1,5 bisphosphate carboxylase/oxygenase large subunit methyltransferase, bound to S-adenosyl-L-methionine, and its non-reactive analogs Aza-adenosyl-L-methionine and Sinefungin, and characterized the binding of these ligands to a homolog of the enzyme. The structural and biochemical data collectively reveal that S-adenosyl-L-methionine is selectively recognized through carbon-oxygen hydrogen bonds between the cofactor's methyl group and an array of structurally conserved oxygens that comprise the methyl transfer pore in the active site. Furthermore, the structure of the enzyme co-crystallized with the product ⑀-N-trimethyllysine reveals a trigonal array of carbon-oxygen interactions between the ⑀-ammonium methyl groups and the oxygens in the pore. Taken together, these results establish a central role for carbon-oxygen hydrogen bonding in aligning the cofactor's methyl group for transfer to the lysine ⑀-amine and in coordinating the methyl groups after transfer to facilitate multiple rounds of lysine methylation.Protein lysine methylation has emerged as a prominent post-translational modification in gene regulatory and intracellular signaling pathways. In the nucleus, site-specific methylation of lysines within histones, transcription factors, and mitotic proteins governs a diverse array of processes within the nucleus including gene expression, DNA damage checkpoint control, cell cycle progression, and mitosis (1). In 2000, a breakthrough in our understanding of this modification occurred with the discovery of the first histone-specific protein lysine methyltransferases (PKMTs) 4 (2). These enzymes possess a conserved catalytic SET domain, a 120-residue motif that was named for three Drosophila gene regulatory factors, SU(VAR)3-9, E(Z), and TRX (3). This domain shares no apparent sequence or structural homology with other S-adenosyl-L-methionine (AdoMet)-dependent enzymes, establishing the SET domain family as a novel class of methyltransferases. This seminal discovery heralded the identification of a multitude of SET domain PKMTs, which methylate histone and non-histone substrates (1).Since their identification, crystal structures of several SET domain PKMTs in complex with various substrates and products have been reported, yielding insights into the catalytic mechanism and protein substrate specificity of this methyltransferase family. These structures include the histone methyltransferases SET7/9 (4 -8), SET8 (also known as PR-SET7) (9, 10), and Neurospora DIM-5 (11) as well as pea R...

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“…The chemical syntheses of AzaAdoMet (41) were started from 2 0 ,3 0 -O-isopropylidene-5 0 -O-tosyladenosine (23), which was first converted with methylamine to protected 5 0 -deoxy-5 0 -methylaminoadenosine and then 5 0 -N-alkylated with iodides of amino acid side chain precursors. After deprotection, AzaAdoMet (41) was obtained as a diastereomeric mixture at the amino acid center [147,148], and later as a single diastereoisomer [149,150]. As expected, AzaAdoMet (41) does not serve as a methyl group donor for MTases [151].…”

Section: Nitrogen Analogues Of Adometmentioning

confidence: 65%

S‐Adenosyl‐L‐Methionine and Related Compounds

Dalhoff¹,

Weinhold

2008

Modified Nucleosides

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The sulfonium compound S-adenosyl-L-methionine (AdoMet, also known as SAM or SAMe, 1) is one of the most versatile biomolecules in nature and one of the most widely used enzyme substrates, second perhaps only to adenosine triphosphate (ATP) (Schemes 9.1 and 9.2). AdoMet (1) may be found in all phyla of life, and is one of the molecules crucial for the existence of living organisms. First identified by Cantoni in 1953 [1, 2] as the active methyl donor formed from L-methionine and ATP, AdoMet (1) proved to be not only the major methyl donor in nature but also to be involved in many other metabolic reactions [3,4]. The versatility of the cofactor is based on the reactivity of the pivotal sulfonium center, which activates the adjacent carbon atoms for nucleophilic attack, deprotonation, and radical formation. This leads to a unique cofactor in which all constituents are used in biochemical reactions. The group transfer reactions result in the release of one of three different thioether products which are more stable than the sulfonium compound, and thereby providing the driving force for these enzyme-catalyzed reactions. These highly preferable thermodynamics of AdoMet-dependent transfer reactions result in a strong preference for this cofactor compared, for example, to other methyl donors such as N5-methyltetrahydrofolate. Due to the electron lone pair in addition to the three different substituents, the sulfonium group is chiral, and the naturally occurring AdoMet (1) is S-configured at sulfur [5].Many other naturally occurring alkylated thioadenosines are derived from AdoMet (1) such as S-adenosyl-L-homocysteine (AdoHcy, also called SAH, 2) and 5 0 -deoxy-5 0 -methylthioadenosine (MTA, 3) (Scheme 9.3), although these compounds and their related 5 0 -thioethers are beyond the scope of this chapter. AdoMet (1) and its derivatives are involved in key metabolic reactions, cell cycle regulation and the storage of epigenetic information, which makes them not only highly interesting for studying biological pathways but also as in-vitro or in-vivo biochemical tools and candidates for diagnostics and therapeutics.

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Synthesis of Two Stable Nitrogen Analogues of S-Adenosyl-l-methionine

Cited by 33 publications

References 30 publications

Encephalitozoon cuniculi mRNA Cap (Guanine N-7) Methyltransferase

Encephalitozoon cuniculi mRNA Cap (Guanine N-7) Methyltransferase

Catalytic Roles for Carbon-Oxygen Hydrogen Bonding in SET Domain Lysine Methyltransferases

S‐Adenosyl‐L‐Methionine and Related Compounds

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