Kinetic properties of fluorinated substrate analogues on 5′-methylthioadenosine nucleosidase from Escherichia coli

Gâtel, Marie; Muzard, Murielle; Guillerm, D.; Guillerm, Georges

doi:10.1016/s0223-5234(96)80004-3

Cited by 7 publications

(8 citation statements)

References 21 publications

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“…Involvement of the 6-amino group and the N7 atom of the adenine ring in enzyme-substrate binding have been demonstrated [5], but the conformation of the ribonucleoside required for the recognition process had not been investigated. Since it has been observed [5,12,33] that the 5′ side chain region is not relevant in MeSAdo binding, synthesis of one of the C5′ epimers of (8,5′)-cycloMeSAdo, the least-modified anti conformer of MeSAdo, could provide a useful tool to study the initial contact and binding of MeSAdo to the enzyme. We therefore prepared compound 6.…”

Section: Essential Functional Groups For Binding and Catalysis Contrmentioning

confidence: 99%

The catalytic mechanism of adenosylhomocysteine/methylthioadenosine nucleosidase from Escherichia coli

Allart

Gâtel

Guillerm

et al. 1998

European Journal of Biochemistry

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The substrate and inhibitory specificity of Escherichia coli adenosylhomocysteine (AdoHcy)/methylthioadenosine (MeSAdo) nucleosidase has been explored with several MeSAdo analogues modified on the sugar moiety at the 2′, 3′ and 5′ positions. Alteration at C3′ or at C2′ and C3′ positions in MeSAdo abolished substrate activity. However, the 2′-deoxy analogue of MeSAdo is effective as a substrate; this result provides evidence against a possible general-base catalysis involving the anchimeric assistance of the 2′-A-hydroxy group and the formation of a 1,2-epoxide as an intermediate in the catalytic process. The results of a study of the interaction of an 8,5′-cyclo analogue of MeSAdo with the enzyme indicate the importance of the glycosidic conformation of the substrate for binding to the active site. The enzyme discriminates against methanol attack from the solvent during catalysis. This implies the participation of an enzyme-directed water nucleophile. A poor solvent kinetic deuterium-isotope effect was measured (0.93) on the V max . Plots of log V max and log (V max /K m ) for MeSAdo as a function of pH values from 5.0 to 8.5 are similar, with two presumably essential ionisable groups for catalysis with apparent pK a values of 5.6 and 8.2, whereas K m is independent of pH. When the 2′-A-hydroxy group of MeSAdo is substituted by fluorine, a significant decrease (28 500-fold) in the V max for enzyme-catalysed hydrolysis of the modified substrate is observed. This result indicates a transition state with a substantial oxocarbenium character. From these data, the reaction mechanism for AdoHcy/MeSAdo nucleosidase is discussed.Keywords : adenosylhomocysteine nucleosidase ; substrate; inhibitor ; catalytic mechanism.S-Adenosylhomocysteine (AdoHcy) is the product of biological transmethylation reactions that utilise S-adenosylmethionine (AdoMet) as a methyl donor [1,2]. In various microorganisms (bacteria and protozoa), this compound and 5′-methylthioadenosine (MeSAdo), formed from adenosylmethionine by several independent pathways [3], are substrates of AdoHcy/ MeSAdo nucleosidase. This enzyme catalyses the cleavage of the metabolites into S-ribosylhomocysteine and methylthioribose, respectively, adenine also being generated by both reactions [4,5].AdoHcy/MeSAdo nucleosidase is involved in a variety of biological processes. In particular it is required for the regeneration of free Hcy from AdoHcy in various prokaryotes [5,6], and plays a significant role in the metabolism of these microorganisms via the regulation of the MeSAdo concentration (a potent inhibitor of spermidine and spermine synthases) [7Ϫ9]. In microorganisms in which MeSAdo phosphorylase is missing, AdoHcy/MeSAdo nucleosidase is essential for methionine salvage [10Ϫ12].Correspondence to G. Guillerm, Laboratoire de Chimie Bioorganique, U.M.R. 6519, U.F.R. Sciences de Reims, Moulin de la Housse, B.P. 1039, F-51687 Reims cedex 2, France Fax: ϩ33 3 26 05 31 66. E-mail: georges.guillerm@univ-reims.fr Abbreviations. AdoHcy, S-adenosylhomocysteine; MeSAdo, 5′-d...

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Section: Essential Functional Groups For Binding and Catalysis Contrmentioning

confidence: 99%

The catalytic mechanism of adenosylhomocysteine/methylthioadenosine nucleosidase from Escherichia coli

Allart

Gâtel

Guillerm

et al. 1998

European Journal of Biochemistry

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“…2). [98][99][100][101][102][103][104] In 2015, Rovis and co-workers published a review article with a detailed overview of NHCs synthesis, properties and catalytic application in organic synthesis. This study focuses on the accomplishments made in the time frame 1970 to 2014.…”

Section: Introductionmentioning

confidence: 99%

Recent Advances in Enantioselective Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes (NHCs) Containing Triazolium Motifs

Sharma¹,

Chatterjee

Dhayalan

et al. 2022

Synthesis

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N-Heterocyclic carbenes (NHCs) containing triazolium motifs have emerged as a powerful tool in organocatalysis. Recently, various NHC pre-catalyst mediated organic transformations have been developed successfully. This article aims to compile the current state of knowledge on NHC-triazolium catalysed enantioselective name reactions and introduce newly developed catalytic methods. Furthermore, this review article framework provides an excellent opportunity to highlight some of the unique applications of these catalytic procedures in the natural product synthesis of biologically active compounds, notably the wide range of preparation of substituted chiral alcohols, and their derivatives. This article provides an overview of chiral NHC triazolium-catalyst libraries synthesis and their catalytic application in enantioselective reactions.

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“…(B) Insecticidal agent pyrafluprole [12] . (C) 5'‐(monofluoromethylthio)adenosine (MFMTA) [13] . (D) LXR modulator [14] .…”

Section: Introductionmentioning

confidence: 99%

“…Representative examples from the fields of agrochemistry and pharmaceutical and agrochemistry are illustrated in Figure 1 A–E [11–15] . However, unlike β‐fluoro sulfur motifs, interrogation of the α‐fluoro system must consider the related anomeric effect (Figure 1, centre) inherent to systems that permit hyperconjugative n S →σ * interactions [16–18]…”

Section: Introductionmentioning

confidence: 99%

Conformational Analysis of Acyclic α‐Fluoro Sulfur Motifs

Erdeljac

Mück‐Lichtenfeld

Daniliuc

et al. 2020

Chemistry A European J

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Bioactive small molecules containing α‐fluoro sulfur motifs [RS(O)nCH2F] are appearing with increasing frequency in the pharmaceutical and agrochemical sectors. Prominent examples include the anti‐asthma drug Flovent® and the phenylpyrazole insecticide pyrafluprole. Given the popularity of these structural units in bioactive small molecule design, together with the varying oxidation states of sulfur, a conformational analysis of α‐fluoro sulfides, sulfoxides, and sulfones, would be instructive in order to delineate the non‐covalent interactions that manifest themselves in structure. A combined crystallographic and computational analysis demonstrates the importance of hyperconjugative donor‐acceptor interactions in achieving acyclic conformational control. The conformational disparity in the syn‐ and anti‐diastereoisomers of α‐fluorosulfoxides is particularly noteworthy.

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Kinetic properties of fluorinated substrate analogues on 5′-methylthioadenosine nucleosidase from Escherichia coli

Cited by 7 publications

References 21 publications

The catalytic mechanism of adenosylhomocysteine/methylthioadenosine nucleosidase from Escherichia coli

The catalytic mechanism of adenosylhomocysteine/methylthioadenosine nucleosidase from Escherichia coli

Recent Advances in Enantioselective Organocatalytic Reactions Enabled by N-Heterocyclic Carbenes (NHCs) Containing Triazolium Motifs

Conformational Analysis of Acyclic α‐Fluoro Sulfur Motifs

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